Artículos de revistas: "INTERFERON-GAMMA ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION GVHD"

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Thiele Orberg, Erik, Julius Clemens Fischer, Sascha Göttert, Florian Bassermann y Hendrik Poeck. "Type I Interferon Signaling before Hematopoietic Stem Cell Transplantation Lowers Donor T Cell Activation Via Reduced Allogenicity of Recipient Cells". Blood 134, Supplement_1 (13 de noviembre de 2019): 4431. http://dx.doi.org/10.1182/blood-2019-128784.

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Background: Recent studies highlight immunoregulatory functions of type I interferons (IFN-I) during the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that selective activation of IFN-I pathways including RIG-I/MAVS and cGAS/STING prior to allo-HSCT conditioning therapy can ameliorate the course of GVHD. However, direct effects of IFN-Is on immune cells remain ill characterised. Methods: We applied selective RIG-I agonists (3pRNA) to stimulate IFN-I production in murine models of conditioning therapy with total body irradiation (TBI) and GVHD. Results: Using IFNAR1-deficient donor T and hematopoietic donor cells, we found that endogenous and RIG-I-induced IFN-Is do not reduce GVHD by acting on these respective cell types. However, 3pRNA applied before conditioning therapy reduced the ability of CD11c+ recipient cells to stimulate proliferation and interferon gamma expression of allogeneic T cells. Consistently, RIG-I activation before TBI reduced the proliferation of transplanted T-cells after allo-HSCT. The reduced allogenicity of CD11c+ recipient cells was dependent on IFN-I signalling. Notably, this immunosuppressive function of DCs was restricted to a scenario of genotoxic tissue damage as neither RIG-I activation and IFN-I induction in naive (non-irradiated) mice altered allogeneic T cell activation. Conclusion: Our findings uncover a hitherto unknown IFN-I- and context dependent immunosuppressive function of dendritic cells. This needs to be considered in the development of IFN-I based therapeutic approaches to modulate donor T cell activation after allo-HSCT. Disclosures No relevant conflicts of interest to declare.

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Wu, Yongxia, Corey Mealer, Mohammed Sofi, Linlu Tian, David Bastian, Steven Schutt, Hee-Jin Choi, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu y Xue-Zhong Yu. "STING Negatively Regulates Allogeneic T Cell Responses by Constraining Function of Antigen Presenting Cells". Journal of Immunology 204, n.º 1_Supplement (1 de mayo de 2020): 87.11. http://dx.doi.org/10.4049/jimmunol.204.supp.87.11.

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Abstract Stimulator of interferon genes (STING) plays an important role in eliciting innate immune responses by sensing tumor and microbial DNA in anti-tumor and anti-infection responses, respectively. How the STING signal affects allogeneic response is not clear. To address this question, we utilized murine models of allogeneic hematopoietic stem cell transplantation (allo-HCT). By transferring donor bone marrow (BM) and T cells into allogeneic recipients, we found that significantly more severe graft-versus-host disease (GVHD) was induced in STING−/− recipients as compared to WT controls. By generating BM-chimeric mice in which STING was deficient in hematopoietic or non-hematopoietic antigen-presenting cells (APCs), we confirmed that STING on hematopoietic cells was primarily responsible for constraining host APC function. We further demonstrated that STING on host CD11c+ APCs played a predominant role in the regulation of allogenic T-cell responses. Mechanistically, we found that host CD11c+IAb+ cells deficient for STING could survive better and be activated more strongly after allo-HCT. As a consequence, STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression and migration into intestinal tissues, resulting accelerated/exacerbated GVHD after allo-HCT. Using pharmacologic approaches, we further demonstrated that systemic administration of STING agonist (c-diGMP) on recipient mice before irradiation significantly reduced GVHD mortality. In conclusion, we reveal a novel role of STING in APC activity that dictates T-cell allogenic responses, and validate STING as a potential therapeutic target for controlling GVHD after allo-HCT.

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Bader, Cameron S., Lei Jin y Robert B. Levy. "STING and transplantation: can targeting this pathway improve outcomes?" Blood 137, n.º 14 (8 de abril de 2021): 1871–78. http://dx.doi.org/10.1182/blood.2020008911.

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Abstract Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic dsDNA originating from microorganisms and host cells. STING plays an important role in the regulation of murine graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be similarly activated during other transplantation modalities. In this review, we discuss STING in allo-HSCT and its prospective involvement in autologous HSCT (auto-HSCT) and solid organ transplantation (SOT), highlighting its unique role in nonhematopoietic, hematopoietic, and malignant cell types.

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Ara, Takahide, Daigo Hashimoto, Eiko Hayase, Clara Noizat, Ryo Kikuchi, Yuta Hasegawa, Kana Matsuda et al. "Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8". Science Translational Medicine 12, n.º 550 (1 de julio de 2020): eaaw0720. http://dx.doi.org/10.1126/scitranslmed.aaw0720.

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Graft-versus-host disease (GVHD) and infection are major obstacles to successful allogeneic hematopoietic stem cell transplantation (HSCT). Intestinal goblet cells form the mucus layers, which spatially segregate gut microbiota from host tissues. Although it is well known that goblet cell loss is one of the histologic features of GVHD, effects of their loss in pathophysiology of GVHD remain to be elucidated. In mouse models of allogeneic HSCT, goblet cells in the colon were significantly reduced, resulting in disruption of the inner mucus layer of the colon and increased bacterial translocation into colonic mucosa. Pretransplant administration of interleukin-25 (IL-25), a growth factor for goblet cells, protected goblet cells against GVHD, prevented bacterial translocation, reduced plasma concentrations of interferon-γ (IFN-γ) and IL-6, and ameliorated GVHD. The protective role of IL-25 was dependent on Lypd8, an antimicrobial molecule produced by enterocytes in the colon that suppresses motility of flagellated bacteria. In clinical colon biopsies, low numbers of goblet cells were significantly associated with severe intestinal GVHD, increased transplant-related mortality, and poor survival after HSCT. Goblet cell loss is associated with poor transplant outcome, and administration of IL-25 represents an adjunct therapeutic strategy for GVHD by protecting goblet cells.

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Kaufman, CL, YL Colson, SM Wren, S. Watkins, RL Simmons y ST Ildstad. "Phenotypic characterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells". Blood 84, n.º 8 (15 de octubre de 1994): 2436–46. http://dx.doi.org/10.1182/blood.v84.8.2436.2436.

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Abstract Bone marrow transplantation is an accepted therapy for hematologic malignancies, aplastic anemia, metabolic disorders, and solid tumors. However, graft-versus-host disease (GVHD) and failure of engraftment have limited the widespread application of this technology to nonmalignant disease states. The use of purified bone marrow stem cells has been suggested as an approach to promote engraftment yet avoid GVHD. Although bone marrow stem cells, purified by cell sorting, engraft and repopulate lethally irradiated genetically identical recipients, they do not engraft in major histocompatibility complex (MHC)-disparate allogeneic recipients. We report for the first time the characterization of a novel cell population of donor bone marrow origin, separate from the hematopoietic stem cell, that facilitates engraftment of purified allogeneic bone marrow stem cells in an MHC- specific fashion without causing GVHD. Although 1,000 purified stem cells (c-kit+/Sca-1+/lineage-) reliably repopulate syngeneic mouse recipients, 10 times that number do not engraft in MHC-disparate allogeneic recipients. The addition of as few as 30,000 facilitating cells (CD8+/CD45R+/TCR-) is sufficient to permit engraftment of purified stem cells in MHC-disparate recipients. The cell surface phenotype of this purified cellular population differs significantly from other characterized lineages of lymphoid or myeloid origin. Based on multiparameter rare-events cell sorting, the facilitating fraction is CD8+, CD3+, CD45R+, Thy 1+, class IIdim/intermediate but alpha beta- TCR- and gamma delta-TCR-. This cellular population comprises approximately 0.4% of the total bone marrow and is separate from the hematopoietic stem cell. The coadministration of purified facilitating cells plus stem cells to optimize engraftment yet avoid GVHD may expand the potential application of bone marrow transplantation to disease states in which the morbidity and mortality associated with conventional BMT cannot be justified.

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Kaufman, CL, YL Colson, SM Wren, S. Watkins, RL Simmons y ST Ildstad. "Phenotypic characterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells". Blood 84, n.º 8 (15 de octubre de 1994): 2436–46. http://dx.doi.org/10.1182/blood.v84.8.2436.bloodjournal8482436.

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Bone marrow transplantation is an accepted therapy for hematologic malignancies, aplastic anemia, metabolic disorders, and solid tumors. However, graft-versus-host disease (GVHD) and failure of engraftment have limited the widespread application of this technology to nonmalignant disease states. The use of purified bone marrow stem cells has been suggested as an approach to promote engraftment yet avoid GVHD. Although bone marrow stem cells, purified by cell sorting, engraft and repopulate lethally irradiated genetically identical recipients, they do not engraft in major histocompatibility complex (MHC)-disparate allogeneic recipients. We report for the first time the characterization of a novel cell population of donor bone marrow origin, separate from the hematopoietic stem cell, that facilitates engraftment of purified allogeneic bone marrow stem cells in an MHC- specific fashion without causing GVHD. Although 1,000 purified stem cells (c-kit+/Sca-1+/lineage-) reliably repopulate syngeneic mouse recipients, 10 times that number do not engraft in MHC-disparate allogeneic recipients. The addition of as few as 30,000 facilitating cells (CD8+/CD45R+/TCR-) is sufficient to permit engraftment of purified stem cells in MHC-disparate recipients. The cell surface phenotype of this purified cellular population differs significantly from other characterized lineages of lymphoid or myeloid origin. Based on multiparameter rare-events cell sorting, the facilitating fraction is CD8+, CD3+, CD45R+, Thy 1+, class IIdim/intermediate but alpha beta- TCR- and gamma delta-TCR-. This cellular population comprises approximately 0.4% of the total bone marrow and is separate from the hematopoietic stem cell. The coadministration of purified facilitating cells plus stem cells to optimize engraftment yet avoid GVHD may expand the potential application of bone marrow transplantation to disease states in which the morbidity and mortality associated with conventional BMT cannot be justified.

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Choi, Jaebok, Edward D. Ziga, Julie Ritchey, Lynne Collins, Julie L. Prior, Matthew L. Cooper, David Piwnica-Worms y John F. DiPersio. "IFNγR signaling mediates alloreactive T-cell trafficking and GVHD". Blood 120, n.º 19 (8 de noviembre de 2012): 4093–103. http://dx.doi.org/10.1182/blood-2012-01-403196.

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Abstract The clinical goal of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to minimize GVHD while maintaining GvL. Here, we show that interferon γ receptor-deficient (IFNγR−/−) allogeneic Tconv, which possess normal alloreactivity and cytotoxicity, induce significantly less GVHD than wild-type (WT) Tconv. This effect is mediated by altered trafficking of IFNγR−/− Tconv to GVHD target organs, especially the gastrointestinal (GI) tract. We show that the chemokine receptor CXCR3 is induced via IFNγR-mediated signaling and partially contributes to the trafficking of WT Tconv to GVHD target organs. Indeed, CXCR3−/− Tconv recapitulate the reduced GVHD potential of IFNγR−/− Tconv in a minor-mismatched GVHD model. Most importantly, IFNγR−/− (and CXCR3−/−) Tconv mediate a robust and beneficial GvL effect. In addition, we show that IFNγR−/− regulatory T cells (Tregs) are fully suppressive in vitro although defective in suppressor function in vivo and that WT Tregs suppress GVHD in vivo only when allogeneic Tconv produce interferon γ (IFNγ), suggesting that the IFNγR signaling pathway is the major mechanism for both Tregs and Tconv to migrate to GVHD target organs. Finally, pharmacologic inhibition of IFNγR signaling with inhibitors of JAK1/JAK2, which are mediators of IFNγR signaling, results in the decreased expression of CXCR3 and reduced GVHD and improved survival after allo-HSCT and this effect is mediated by altered trafficking of Tconv to GVHD target organs.

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Göttert, Sascha, Julius Clemens Fischer, Gabriel Eisenkolb, Erik Thiele Orberg, Dirk Busch, Sebastian Jarosch, Ernst Holler et al. "IFN-Gamma Producing Regulatory T Cells Counterbalance T Cell-Mediated Injury to the Intestinal Stem Cell Compartment in Mice and Humans". Blood 138, Supplement 1 (5 de noviembre de 2021): 89. http://dx.doi.org/10.1182/blood-2021-152925.

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Abstract Background: Graft-versus-host disease (GVHD) is a dreaded complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Such inflammatory diseases are fostered by damage to the intestinal barrier after transplantation. Consequently, the integrity and regeneration of the intestinal barrier is a key factor in the prevention of GVHD. On one side the main driver for regeneration of damaged gut epithelium are intestinal stem cells (ISC), but on the other side these cells are themselves primary targets of donor-derived T cells. One known mechanism of T cell mediated damage to the stem cell compartment is through IFN-γ dependent ISC toxicity. Yet, little is known about how T cells are contributing to the regeneration of damaged tissue after allo-HSCT and GVHD. Methods: To address this, we used preclinical models for allo-HSCT and GVHD including transplantation of recipient mice with escalating doses of Wildtype or IFN-γ-deficient allogeneic T cells and in the presence or absence of the JAK-1/2 inhibitor ruxolitinib. Intestinal regeneration was assessed by RNA-seq, flow cytometry and a newly established ex vivo organoid recovery assay. GVHD outcome was assessed by clinical scoring, histology and survival. Additionally, we established an allogeneic co-culture system of murine or human intestinal organoids with CD4+ conventional T cells or T regs -/+ Ruxolitinib. Effects on organoid growth and cell death were assessed by size measurements and manual counting after passaging. Results: We here demonstrate that recipient mice with increasingly dense intestinal infiltration by allogeneic T cells not only developed more severe GVHD (Fig. 1A), but also showed augmented recovery potential early after allo-HSCT (Fig. 1B). This was associated with intestinal gene signatures related to epithelial regeneration and protection from GVHD. Utilizing ex vivo cultures of intestinal organoids generated from murine allo-HSCT recipients, we found that development of GVHD but also regenerative capacity of ISCs were dependent on interferon (IFN)-γ-producing T cells in the intestine (Fig. 2A-B). Mice with fulminant GVHD and enhanced organoid recovery showed accumulation of intestinal regulatory T cells (Tregs) (Fig. 2C). Ex vivo, T regs nurtured growth of intestinal organoids in an IFN-γ dependent manner (Fig. 2D-E). This effect was diminished in intestinal organoids lacking IFNγR signaling, but was independent of T reg intrinsic IFNγR signaling (Fig. 2E-F). Intriguingly, treatment of murine allo-HSCT recipients with the JAK-1/2 inhibitor ruxolitinib enhanced epithelial organoid regeneration and numbers of intestinal Tregs (Fig. 3A-B). Similarily, growth of human intestinal organoids co-cultured with allogeneic T cells could be augmented by ruxolitinib treatment (Fig. 3C). We thus propose that the level and differentiation of infiltrating intestinal T cells determines both ISC damage and epithelial regeneration during immune-mediated tissue injury, leading to a sensitive equilibrium that can be modulated by therapeutic intervention. We also provide evidence that ruxolitinib improves ISC regeneration via IFNγ-producing Treg cells. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Bregni, Marco, Anna Dodero, Jacopo Peccatori, Alessandra Pescarollo, Massimo Bernardi, Isabella Sassi, Claudia Voena, Alberto Zaniboni, Claudio Bordignon y Paolo Corradini. "Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer". Blood 99, n.º 11 (1 de junio de 2002): 4234–36. http://dx.doi.org/10.1182/blood.v99.11.4234.

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The feasibility and toxicity of allogeneic stem cell transplantation after nonmyeloablative conditioning including thiotepa, fludarabine, and cyclophosphamide have been investigated in 6 patients with breast cancer and 7 patients with renal cell cancer. The program included the use of escalating doses of donor lymphocyte infusions (DLI) and/or interferon alpha (IFNα) for patients showing no tumor response and no graft-versus-host disease (GVHD). Patients were at high risk of transplant-related mortality (TRM) because of age, advanced stage, and previous treatments. We observed a partial remission in 4 renal cancer and in 2 breast cancer patients (one at the molecular level in the bone marrow), occurring after cyclosporine withdrawal or after DLI and/or IFNα. All the responses were accompanied by the occurrence of acute GVHD. We conclude that reduced-intensity allogeneic stem cell transplantation is a feasible procedure in renal and breast cancer, and that the exploitation of graft-versus-tumor effect after DLI is a promising finding.

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Wagner, Anna-Margaretha, Konstantin Beier, Elli Christen, Georg A. Holländer y Werner Krenger. "Leydig cell injury as a consequence of an acute graft-versus-host reaction". Blood 105, n.º 7 (1 de abril de 2005): 2988–90. http://dx.doi.org/10.1182/blood-2004-07-2646.

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Abstract Hematopoietic stem cell transplantation (HSCT) is associated with significant posttransplantation gonadotoxicity. This deficit has been mainly attributed to pretransplantation conditioning, but lower sperm counts in humans also appear to be associated with graft-versus-host disease (GVHD) following allogeneic HSCT. However, the mechanisms leading to diminished spermatocyte levels during GVHD remain unknown. Here we demonstrate that injury to intratesticular cells occurs in unconditioned F1 mice following the infiltration of donor alloreactive T cells during an acute graft-versus-host reaction (GVHR). Using computer-aided quantitative microscopic morphometry we demonstrate that the nadir of Leydig cell volume density coincides with the peak of intratesticular infiltration by donor T cells. Injury to Leydig cells correlates with an intratesticular inflammatory response characterized by interferon-γ and tumor necrosis factor-α production. These results demonstrate impairment of testosterone-producing Leydig cells during a local alloresponse, thus representing a mechanism that contributes to gonadal insufficiency following allogeneic HSCT.

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Kharbanda, Sandhya, James L. Zehnder y Bertil Glader. "Steroid Responsive T-Cell Mediated Pure Red Cell Aplasia Following Allogeneic Hematopoietic Stem Cell Transplantation". Blood 122, n.º 21 (15 de noviembre de 2013): 5498. http://dx.doi.org/10.1182/blood.v122.21.5498.5498.

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Abstract Pure red cell aplasia (PRCA) is an unusual complication following allogeneic hematopoietic stem cell transplantation (HSCT), the true incidence of which is not known. Almost all cases reported in the literature describe major ABO-incompatibility between the recipient and the donor as the major risk factor for this complication. Delayed recovery of reticulocyte counts and hypoplasia of erythroblasts in the marrow is attributed to incompatible hemagglutinins in recipients. There are reports of successful treatment of PRCA using different strategies include rapid tapering of calcineurin inhibitors, corticosteroids, donor lymphocyte infusion, rituximab, and/or plasma exchange. Additional causes of PRCA following allogeneic HSCT include parvovirus B19 infection and graft-versus-host disease (GVHD). The pathogenesis of PRCA in parvovirus infection is thought to be viral-mediated suppression of erythroid precursors in the bone marrow and this is due to the tropism of this virus for erythroid progenitor cells. Nonmyeloablative and reduced intensity conditioning regimens have been reported to have an increased risk of PRCA due to persistence of recipient lymphocytes. Here we report two cases of PRCA following allogeneic HSCT from major ABO mismatched donors. Both cases were correlated with the presence of a T-cell clone in the peripheral blood and bone marrow, and there was complete resolution of anemia with a short course of steroid treatment, as well as disappearance of the T-cell clone. Patient # 1 – A 24 year old female of Mediterranean descent underwent an HLA- 8/10 matched and major ABO-mismatched sibling donor bone marrow transplant for Sickle-Beta Thalassemia. She received a myeloablative but reduced toxicity conditioning regimen consisting of busulfan 16mg/kg, fludarabine 140mg/m2, cyclophosphamide 105mg/kg, and alemtuzumab 52mg/m2. Her immediate post-transplant course was relatively benign and significant for a mild CMV colitis which responded with resolution after treatment with anti-viral therapy. Her red cell transfusion needs had significantly decreased to every four weeks by day 130. However, at day 146 from HSCT, she started requiring red cell transfusions every two weeks, with a drop in the reticulocyte count to 0.6%. No antibodies were detected, and the patient was negative for parvovirus B19 and did not have any evidence of GVHD. However, her bone marrow showed an marked erythroid hypoplasia, and was positive for a T-cell clone with gamma chain gene rearrangement in the T-cell receptor. Due to a new onset of transfusion need, she was treated with a short course of steroids with an excellent response and disappearance of the T-cell clone from peripheral blood. She remained on immunosuppression during this entire period with a calcineurin inhibitor. Patient# 2 – A 10 year old Hispanic girl underwent a 10/10 HLA-matched and major ABO-mismatced sibling donor bone marrow transplant for idiopathic acquired severe aplastic anemia. Her preparative regimen consisted of 200 mg/kg of cyclophosphamide and 16mg/kg of rabbit-anti-thymocyte globulin. Her immediate post-transplant course was complicated by E.coli bacteremia. She had prompt engraftment and became transfusion independent on day 86. A cyclosporine taper was initiated at day 100 but held at day 119 when anemia was first noted. Peripheral blood showed a T-cell clone with gamma and beta chain gene rearrangement. She was started on a moderate dose of steroids with a good response, and has been tapered down to physiologic replacement dose of steroids with normal Hb and transfusion independence. With the resolution of anemia, the gamma chain gene rearrangement is not seen in the T-cell clonality assay, however, the beta chain gene rearrangement persists. To our knowledge, this is the first report of a T-cell mediated PRCA following allogeneic HSCT. Moreover, the PRCA was steroid responsive and not associated with GVHD in both the patients. Disclosures: No relevant conflicts of interest to declare.

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Ye, Fang, Zhenhua Qiao, Tao Yang, Li Zhang y Ning Jia. "Cytokine Expressions In Peripheral Blood Mononuclear Cells During Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation". Blood 116, n.º 21 (19 de noviembre de 2010): 4708. http://dx.doi.org/10.1182/blood.v116.21.4708.4708.

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Abstract Abstract 4708 Objective To investigate the relationship between cytokines and human graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods In 21 patients undergoing allo-HSCT, the plasma concentrations of cytokines (interleukin 2(IL-2), soluble interleukin 2 recepter (sIL-2R), interferon-gama (IFN-γ), interleukin 4(IL-4), transforming growth fator-beta1(TGF-β1)) were measured by using sandwich enzyme-linked immunological assay (ELISA) and the gene messanger RNA expressions of these five cytokines were analysed by using semi-quantitate reverse transcriptase-polymerase chain reaction (RT-PCR). Results 1. The concentrations and gene messanger RNA expressions of IL-2, sIL-2R and IFN-γ in the patients with GVHD were significantly higher than those without GVHD (P<0.01); these three cytokines expression levels in the patients with aGVHD were higher than with cGVHD and without GVHD (P<0.05); The levels of IL-4 showed no difference between the patients with or without GVHD (P>0.05); the levels of TGF-β1 in the patients with GVHD were significantly declined (P<0.01) but in those without aGVHD were obviously increased (P<0.05). After effective treatment, unnormal IL-2, sIL-2R, IFN-γ and TGF-β1 expressions recovered to the levels before transplantation. 2. The results of multivariate logistic regression modles and Kaplan-Meier survival curves analyses showed: age, sex, infection, HLA-matched, blood type, conditioning regiment and the times of absolute neutrophil counts and platelets recovering to normal, had no association with the incidence of GVHD (P>0.05). A multivariate COX survival function modle analysis showed IL-2, sIL-2R and TGF-β1 are independent prognostic factors for GVHD (=11.149, P<0.0001). 3. The results of IL-2, sIL-2R, IFN-γ and TGF-β1 measured by RT-PCR and ELISA for detecting peripheral blood cytokines expression levels had no difference. Conclusions 1. IL-2, sIL-2R, IFN-γ and TGF-β1 play important roles in the development of GVHD after allo-HSCT. Monitoring the changes of IL-2, sIL-2R, IFN-γ and TGF-β1 expression levels (especially IL-2, sIL-2R and TGF-β1) might provide predictive markers for GVHD, especially aGVHD. 2. Different conditioning regiments resultes in different IL-2, sIL-2R, IFN-γ and TGF-β1 expression levels. 3. IL-4 expression had no effect on the developing of GVHD after allo-HSCT. 4. The sensitivity between RT-PCR and ELISA for detecting peripheral blood cytokines expression levels had no difference. Disclosures: No relevant conflicts of interest to declare.

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Kordelas, Lambros, Matthias Junge, Rudolf Trenschel, Ahmet H. Elmaagacli y Dietrich W. Beelen. "Improved Overall Survival in Patients Recovering with High Gamma/Delta T Cells after Allogeneic Haematopoietic Stem Cell Transplantation." Blood 112, n.º 11 (16 de noviembre de 2008): 2223. http://dx.doi.org/10.1182/blood.v112.11.2223.2223.

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Abstract T-cells play a crucial role in the Graft-versus-Leukemia (GvL)-effect, since T-cells depleted grafts are associated with a higher relapse risk. Unfortunately, the GvL-effect is often associated with Graft-versus-Host-Disease (GvHD). T-cells can be divided into two phenotypic sub-groups by the expression of specific alpha/beta- and gamma/delta T-cell receptors. Gamma/delta-T-cells might provide a useful source for T-cell-immunotherapy since they may exert a GvL-effect without inducing a GvHD-risk. Only few studies have been carried out investigating the possible impact of gamma/delta-T-cell recovery following allogeneic hematopoietic stem cell transplantation (HSCT). A recent prospective study (Godder et al., BMT 2007) indicates a survival advantage for patients (pts) recovering with higher gamma/delta-T-cell numbers following HSCT. The data presented here emerge from a single-centre analysis evaluating the possible impact of higher gamma/delta-T-cell numbers following HSCT in pts with hematologic malignancies. We included all patients who had at least three consecutive analyses of alpha/beta- and gamma/delta-T-cell numbers within the first year after HSCT. This cohort of 107 patients includes the following haematological malignancies: AML (n=40), CML (n=19), ALL (n=13), MDS (n=11), OMF (n=9), NHL (n=7), and other diseases (n=8). Median patient age was 41 years (range 16 – 67 years). Median donor age was 38 years (range 18 – 70 years). HSCT was performed with related donors in 37 pts (35%) and with unrelated donors in 70 pts (65%). We defined the threshold for “high” gamma/delta-T-cell recovery as three ore more absolute gamma/delta-T-cell numbers above the absolute median gamma/delta-T number in the peripheral blood within the first 12 months after HSCT. According to this threshold 29 pts (27%) recovered with “high” gamma/delta-T-cells. These pts achieved a significantly higher overall survival with lower gamma/delta-T-cell numbers (log-rank p .029). This resulted from a lower relapse risk and a lower risk for acute GvHD. In multivariate analysis including other prognostic factors of overall survival (patient age, disease status, donor type, grades of acute GvHD and relapse), the beneficial effect of “high” gamma/delta-T-cell recovery could be confirmed. In contrast, recovery of alpha/beta T-cell numbers in peripheral blood had no significant influence on HSCT endpoints and were further not associated with the recovery of gamma/delta T-cells. This analysis supports the hypothesis of a beneficial effect of high gamma/delta-T-cells recovery following HSCT regarding overall survival. Further analyses and research are warranted to determine more accurately the importance of increased recovery of gamma/delta-T-cells to possibly develop new therapeutic options in HSCT as e.g. graft engineering.

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Hill, Geoffrey R., Rachel D. Kuns, Neil C. Raffelt, Alistair L. J. Don, Stuart D. Olver, Kate A. Markey, Yana A. Wilson et al. "SOCS3 regulates graft-versus-host disease". Blood 116, n.º 2 (15 de julio de 2010): 287–96. http://dx.doi.org/10.1182/blood-2009-12-259598.

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Abstract Suppressor of cytokine signaling-3 (SOCS3) is the main intracellular regulator of signaling by granulocyte colony-stimulating factor, an immune-modulatory cytokine used to mobilize stem cells for transplantation. We have therefore studied the contribution of SOCS3 to the spectrum of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Grafts from SOCS3−/Δvav donor mice in which SOCS3 deficiency is restricted to the hematopoietic compartment had an augmented capacity to induce acute GVHD. With the use of SOCS3−/ΔLysM and SOCS3−/Δlck donors in which SOCS3 deficiency was restricted to the myeloid or T-cell lineage, respectively, we confirmed SOCS3 deficiency promoted acute GVHD mortality and histopathology within the gastrointestinal tract by effects solely within the donor T cell. SOCS3−/Δlck donor T cells underwent enhanced alloantigen-dependent proliferation and generation of interleukin-10 (IL-10), IL-17, and interferon-γ (IFNγ) after SCT. The enhanced capacity of the SOCS3−/Δlck donor T cell to induce acute GVHD was dependent on IFNγ but independent of IL-10 or IL-17. Surprisingly, SOCS3−/Δlck donor T cells also induced severe, transforming growth factor β– and IFNγ-dependent, sclerodermatous GVHD. Thus, the delivery of small molecule SOCS3 mimetics may prove to be useful for the inhibition of both acute and chronic GVHD.

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Spoerl, Silvia, Sophia Chen, Michael Bscheider, Nimitha Mathew, Martina Schmickl, Tony Mueller, Annette Schmitt-Graeff et al. "JAK1/2 Inhibition Suppresses T Cell Proliferation and Inflammatory Cytokine Production In An Allogeneic Setting and Ameliorates Graft-Versus-Host Disease (GvHD) In a Murine GvHD Model". Blood 122, n.º 21 (15 de noviembre de 2013): 3253. http://dx.doi.org/10.1182/blood.v122.21.3253.3253.

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Abstract Graft-versus-host-disease (GvHD) constitutes a severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In GvHD, tissue damage is mediated by pro-inflammatory cytokines. Cytokine responses are mediated by activated Janus kinases (JAKs). We hypothesized that JAK1/2 inhibition might reduce T effector cell responses and inflammatory cytokine production in an allogeneic system, thereby ameliorating GvHD. We established an allogeneic (major mismatch) cell culture system using naive BALB/c CD4+ CD62Lhigh T cells that were co-cultured with C57BL/6 (B6) bone marrow derived dendritic cells (DC). JAK 1/2 signaling was specifically blocked using the small molecule inhibitor Ruxolitinib (INCB018424). By using a 3H Thymidine proliferation assay, we found that Ruxolitinib was able to inhibit the proliferation of allogeneic CD4+ effector T cells. In our intracellular cytokine staining experiments Ruxolitinib was able to impair the differentiation of naïve T cells into IFN-gamma and IL17A-producing T effector cells. Both cytokines – IFN-gamma and IL-17A – have been linked to aggravated courses of GvHD severity. In vivo administration of Ruxolitinib signficantly reduced lethal GvHD after allo-HSCT in a murine major mismatch model. BALB/c recipient mice were irradiated and received C57BL/6 (B6) T cell depleted bone marrow along with CD4+ and CD8+ T cells. Animals that were treated with an oral gavage of Ruxolitinib twice daily displayed significantly lower serum levels of IFN-gamma, TNF-alpha, IL-10 and IL-12p70, lower histological and clinical GvHD scores and improved overall survival compared to the control group. By using luciferase-positive (luc+) CD4+ and CD8+ T cells, we were able to visualize and quantify T cell migration after GvHD induction. The recipient mice received luc+ T cells along with conventional T cell depleted bone marrow. We were able to detect the luc+ T cell signal with a bioluminescence imaging system. At day 9 after allogeneic bone marrow transplantation, migration of donor T cells to GvHD target sites was significantly reduced in Ruxolitinib treated mice compared to control mice. In summary, our data demonstrate that suppression of inflammatory cytokine responses by JAK1/2 inhibitors modulates T effector cell responses in an allogeneic setting and improves survival in a murine major mismatch GvHD model. These observations suggest that JAK1/2 inhibition might be used for the treatment of GvHD following allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

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Paralkar, Vikram R., Sunita Dwivedy Nasta, Kelly Morrissey, Jacqueline Smith, Pavel Vassilev, Mary Ellen Martin, Steven C. Goldstein et al. "Graft-Vs-Lymphoma (GVL) Induction with Allogeneic Hematopoietic Stem Cell Transplantation (SCT) for Primary Cutaneous T Cell Lymphomas (CTCL)." Blood 116, n.º 21 (19 de noviembre de 2010): 4574. http://dx.doi.org/10.1182/blood.v116.21.4574.4574.

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Abstract Abstract 4574 Background CTCLs are generally incurable with conventional therapies. In particular, advanced mycosis fungoides (MF), Sézary syndrome (SS) and gamma delta varieties of CTCL have poor survival rates and are often refractory to traditional chemotherapy. Allogeneic SCT may provide a GVL effect and improve outcomes for these patients. Methods A retrospective analysis was performed at the University of Pennsylvania to identify all patients with CTCL who underwent allogeneic transplantation. 12 patients were identified who were transplanted between 2004 to 2010. A chart review was performed to obtain data about demographics, diagnosis, staging, treatment, transplantation and outcomes. Results Median age at diagnosis was 49 yrs and M:F ratio was 5:7. Prior to transplantation, 4 had MF (stages IIB, IIIB, IVA1, IVB; 2 with nodal transformation), 4 had SS (one stage IVA1, three IVA2; 1 with nodal transformation), and 3 had gamma delta T-cell lymphoma (all T3b). Median time from diagnosis to transplantation was 3.3 yrs (range 0.5@02b97 yrs). Patients had received a median of 8 non-chemotherapy, and 2 chemotherapy-based treatment modalities before being transplanted. Only 3 patients were in complete remission (CR) at the time of conditioning and 9 had evidence of active disease. Reduced intensity conditioning (RIC) was used in 10 cases (Flu/Bu, Flu/Cy or Flu/Mel), and conventional myeloablative conditioning (Cy/TBI) was used in 2. GVHD prophylaxis consisted of calcineurin inhibitor and methotrexate in all patients. The median follow up for all pts is 6.6 months (range 1.4 to 37.1 months) and 11.2 months for surviving patients. All patients engrafted with an ANC >500 a median 13 days after SCT. Median donor chimerism at day 100 after SCT in 10 evaluable pts was 97%. 7 of 12 patients developed acute GVHD, 4 of whom had grade 3 GVHD. Two patients died within the first 100 days, from sepsis with active disease. At day 100, 7 of 10 evaluable patients were in CR, with an additional patient achieving CR shortly after; therefore transplant induced and maintained CR in 6 pts with active disease. 3 patients relapsed after achieving CR a median of 11.4 months (range 5.3–13.0 months) after SCT. 2 patients never achieved CR, and progressed within a month of transplantation. The median PFS for all pts was 31 wks, and 1 yr and 2 yr PFS were 48% and 32% without an obvious plateau. 2 year OS was 53% (Figure 1). Median OS is not reached. 6 patients have died from progression (5) and GVHD (1), 5 remain in CR and 1 is alive with active disease. Conclusion RIC SCT can provide long-term disease control in patients with advanced CTCL otherwise refractory to immunotherapy and chemotherapy. Given the limited TRM, consideration for earlier transplant should be given. Larger retrospective and ideally prospective studies will further define the role of allogeneic SCT in this disease. Disclosures: Rook: Therakos: Speakers Bureau; HY Biopharma: Consultancy. Kim:TenX: Research Funding; Biocryst: Research Funding; Genmab: Research Funding; Glouchester: Research Funding; Celgene: Research Funding; Eisai: Consultancy.

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Kamel, Azza M., Nahla M. El-Sharkawy, Eman K. Abd El-Fattah, Raafat Abd El-Fattah, Mohammed A. Samra, Paul K. Wallace y Hossam K. Mahmoud. "Interleukin 12 (IL12) and Interferon Gamma (IFNγ) of Donor Origin Not of Patient Origin May Predict Acute Graft Versus Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)". Blood 120, n.º 21 (16 de noviembre de 2012): 1956. http://dx.doi.org/10.1182/blood.v120.21.1956.1956.

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Abstract Abstract 1956 One persistent problem following allogeneic HSCT is acute graft versus host disease (GVHD). A major role of cytokines in the pathogenesis of GVHD has been acknowledged with a lot of controversial reports. This study aimed at the possible prediction of the occurrence of acute GVHD through studying the pattern of interleukin 12 (IL12) and interferon γ (IFNγ) production. We used two approaches: (i) In vitro cytokine production by graft cells in response to recipient antigens, in a mixed lymphocyte culture setup. (ii) Measurement of cytokines levels in the patient's plasma prior to transplant and during the aplastic phase representing cytokines of patient's origin as well as at engraftment representing cytokines of donor's origin. The work was performed according to Helsinki declaration, the protocol was approved by the IRB of the NCI, Cairo University and an informed consent was obtained from all subjects. The study comprised 45 patients who received fully matched allogeneic peripheral blood stem cell transplantation from a sibling donor in the period from November 2006 until May 2010 at Nasser Institute. They included 26 males and 19 females with an age range of 6–41 with a median of 22 years. The study cohort included 18 AML, 15 CML, 4 ALL, 4 aplastic anemia, 3 MDS and one patient with Fanconi's anemia. IL12 and IFNγ were measured by microbead array technology using Luminex 200 and Flourokine MAP kit provided by R& D Company. Patients were followed up for at least one year. Fourteen/45 patients developed acute GVHD, 4 grade I, six grade II and 4 grade III. Seven patients developed chronic GVHD; 3 of them on top of acute GVHD. Patients who developed chronic GVHD showed no statistically significant differences in any of the tested parameters and will not be mentioned any more. Positive correlation between IL12 and IFNγ of donor's origin was encountered in both culture supernatant (r = 0.75, P <0.001) and patient's plasma at engraftment (r = 0.57, P <0.001). In culture supernatant, IL12 was undetectable in 7/14 cases with acute GVHD. The other 7 cases showed a level of 2.0 – 463.5 with a median of 14.6 pg/ml. It was not detected in any of the 31 cases without GVHD (P <0.001). IFNγ was undetectable in 4/14 cases with acute GVHD. The other 10 cases showed a level of 6.2 – 19.000 with a median of 133.5pg/ml. It was undetectable in 28/31 cases without GVHD. The other 3/31 cases showed a level of 1.1– 80.01 with a median of 8.1 pg/ml. (P <0.001). In patient's plasma at engraftment, IL12 was undetectable in 7/14 cases with acute GVHD; the other 7 cases showed a level of 3.89 – 608.5 with a median of 51.8 pg/ml. It was undetectable in 26/31 cases without GVHD; the other 5 cases showed a level of 2.0 – 6.88 with a median of 2.93 pg/ml. (P = 0.008). IFN γ was undetectable in 3/14 cases with acute GVHD; the other 11cases showed a level of 11 – 427 with a median of 77.9 pg/ml. It was undetectable in 24/31 cases without GVHD; the other 7 cases showed a level of 0.27– 26.67 with a median of 15.8 pg/ml (P <0.001). At a cut off value of 15.9 pg/ml in either culture supernatant or patient's plasma at engraftment, IFN γ showed a sensitivity of 64.3%, a specificity of 96.8 % and a total accuracy of 80.4%. Nine/10 cases that had a level ≥the cutoff in the culture supernatant developed acute GVHD as compared to 5/35 with levels below the cutoff (p=0.001). While 9/12 cases that had a level ≥the cutoff in patient's plasma at engraftment developed acute GVHD as compared to 5/33 with levels below the cutoff (p=0.001). At a cutoff value of 0.89 pg/ml, the level of IL12 in culture supernatant showed a sensitivity of 50.0%, absolute specificity of 100.0% and a total accuracy of 83.3%. All 7 cases that had a level ≥the cutoff developed acute GVHD as compared to 7/38 with levels below the cutoff (p=0.000). At a cutoff value of 1.0 pg/ml, the level of IL12 at engraftment showed a sensitivity of 50.0%, a specificity of 83.9% and a total accuracy of 72.3%. Seven/12 cases that had a level ≥the cutoff developed acute GVHD as compared to 7/33 with levels below the cutoff (p=0.023). On the other hand no significant difference was encountered in the levels of either cytokine of patient's origin between cases who developed and those who did not develop acute GVHD. In conclusion, IFN γ and IL12 of donor but not of patient's origin might predict the occurrence of acute GVHD. IL12 in culture supernatant is a potential absolute positive but not negative predictor. A validation cohort is needed to verify these assumptions. Disclosures: No relevant conflicts of interest to declare.

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van Bergen, Cornelis A. M., Michel G. D. Kester, Inge Jedema, Mirjam H. M. Heemskerk, Simone A. P. van Luxemburg-Heijs, Freke M. Kloosterboer, W. A. Erik Marijt et al. "Multiple myeloma–reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene". Blood 109, n.º 9 (18 de enero de 2007): 4089–96. http://dx.doi.org/10.1182/blood-2006-08-043935.

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Abstract Minor histocompatibility antigens (mHags) play an important role in both graft-versus-tumor effects and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. We applied biochemical techniques and mass spectrometry to identify the peptide recognized by a dominant tumor-reactive donor T-cell reactivity isolated from a patient with relapsed multiple myeloma who underwent transplantation and entered complete remission after donor lymphocyte infusion. A frequently occurring single nucleotide polymorphism in the human ATP-dependent interferon-responsive (ADIR) gene was found to encode the epitope we designated LB-ADIR-1F. Although gene expression could be found in cells from hematopoietic as well as nonhematopoietic tissues, the patient suffered from only mild acute GVHD despite high percentages of circulating LB-ADIR-1F–specific T cells. Differential recognition of nonhematopoietic cell types and resting hematopoietic cells as compared with activated B cells, T cells, and tumor cells was demonstrated, illustrating variable LB-ADIR-1F expression depending on the cellular activation state. In conclusion, the novel mHag LB-ADIR-1F may be a suitable target for cellular immunotherapy when applied under controlled circumstances.

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19

Lin, Yan, Quan Gu, Hui Cheng, Zhaofeng Zheng, Sun Guohuan, Xiaobao Xie, Tao Cheng y Weiying Gu. "Alterations of Bone Marrow Microenvironment in Acute Graft-Versus-Host Disease". Blood 134, Supplement_1 (13 de noviembre de 2019): 5009. http://dx.doi.org/10.1182/blood-2019-126322.

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Severe acute graft-versus-host disease (aGVHD) indicates a poor prognosis after allogeneic hematopoietic stem cell transplantation. In our previous study, we found that hematopoiesis was progressively suppressed during aGVHD, while the hematopoietic regenerative potential of donor-derived hematopoietic stem cells remains intact. It prompts us to investigate whether bone marrow niche is a major target of GVHD. We addressed this issue by studying the critical components in bone marrow microenvironment, including mesenchymal stem cell (MSC), osteoblasts and adipocytes in haplo-MHC-matched murine bone marrow transplantation model. By comparing confocal images of femurs from control and aGVHD SCF-GFP mice or Col2.3-GFP mice, we found that both MSCs and osteoblasts were significantly reduced during aGVHD development. In addition, anti-perilipin staining showed that adipocytes were also decreased in aGVHD mice. We found a defect in the differentiation potential of MSCs from aGVHD niche by in vitro culture of both murine and human bone marrow niche cells. qRT-PCR showed decreased gene expressions of PPAR-gamma, Adipoq, Runx1 and Col2a1, suggesting the potential of MSCs differentiation into adipocytes and osteoblasts was blocked. These data provide new insights into the pathogenesis of aGVHD and may improve the clinical management of aGVHD. Disclosures No relevant conflicts of interest to declare.

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20

Li, Jian-Ming, Lauren Southerland, Cindy Giver, Doug McMillion, Wayn Harris, David L. Jaye y Ned Waller. "CD11b-Donor Dendritic Cells Elevate Donor T-Cell Production of Interferon-Gamma and Graft-Versus-Leukemia Activity in Allogeneic Bone Marrow Transplantation." Blood 110, n.º 11 (16 de noviembre de 2007): 2181. http://dx.doi.org/10.1182/blood.v110.11.2181.2181.

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Abstract Host antigen-presenting cells (APC) persist after high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT) and initiate graft-versus-host disease (GvHD) in mouse models of HSCT. The role for donor APC on transplant outcomes is less clear. In clinical allogeneic HSCT from HLA-matched siblings, larger numbers of donor plasmacytoid dendritic cell (DC) precursors were associated with more relapse, and worse survival. Depletion of CD11b+ cells from bone marrow (containing CD11b+ DC) modestly augmented graft-versus-leukemia (GvL) activity in murine allogeneic HSCT. In this study, using allogeneic MHC mis-matched HSCT (C57BL/6→B10.BR) of mice bearing a lymphoblastic leukemia (LBRM), recipients of FACS–purified CD11b− donor DC plus FACS–purified HSC and T-cells had dramatically improved long-term survival (45% alive at >100 days) compared to d 5% survival among recipients of HSC and T-cells, or HSC, T-cells and CD11b+ DC (p<0.001). Both donor CD11b− and CD11b+ DC homed to lymphoid organs, and physically contacted donor T-cells, but only the CD11b− DC subset led to higher levels of interferon-γ (IFN- γ) in serum and higher levels of donor spleen-derived T-cells that synthesized IFN-γ in vivo in the first 10 days post-transplant. In contrast, recipients of CD11b+ DC had higher level of sera of IL–10. In CD11b− DC recipients, donor effector-memory CD8+ T-cells proliferated more rapidly and expanded in recipients, but did not cause debilitating GvHD in mice transplanted without leukemia. Donor-spleen-derived T-cells among recipients of CD11b− DC were predominately CD8+ (CD4:CD8 ratio 0.7:1), while donor spleen-derived T-cells were predominately CD4+ (p<0.02; CD4:CD8 ratio 1.3:1) among recipients of CD11b+ DC. In vitro co-culture of purified DC with homologous T-cells responding to allo-antigen demonstrated the same pattern of cytokine production as found in vivo, supporting the ability of CD11b− DC to generate Th1 immune responses that are associated with enhanced GvL effects and improved immune reconstitution. In vitro stimulation of DC subsets by CD40L (1μg/mL) and LPS (1μg/mL) showed that CD11b+ DC had higher level of PD–L1 expression compared to CD11b− DC. In vitro exposure of LBRM to IFN-γ, at doses of 10–300 pg/ml, similar to those observed in vivo, had no direct cytotoxic effect, and had no long-term growth-inhibitory effect on proliferation during 5 days of culture. CD11b+ DC expressed higher levels of PD–L1 and led to higher T-cell synthesis of IL–10 in vivo and in vitro. Transplantation of CD11b− DC resulted in higher levels of donor T-cell production of IFN-γ, and enhanced the GvL effect of donor T-cells without producing debilitating GvHD. These data indicated that purified donor DC can regulate post-transplant immunity via indirect antigen presentation to donor T-cells. CD11b+ DC expressed higher level of PD–L1 and led to higher level of IL–10 that resulted in more relapse and light GvHD. CD11b− DC led to higher level of donor IFN-γ that resulted in a stronger GvL effect while no debilitating GvHD. Engineering the DC content of an allograft may augment immune reconstitution and GvL activity without significantly increasing GvHD in allogeneic HSCT.

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21

Cai, Zhen, Xingkui Xue, Wenji Sun y Hangping Yao. "Rerovirus Mediated HSV-TK Gene Transfer Can Influence the Function of Human T-Lymphocyte." Blood 106, n.º 11 (16 de noviembre de 2005): 5245. http://dx.doi.org/10.1182/blood.v106.11.5245.5245.

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Abstract To control graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell (HSC) transplantation while maintaining the graft antileukemic effects of donor T cells, a suicide gene encoding the herpes simplex virus thymidine kinase (HSV-TK) enzyme was introduced ex vivo via a retroviral vector into donor T cells. Although previous clinical trials showed that it was an efficient tool for controlling GVHD, the gene transduction process of donor T lymphocytes may influence the immunocompetence of the T cells. In the current study, we investigated the impact that the gene manipulation in vitro had on the phenotype and functionality of human donor T lymphocytes. We engineered human T lymphocytes with HSV-TK and puromycin resistance gene with a retrovirus vector and analyzed the phenotype change of gene modified cells with flowcytometry. The secretion of gamma-interferon and interleukin-4 of T lymphocyte were detected with enzyme-linked immunospot(ELIPOT)assays. We also analyzed the lytic activity of T cells against allogeneic targets. The result showed that the number of TK gene transduced T lymphocyte was sufficient for clinical use. There was an inversion of the CD4+/CD8+ ratio in the gene modified T cell (GMC) compared with the fresh peripheral blood lymphocytes (PBLs). In addition, the GMCs showed a higher expression of HLA-DR and had more antigen-experienced cells than did the PBLs. In ELIPOT assays, significantly less gamma-interferon secretion by GMCs was observed compared to PBLs (50 vs. 115 spots/well-3×104cells, p<0.05). The results also showed that IL-4-secreting cell frequencies was similar in GMCs and in PBLs (19.3 vs. 20.3 spots/well-3×104cells, p>0.05). After stimulated by allogeneic PBMCs, the GMCs effectors showed a significant reduction in lytic activity against allogeneic targets in contrast with PBL. In conclusion, HSV-TK gene transduction and selection procedure can change the phenotype and functions of human T lymphocyte. The gene modified T lymphocytes still showed biological activities although lower than those of PBLs.

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Geraghty, Nicholas J., Amal Elhage, Peter Cuthbertson, Debbie Watson y Ronald Sluyter. "The P2X7 Receptor Antagonist AZ10606120 Does Not Alter Graft-Versus-Host Disease Development and Increases Serum Human Interferon-γ in a Humanized Mouse Model". OBM Transplantation 6, n.º 3 (6 de junio de 2022): 1. http://dx.doi.org/10.21926/obm.transplant.2203166.

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Allogeneic hematopoietic stem cell transplantation is a curative therapy for hematological malignancies, but its efficacy is limited by graft-versus-host disease (GVHD). This life-threatening disorder develops when donor (graft) immune cells cause inflammatory damage to recipient (host) tissues. The immune cell receptor channel P2X7 and its ligand adenosine 5’-triphosphate (ATP) have been implicated in GVHD pathogenesis. Therefore, this signaling axis represents a potential therapeutic target. This study aimed to investigate if the specific P2X7 antagonist AZ10606120 (AZ10) could prevent GVHD development in a preclinical, humanized mouse model, in which NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice are injected with human peripheral blood mononuclear cells (hPBMCs). Flow cytometric measurements of ATP-induced cation dye uptake revealed that AZ10 blocked P2X7 activity in human RPMI 8226 multiple myeloma cells (IC50 of 1 ± 1 nM) and murine RAW 264.7 macrophages (IC50 of 3 ± 1 nM), as well as primary donor CD4+ and CD8+ T cells. However, AZ10 (2 mg/kg), injected intraperitonealy (i.p.) daily for the first 10 days post-hPBMC injection, did not reduce clinical or histological GVHD development in mice. AZ10 did not impact engraftment of human leukocytes, predominantly CD4+ and CD8+ T cells. However, AZ10 increased serum human interferon gamma (hIFN-γ) concentrations, with CD8+ T cells being the main hIFN-γ producing T cell subset. In conclusion, this study suggests a role for P2X7 activation in impairing hIFN-γ production during GVHD pathogenesis, with the use of P2X7 blockade as a therapeutic strategy warranting further investigation.

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Bergmann, Liane, Matthias Staudinger, Christiane Pott, Ingrid Bolz, Martin Gramatzki, Michael Kneba y Benedikt Gahn. "Potent Activation of Healthy Donor T-Cells Specific for Mantle Cell Lymphoma Immunoglobulin Derived Peptides by CD40- and TLR7/8-Ligand Matured Dendritic Cells in Vitro". Blood 112, n.º 11 (16 de noviembre de 2008): 3502. http://dx.doi.org/10.1182/blood.v112.11.3502.3502.

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Abstract Patients with mantle cell lymphoma (MCL) and MRD after intensive radiochemotherapy and autologous stem cell transplantation have a high risk of relapse. Allogeneic stem cell transplantation offers the possibility of cure but is associated with a high risk of severe “graft versus host disease”(GvHD). A way to decrease the risk of GvHD while augmenting the “graft versus lymphoma” effect may be the in vitro activation and subsequent transplantation of allogeneic idiotyp-specific T-cells. This study was set out to determine whether cytotoxic T-cell responses specific for peptides derived from the mantle cell idiotype immunoglobulin can be activated in healthy individuals. In four patients with MCL treated in the European Mantle Cell Lymphoma Study Group the immunoglobulin heavy chain (IgH) gene family was amplified in lymphoma samples by PCR and sequenced. Using bioinformatics, the corresponding aminoacid sequence was analyzed for nonapeptides potentially binding to the individual HLA-haplotype. Peptides with a Rammensee-score >20 were synthesized. To determine whether these peptides could indeed elicit CD8+ T-cell responses they were used for dendritic cell (DC) pulsation and subsequent T-cell activation. The specificity of the CD8+ T-cells was tested against idiotype-pulsed DC and measured by flow cytometric intracellular interferon (IFN)-gamma staining. The lymphoma specific IgH rearrangements were successfully amplified and sequenced in all patients. In a HLA-A3 positive patient who was in remission after intensive radiochemotherapy and autologous hematopoietic stem cell transplantation three different idiotype HLA-matching peptides with a HLA-A3 binding score >20 were predicted from the VH-region, one additional nonapeptide was overlapping to the N-region of the immunoglobulin, rendering this peptide lymphoma-specific. This pool of peptides was synthesized and used for pulsation of monocyte derived dendritic cells (moDC) in two healthy HLA-A3 positive individuals. The maturation of the DC was done according to a standard protocol using proinflammatory cytokines (IL-6, IL-1 beta, TNF-alpha, PGE2). After 2–3 weekly stimulations of lymphocytes that had been depleted of regulatory T-cells 2.1% idiotype-specific CD8+ T-cells were activated in both healthy donors. Interestingly, T-cell stimulation using moDC matured with CD40− and TLR7/8-ligands was more efficient in comparison to the standard protocol and resulted in 12.3% IFN-gamma positive CD8+ cells. In summary, these data suggest, that idiotype-specific T-cells can be activated from healthy individuals by standard lymphocyte stimulating protocols in vitro. Moreover, the ability of moDC to activate idiotype-specific T-cells is exceeded by DC maturation using CD40− in combination with TLR7/8-ligands. These findings may help to improve immunotherapy in the settings of allogeneic transplantation strategies in relapsed MCL patients.

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24

Sadeghi, Behnam, Suleiman Al-Hashmi, Zuzana Hassan, Bjorn Rozell, Hernan Concha, Carin Lundmark, Kjell-Olov Grönvik, Manuchehr Abedi-Valugerdi y Moustapha Hassan. "Expansion and Activation Kinetics of Immune Cells during Early Phase of GVHD in Mouse Model Based on Chemotherapy Conditioning". Clinical and Developmental Immunology 2010 (2010): 1–13. http://dx.doi.org/10.1155/2010/142943.

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In the present paper, we have investigated early pathophysiological events in graft-versus-host disease (GVHD), a major complication to hematopoietic stem cell transplantation (HSCT). BLLB/c female mice conditioned with busulfan/cyclophosphamide (Bu-Cy) were transplanted with allogeneic male C57BL/6. Control group consisted of syngeneic transplanted Balb/c mice. In allogeneic settings, significant expansion and maturation of donor dendritic cells (DCs) were observed at day +3, while donor T-cells CD8+ were increased at day +5 (230%) compared to syngeneic HSCT. Highest levels of inflammatory cytokines IL-2, IFN-gamma, and TNF-alfa at day +5 matched T-cell activation. Concomitantly naïve T-cells gain effecr-memory phenotype and migrated from spleen to peripheral lymphoid organs. Thus, in the very early phase of GHVD following Bu-Cy conditioning donor, DCs play an important role in the activation of donor T cells. Subsequently, donor naïve T-cells gain effector-memory phenotype and initiate GVHD.

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Arditti, Fabian David, Thea M. Friedman, George Murphy y Robert Korngold. "A Novel In Vitro Murine Epithelial Culture System To Study Cutaneous GVHD (102.6)". Journal of Immunology 178, n.º 1_Supplement (1 de abril de 2007): S205. http://dx.doi.org/10.4049/jimmunol.178.supp.102.6.

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Abstract Graft-versus-host disease (GVHD), following allogeneic hematopoietic stem cell transplantation, involves a donor T cell attack against a number of tissue systems, including the skin, resulting in high levels of morbidity and mortality. The development of an in vitro murine model system for examining the underlying processes of specific target cell injury would be invaluable for increasing the understanding of the immunobiology of GVHD. In an effort to mimic the in situ nature of the target tissue, primary skin epithelial cell cultures were generated from ear skin of adult mice, after aggressive enzymatic digestion, without addition of growth factors or chemokines. The cultured cytokeratin-positive epithelial cells can be expanded and cryo-preserved for several passages. To test the ability of alloreactive T cells to mount responses against cultured epithelial cells, T lymphocytes from C57Bl/6 (B6) mice were added to the epithelial cells grown from minor histocompatibility antigen-mismatched BALB.B or syngeneic B6 mice. In vitro responses were characterized by day 6 supernatant interferon gamma levels (anti-BALB.B, 336.5 ± 32 pg/ml; anti-B6, 16.7 ± 12.2 pg/ml). Up-regulation of H2Kb was also observed on the surface of BALB.B epithelial cells (3.5 ± 2.2 and 90.5 ± 25 MFI on days 1 and 7, respectively). In addition, there was an increased amount of epithelial cell death, as denoted by 7-AAD staining.

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Wang, Hui, Wannee Asavaroengchai, Beow Yong Yeap, Min-Guang Wang, Shumei Wang, Megan Sykes y Yong-Guang Yang. "Paradoxical effects of IFN-γ in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury". Blood 113, n.º 15 (9 de abril de 2009): 3612–19. http://dx.doi.org/10.1182/blood-2008-07-168419.

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Abstract Interferon-γ (IFN-γ) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving allogeneic hematopoietic cell transplantation (allo-HCT) but promotes lethality in unirradiated and sublethally irradiated recipients. We investigated the role of IFN-γ in GVHD in sublethally irradiated B6D2F1 recipients of B6 allo-HCT. B6D2F1 mice receiving wild-type B6 splenocytes alone died rapidly, whereas those receiving wild-type B6 splenocytes plus marrow survived long-term. Mice in both groups showed rapid elimination of host hematopoietic cells but minimal parenchymal tissue injury. However, mice receiving allo-HCT from IFN-γ–deficient donors died rapidly regardless of whether donor marrow was given, and they exhibited severe parenchymal injury but prolonged survival of host hematopoietic cells. IFN-γ plays a similar role in another model involving delayed B6 donor leukocyte infusion (DLI) to established mixed allogeneic (B6→BALB/c) chimeras. IFN-γ promotes DLI-mediated conversion from mixed to full donor chimerism while attenuating GVHD. Importantly, IFN-γ enhances graft-versus-leukemia (GVL) effects in both models. Our data indicate that previously reported IFN-γ–induced early mortality in allo-HCT recipients is due to augmentation of lymphohematopoietic graft-versus-host reaction (LGVHR) and can be avoided by providing an adequate source of donor hematopoietic stem/progenitor cells. Furthermore, the magnitude of GVL is correlated with the strength of LGVHR, and IFN-γ reduces the potential of this alloreactivity to cause epithelial tissue GVHD.

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Koldehoff, Michael, Ahmet H. Elmaagacli, Reinhild Klein y Dietrich Beelen. "Incidence and Outcome of Auto/Alloimmune Hepatitis with Hepatic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation." Blood 116, n.º 21 (19 de noviembre de 2010): 4534. http://dx.doi.org/10.1182/blood.v116.21.4534.4534.

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Abstract Abstract 4534 Auto/alloimmune hepatitis (AIH) is an inflammatory liver disease characterized histological by a dense mononuclear cell infiltrate in the portal tract and serological by the presence of non-organ and liver-specific antibodies, high transaminases and increased levels of IgG. The relation between allogeneic hematopoietic stem cell transplantation (HSCT) and auto/alloimmune disease is complex. To examine this association, we retrospectively studied 1,636 allogeneic patients (median age 43, range 18–73 years) between May 1996 and December 2008. Among these patients, 311 (19%) developed hepatic graft-versus-host disease (GvHD) (162 pts had a hepatic GvHD of grade > II). We followed 25 patients (11 male, 14 female) in whom GvHD of the liver presented with marked elevation of serum aminotransferases, clinically resembling acute hepatitis and auto/antibodies characteristics for AIH. The median age at transplant was 35 (range, 18–54) years. Onset of liver dysfunction was at 286 days (range, 55–2766) after HSCT. Median peak serum was 312 (range 105–1750) U/L for alanine aminotransferase, 629 (133-2410) U/L for gamma-glutamyl transferase and 1.74 (0.5-23.4) mg/dl for bilirubin. The autoantibody profiles of AIH were 60% for anti-nuclear antibody, 44% for antibodies to liver-kidney microsomes, 24% for antibodies to smooth-muscle antigens, 28% for anti-mitochondrial antibody, 16% for antibodies to actin, 8% for antibodies to nucleoli, and 4% for other autoantibodies. AIH had a higher prevalence in younger and in female patients. AIH occurred in 92% in patients, who were transplanted with G-CSF mobilized and peripherally collected stem cells (PSC), but in only 8% in patients with bone marrow (BM) source (p<0.02), comparing all transplanted patients (1326 PSC, 310 BM). Stem cell grafts from matched sibling donor or matched unrelated donor were similar in the two groups. Acute GvHD of grade> II occurred more frequently in the groups with AIH (15/25 vs. 649/1636, p<0.002), and chronic GvHD (11 limited, 14 extensive) was ascertained in all AIH patients vs. 49.8% in all transplanted patients (p<0.0001). Three patients with AIH died from pulmonary bleeding, chronic GvHD, and relapse, whereas 22 patients with AIH are still alive (88%) at a median survival time of 2570 days. In conclusion, our evaluation confirms a strong association between G-CSF mobilized PSC, chronic GvHD and the development of AIH. Disclosures: No relevant conflicts of interest to declare.

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Choi, Jaebok, Matthew L. Cooper, Julie Ritchey, Lynne Collins, Julie Prior, David Piwnica-Worms y John F. Dipersio. "IFNγR Signaling As a Therapeutic Target To Prevent GvHD While Preserving Gvl". Blood 122, n.º 21 (15 de noviembre de 2013): 4464. http://dx.doi.org/10.1182/blood.v122.21.4464.4464.

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with relapsed/refractory leukemia, and marrow failure states such as myelodysplasia and aplastic anemia. However, allo-HSCT is complicated by allogeneic donor T cell-mediated graft-versus-host disease (GvHD) which can be life-threatening especially in recipients of unrelated or HLA-mismatched hematopoietic stem cell products. These same alloreactive donor T cells also mediate a beneficial graft-versus-leukemia (GvL) effect. We have recently reported that interferon gamma receptor deficient (IFNγR-/-) allogeneic donor T cells induce significantly less GvHD in both a MHC fully-mismatched (B6 (H-2b) → Balb/c (H-2d)) (75% vs 0% overall survival) and a minor-mismatched (B6 (H-2b) → B6x129 (H-2b)) allo-HSCT models (100% vs 10% overall survival) compared to WT T cells (Choi et al Blood 2012). In addition, IFNγR-/- donor T cells maintain a beneficial GvL effect, which has been examined in both systemic leukemia and solid tumor models using luciferase-expressing A20 cells derived from Balb/c. We also found that IFNγR-/- T cells migrate primarily to the spleen while WT T cells to GI tract and peripheral lymph nodes (LNs) using bioluminescence imaging (BLI), suggesting that altered T cell trafficking of IFNγR-/- T cells to GvHD target organs might be the major reason for the reduced GvHD. We further demonstrated that the IFNγR-mediated signaling (via JAK1/2 - STAT pathway) in alloreactive donor T cells is required for expression of CXCR3 which has been implicated in trafficking of T cells to areas of inflammation and target organs, commonly known to be the sites of GvHD. Here, we examine if inhibition of IFNγR signaling using a small molecule inhibitor can recapitulate the reduced GVHD with potent anti-leukemia effects similarly to that seen with IFNγR-/- T cells. We find that INCB018424, an inhibitor of JAK1/JAK2 which mediate IFNγR signaling, blocks CXCR3 expression in vitro. Most importantly, in vivo administration of INCB018424 (100 ug, s.c., twice a day, day 1-31) after allo-HSCT alters T cell trafficking and significantly reduces GvHD (70% vs. 0% overall survival, n=10/group, p=0.0012). We also find that INCB018424 preserves the beneficial GvL effect, which has been examined in both systemic leukemia and solid tumor models using luciferase-expressing A20 cells derived from Balb/c (B6 to Balb/c model) and APL cells from B6x129 (B6 to B6x129 model). Of note is that INCB018424, when given after transplant, had no significant effect on neutrophil or platelet recovery compared to animals receiving placebo. Thus, the IFNγR signaling pathway represents a promising therapeutic target for future efforts to mitigate GvHD while maintaining GvL after allo-HSCT. Moreover, this pathway could be targeted and exploited in other diseases besides GvHD such as those from organ transplantation, chronic inflammatory diseases and autoimmune diseases. Disclosures: No relevant conflicts of interest to declare.

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Hu, Yongxian, Yi Luo, Weiyan Zheng, Yamin Tan y He Huang. "Foxp3+ Regulatory T Cell Subsets Are Induced In Alloreactive Microenvironment and Associated With Chronic Graft-Versus-Host Disease Severity After Allogeneic Hematopoietic Stem Cell Transplantation". Blood 122, n.º 21 (15 de noviembre de 2013): 3307. http://dx.doi.org/10.1182/blood.v122.21.3307.3307.

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Abstract Background Regulatory T cells (Tregs), in particular CD4+ Foxp3+ T cells (CD4+Tregs), have been shown to play important roles in the maintenance of tolerance after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). CD8+ Foxp3+ T cells (CD8+Treg) have also been shown to control alloimmune responses in preclinical and clinical models (Renee J. Robb et al, Blood, 2012;119(24):5898-5908). In our previous study, we found that Foxp3+ gamma delta TCR+ Treg cells (gamma delta Tregs) played important regulatory roles in alloimmunity and in xenogeneic GVHD protection (Hu Yong-xian, et al. Leukemia, 2013;27(7):1580-5). Whether these Treg subsets are simultaneously present or have synergetic functional roles in allo-HSCT or, more specifically, GVHD biology is not known. To address this, we analyzed the frequency and possible roles of these Treg cell subsets in patients after allo-HSCT. Methods Patients who underwent allo-HSCT in our single center from January 2000 to July 2012 were selected. They were divided into 3 groups according to cGVHD criteria including non-cGVHD group, limited cGVHD group and extensive cGVHD group. We also selected healthy volunteers as healthy group. 10ml peripheral blood was drawn from all the selected patients and volunteers for CD4+Tregs, CD8+Tregs and gamma delta Tregs percentage and CD4/CD8 ratio analysis by flow cytometry. Serum cytokine levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (INF-gamma) and transforming growth factor-beta1 (TGF-beta1) were evaluated by ELISA. Data were processed and analyzed using statistical software (SPSS 17.0). Statistical significance for the difference in different groups was assessed by two-sample t-test and one-way analysis of variance (ANOVA). Spearman’s correlation was used to test the correlation between two continuous variables. Findings 21, 18 and 23 patients were selected in non-cGVHD group, limited cGVHD group and extensive cGVHD group respectively. 15 healthy volunteers were also selected in healthy group. As shown in Figure 1A, the percentages of CD4+Tregs, CD8+Tregs and gamma delta Tregs percentage were all significantly increased in non-cGVHD group compared to healthy group, limited cGVHD group and extensive cGVHD group while these 3 types of Tregs were increased in limited cGVHD group compared with extensive cGVHD group (p<0.05 respectively). TNF-alpha, INF-gamma, and CD4/CD8 have been reported to be associated with cGVHD severity. Our results got similar results (Figure 1B and 1D). Foxp3+ Tregs play their immunosuppressive roles partly via TGF-beta1 secretion. As shown in Figure 1C, the levels of TGF-beta1 increased dramatically in non-cGVHD group compared to healthy controls and cGVHD patients (P < 0.05). Spearman’s correlation analysis revealed that the increased level of TGF-beta1 was positively associated with increased regulatory T cell subsets but was negatively associated with cGVHD severity (p<0.05). We also found that all the 3 types of Treg cell percentages were positively correlated with CD4/CD8 ratio in cGVHD cohort. Conclusions Foxp3+ regulatory T cell subsets (CD4+ Tregs, CD8+ Tregs and gamma delta Tregs) can be simultaneously induced in alloreactive microenvironment and may be associated with cGVHD severity after allo-HSCT. They may play synergetic functional roles in controlling cGVHD. Our findings support the development of new strategies to increase the number of 3 types of Treg cells including CD4+ Tregs, CD8+ Tregs and gamma delta Tregs following allo-HSCT to prevent or correct cGVHD. Disclosures: No relevant conflicts of interest to declare.

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Morello, Enrico, Vladia Monsurrò, Elisabetta Pagani, Irene Cavattoni, Silvia Coin, Giuseppe Tridente, Clara Larcher y Sergio Cortelazzo. "IFN-γ Induced by PHA Stimulation as New Marker for Gvhd Prediction in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation." Blood 112, n.º 11 (16 de noviembre de 2008): 2196. http://dx.doi.org/10.1182/blood.v112.11.2196.2196.

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Abstract Background. GVHD is associated with a high morbidity and mortality in alloSCT patients. An early diagnosis of GVHD could reduce this adverse impact on the outcome of alloSCT. The effect of Th1 cytokine IFN-γ is crucial in the pathogenesis of GVHD and, as expected, higher protein levels are reported in the serum of patients with active chronic GVHD. The monitoring of IFN-γ basal levels as well as IFN-γ induced by mitogen stimulation in the blood samples of patients after alloSCT could help the management and the prediction of GVHD. A recent ELISA based test (QuantiFERON®-CMV) could measure specific (anti-CMV) and aspecific production of IFN-γ in whole blood. The aim of this study is to assess the reliability of the positive control of the QuantiFERON®-CMV kit as new marker for GVHD early diagnosis. Methods. The study was performed in 2 phases. In the first phase of the study, 92 whole blood specimens were collected and analyzed from 29 patients undergoing alloSCT. In the second phase 10 patients were observed prospectively with collection of blood samples every 2–3 weeks since engraftment until 4–6 months after SCT in order to study the PHA stimulated IFN-γ production in relationship with the onset of chronic GVHD. QuantiFERON®-CMV is an in vitro diagnostic test that use an antigenic human cytomegalovirus proteins (CMV) peptide cocktail to stimulate cells from whole blood. The mitogen-stimulated (PHA) plasma sample is used as an IFN-γ positive control for each specimen tested. Detection of interferon-γ (IFN-γ) by ELISA is used to identify responses. In order to assess the association between IFN-γ response due to PHA stimulation and GVHD, the positivity of the test was determined according to 2 different cut-off: #1) 0,5 IU/mL as defined by manufacturer, #2) 9 IU/mL as experimentally defined by the median of the observations in our data set. GVHD extension was defined by Seattle criteria and/or the number of involved sites, Chi-square test was used to assess the statistical correlation between IFN-γ production and clinical outcomes. Results. In the first phase, among 92 samples 70 were positive for the PHA stimulated IFN-γ production according to the cut-off #1; 61% (43/70) were associated with GVHD whereas 27% (6/22) with lower PHA stimulated IFN-γ production were associated with GVHD: this difference was proved to be significant (p=0.005). According to the cut-off #2 46 samples out of 92 were positive for the PHA stimulated IFN-γ production; 71% (33/46) were associated with GVHD whereas 34% (16/46) with lower PHA stimulated IFN-γ production were associated with GVHD: this difference was proved to be significant (p=0.000). In the second prospective phase of the study, 7/10 patients became positive for the PHA stimulated IFN-γ production after alloSCT: 6 developed subsequently chronic GVHD. The median time to the onset of GVHD was 100 days from the first sample proved positive above the cut-off #1 and 33 days from the first sample proved positive above the cutoff#2. Four patients received steroid treatment for extensive chronic GVHD and their PHA stimulated IFN-γ production dropped after treatment (figure 1, continuous line). Conclusions: The PHA stimulated IFN-γ production is associated with GVHD. The monitoring of PHA stimulated IFN-γ after alloSCT seems to predict the onset of GVHD and could help in the modulation of immunosuppressive treatment. However, larger prospective studies are needed. Figure Figure

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31

Choi, Jaebok, Edward Dela Ziga, Julie Ritchey, Lynne Collins, Julie Prior, Matthew Cooper, David Piwnica-Worms y John F. DiPersio. "Interruption of IFNγR Signaling Results in Altered T Cell Trafficking in Vivo and Abrogation of GvHD While Maintaining a Robust Gvl Response". Blood 120, n.º 21 (16 de noviembre de 2012): 455. http://dx.doi.org/10.1182/blood.v120.21.455.455.

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Abstract Abstract 455 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with relapsed/refractory leukemia, and marrow failure states such as myelodysplasia and aplastic anemia. However, allo-HSCT is complicated by allogeneic donor T cell-mediated graft-versus-host disease (GvHD) which can be life-threatening especially in recipients of unrelated or HLA-mismatched hematopoietic stem cell products. These same alloreactive donor T cells also mediate a beneficial graft-versus-leukemia (GvL) effect. Thus, the clinical goal in allo-HSCT is to minimize GvHD while maintaining GvL. Recent studies have suggested that this might be achieved by infusing regulatory T cells (Tregs) which in some preclinical models suppress GvHD-causing alloreactive donor T cells but have only limited effects on GvL-promoting alloreactive donor T cells. Unfortunately, Tregs exist in low frequency in the peripheral blood, are costly to purify and expand, and after expansion are difficult to isolate due to the lack of cell surface markers, all of which prevent their routine use in the clinic. Thus, alternative therapeutic approaches that do not require Tregs are needed. We have found that interferon gamma receptor deficient (IFNγR−/−) allogeneic donor T cells induce significantly less GvHD in both a MHC fully-mismatched (B6 (H-2b) → Balb/c (H-2d)) and a minor-mismatched (B6 (H-2b) → B6×129(H-2b)) allo-HSCT models compared to WT T cells. In addition, IFNγR−/− donor T cells maintain a beneficial GvL effect, which has been examined in both systemic leukemia and solid tumor models using luciferase-expressing A20 cells derived from Balb/c. We find that IFNγR−/− T cells migrate primarily to the spleen while WT T cells to GI tract and peripheral lymph nodes (LNs) using bioluminescence imaging (BLI), suggesting that altered T cell trafficking of IFNγR−/− T cells to GvHD target organs might be the major reason for the reduced GvHD. We further demonstrate that the IFNγR-mediated signaling in alloreactive donor T cells is required for expression of CXCR3 which has been implicated in trafficking of T cells to areas of inflammation and target organs, commonly known to be the sites of GvHD. Indeed, CXCR3−/− T cells recapitulate the reduced GvHD potential of IFNγR−/− T cells. In addition, forced overexpression of CXCR3 in IFNγR−/− T cells via retroviral transduction partially rescues the GvHD defect observed in IFNγR−/− T cells. We next examine if inhibition of IFNγR signaling using a small molecule inhibitor can recapitulate the anti-GVHD effects seen in IFNγR−/− T cells. We find that INCB018424, an inhibitor of JAK1/JAK2 which are the mediators of IFNγR signaling, blocks CXCR3 expression in vitro. Most importantly, in vivo administration of INCB018424 after allo-HSCT alters T cell trafficking and significantly reduces GvHD. Thus, the IFNγR signaling pathway represents a promising therapeutic target for future efforts to mitigate GvHD while maintaining GvL after allo-HSCT. Moreover, this pathway can be exploited in other diseases besides GvHD such as those from organ transplantation, chronic inflammatory diseases and autoimmune diseases. Disclosures: DiPersio: genzyme: Honoraria.

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32

Liu, Shuangyou, Biping Deng, Yuehui Lin, Zhichao Yin, Jing Pan, Tong Wu, Zhiyong Gao, Yanzhi Song, Yongqiang Zhao y Chunrong Tong. "Sequential CD19- and CD22-CART Cell Therapies for Relapsed B-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation". Blood 132, Supplement 1 (29 de noviembre de 2018): 2126. http://dx.doi.org/10.1182/blood-2018-99-111856.

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Abstract With traditional therapies, the prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is extremely poor. Chimeric antigen receptor (CAR) T cell therapy targeting at CD19 has demonstrated a significant efficacy on refractory/relapsed (r/r) B-ALL, but single-target CART could not maintain a long-term remission. Recently, CD22-CART has also shown an exciting result in r/r B-ALL. Here we sequentially applied CD19- and CD22-specific CART cells to treat relapsed B-ALL post-HSCT and observed the therapeutic effect. From June 30,2017 through May 31,2018, twenty-four B-ALL patients (pts) relapsing after allo-HSCT with both antigens CD19 and CD22 expression on blasts were enrolled, the median age was 24 (2.3-55) years. Seventeen pts had hematologic relapse, 6 with both bone marrow and extramedullary (EM) involvements and 1 with EM disease (EMD) only. Fourteen pts had failed to previous therapies including chemotherapy, donor lymphocyte infusion, interferon and even murinized CD19-CART in other hospitals. Recipient-derived donor T cells were collected for producing CAR-T cells, which were transfected by a lentiviral vector encoding the CAR composed of CD3ζ and 4-1BB. Eighteen pts were initially infused with murinized CD19-CART, then humanized CD22-CART; while 6 pts (5 failed to prior murinized CD19-CART and 1 had bright CD22-expression) were initially infused with humanized CD22-CART, then humanized CD19-CART. The time interval between two infusions was 1.5-6 months based on patients' clinical conditions. The average dose of infused CAR T cells was 1.4×105/kg (0.4-9.2×105/kg) for CD19 and 1.9×105/kg (0.55-6.6×105/kg) for CD22. All patients received fludarabine with or without cyclophosphamide prior to each infusion, some pts accepted additional chemo drugs to reduce the disease burden. Treatment effects were evaluated on day 30 and then monthly after each CART, minimal residual disease (MRD) was detected by flow cytometry (FCM) and quantitative PCR for fusion genes, EMD was examined by PET-CT, CT or MRI. Sixteen patients finished sequential CD19- and CD22-CART therapies. Three cases could not undergo the second round of CART infusion (1 died, 1 gave up and 1 developed extensive chronic graft-versus-host disease (GVHD)). The rest of 5 pts are waiting for the second CART. After first T-cell infusion, 20/24 (83.3%) pts achieved complete remission (CR) or CR with incomplete count recovery (CRi), MRD-negative was 100% in CR or CRi pts, 3 (12.5%) cases with multiple EMD obtained partial remission (PR), and 1 (4.2%) died of severe cytokine release syndrome (CRS) and severe acute hepatic GVHD. Sixteen patients (15 CR and 1 PR) underwent the second CART therapy. Before second infusion, 3/15 pts in CR became MRD+ and others remained MRD-. On day 30 post-infusion, 1 of 3 MRD+ pts turned to MRD-, 1 maintained MRD+ ( BCR/ABL+) and 1 had no response then hematologic relapse later. The PR patient still had not obtained CR and then disease progressed. As of 31 May 2018, at a median follow-up of 6.5 (4-10) months, among 16 pts who received sequential CD-19 and CD-22 CART therapies, 1 had disease progression, 2 presented with hematological relapse and 2 with BCR/ABL+ only, the overall survival (OS) rate was 100% (16/16), disease-free survival (DFS) was 81.3% (13/16) and MRD-free survival was 68.8% (11/16). CRS occurred in 91.7% (22/24) pts in the first round of T-cell infusion, most of them were mild-moderate (grade I-II), merely 2 pts experienced severe CRS (grade III-IV). The second CART only caused grade I or no CRS since the leukemia burden was very low. GVHD induced by CART therapy was a major adverse event in these post-HSCT patients. After the first CART, 7/24 (29.2%) pts experienced GVHD, of them, 4 presented with mild skin GVHD, 2 with severe hepatic GVHD (1 recovered and 1 died), and 1 developed extensive chronic GVHD. No severe GVHD occurred in the second infusion. Our preliminary clinical study showed that for B-ALL patients who relapsed after allo-HSCT, single CD19- or CD22- CART infusion resulted in a high CR rate of 83.3%, sequentially combined CD19- and CD22-CART therapies significantly improved treatment outcome with the rate of OS, DFS and MRD-free survival being 100%, 81.3% and 68.8%, respectively, at a median follow-up of 6.5 months. The effect of CART on multiple EMD was not good and CART induced GVHD needs to be cautious. Disclosures No relevant conflicts of interest to declare.

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Bader, Cameron S., Henry Barreras, Casey O. Lightbourn, Sabrina N. Copsel, Dietlinde Wolf, Jingjing Meng, Jeonghyun Ahn et al. "STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets". Science Translational Medicine 12, n.º 552 (15 de julio de 2020): eaay5006. http://dx.doi.org/10.1126/scitranslmed.aay5006.

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The stimulator of interferon genes (STING) pathway has been proposed as a key regulator of gastrointestinal homeostasis and inflammatory responses. Although STING reportedly protects against gut barrier damage and graft-versus-host disease (GVHD) after major histocompatibility complex (MHC)–mismatched allogeneic hematopoietic stem cell transplantation (aHSCT), its effect in clinically relevant MHC-matched aHSCT is unknown. Studies here demonstrate that STING signaling in nonhematopoietic cells promoted MHC-matched aHSCT–induced GVHD and that STING agonists increased type I interferon and MHC I expression in nonhematopoietic mouse intestinal organoid cultures. Moreover, mice expressing a human STING allele containing three single-nucleotide polymorphisms associated with decreased STING activity also developed reduced MHC-matched GVHD, demonstrating STING’s potential clinical importance. STING−/− recipients experienced reduced GVHD with transplant of purified donor CD8+ T cells in both MHC-matched and MHC-mismatched models, reconciling the seemingly disparate results. Further examination revealed that STING deficiency reduced the activation of donor CD8+ T cells early after transplant and promoted recipient MHC class II+ antigen-presenting cell (APC) survival. Therefore, APC persistence in STING pathway absence may account for the increased GVHD mediated by CD4+ T cells in completely mismatched recipients. In total, our findings have important implications for regulating clinical GVHD by targeting STING early after aHSCT and demonstrate that an innate immune pathway has opposing effects on the outcome of aHSCT, depending on the donor/recipient MHC disparity.

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Yvon, Eric S., Stephane Vigouroux, Raphael F. Rousseau, Ettore Biagi, Persis Amrolia, Gianpietro Dotti, Hans-Joachim Wagner y Malcolm K. Brenner. "Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells". Blood 102, n.º 10 (15 de noviembre de 2003): 3815–21. http://dx.doi.org/10.1182/blood-2002-12-3826.

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Abstract Graft-versus-host disease (GVHD) represents one of the major complications of allogeneic hematopoietic stem cell transplantation. Techniques to prevent GVHD have included ex vivo T-cell depletion of the graft or prolonged in vivo immunosuppression. Both reduce the frequency and severity of GVHD but also reduce T-cell-mediated graft-versus-malignancy effect, and increase the risk of infection. A major goal in transplantation is to prevent alloreactivity while preserving activity against tumors and infectious agents. We have used activation of the Notch pathway to try to generate T cells able to specifically regulate alloantigen responses. We used allogeneic Epstein-Barr virus lymphoblastoid B cells (EBV-LCLs) as stimulator cells. Such LCLs are excellent (allo) antigen-presenting cells and can be obtained in large numbers even from donors who have received extensive chemo/radiotherapy. We overexpressed a Notch ligand, Jagged-1, in these cells by adenoviral vector transduction. Stimulation of CD45RA+ naive T cells by Jagged-1 EBV-LCL reduces production of interferon-γ, interleukin-2, and interleukin-5, but up-regulates transforming growth factor-β1 synthesis, consistent with induction of a regulatory T-cell phenotype. Transfer of these T cells to fresh lymphocyte cultures inhibits proliferative and cytotoxic immune responses to the priming alloantigens while sparing responses to third-party stimulator cells. Notch activation in the presence of alloantigen-presenting cells may therefore be a means of inducing specific regulatory T cells while preserving other T-cell functionality. (Blood. 2003;102:3815-3821)

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Minculescu, Lia, Hanne Vibeke Marquart, Lars Peter Ryder, Ida Schjødt, Lone Smidstrup Friis, Brian Thomas Kornblit, Søren Lykke Petersen et al. "Improved Relapse-Free Survival and Overall Survival in Patients with High Immune Reconstitution of Gamma Delta T Cells 2 Months after Allogeneic Hematopoietic Stem Cell Transplantation". Blood 132, Supplement 1 (29 de noviembre de 2018): 3396. http://dx.doi.org/10.1182/blood-2018-99-111777.

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Abstract Introduction: The role of T cell receptor (TCR) γδ cells in allogeneic hematopoietic stem cell transplantation (HSCT) is becoming of increasing interest1,2. In contrast to conventional alloreactive TCR αβ cells, TCR γδ cells are believed to have anti-tumor effects without causing graft-versus-host disease (GVHD). We conducted a single-center, prospective study to assess the impact of early TCR γδ cell immune reconstitution on overall survival, relapse and acute GVHD after HSCT. Methods: From October 2015 to March 2017, 108 consecutive patients transplanted for malignant diseases at the Bone Marrow Transplant Unit, Department of Hematology, Copenhagen University Hospital, Rigshospitalet, were included in the study, table 1. Fresh blood samples days 28, 56, 91, 180 and 360 after transplantation were analyzed for absolute concentrations of CD3-, CD4- and CD8 positive T cells together with a multi-color flow cytometry panel with staining for TCRαβ, TCRγδ, Vδ1, Vδ2, CD3, CD4, CD8, HLA-DR, CD196, CD45RO, CD45RA, CD16, CD56, CD314 (NKG2D) and CD337 (NKp30) for immune phenotyping. Results: After a median of 673 (386-913) days, 28 (26%) patients had died from relapse (n=14) and from transplant-related-mortality(n=14), respectively. A total of 24 (22%) patients experienced relapse during the observation time with median time to relapse of 177 (56-778) days. Acute GVHD grade 2-4 was diagnosed in 38 (35%) of patients. Patients were divided into two groups by dichotomization at the median value of TCR γδ cell concentrations for Kaplan-Meier analyses of overall survival (OS), relapse-free survival (RFS) and cumulative incidence analyses (Gray's test for competing risks) of relapse and acute GVHD. Patients with high concentrations of TCR γδ cells 56 days after transplantation had significantly higher OS and RFS compared with patients with low concentrations, p<0.001 and p=0.005, respectively, figure 1. In Cox regression analyses with TCR γδ cell concentrations included as (log2-transformed) continuous variables, increasing concentrations of TCR γδ cells were significantly associated with increased OS and RFS, 0.72 (95% CI 0.58-0.87), p=0.001 and 0.82 (95% CI 0.68-0.98), p=0.03, respectively. High concentrations of TCR γδ cells remained significantly associated with increased OS and RFS in Cox regression multivariate analysis adjusted for disease stage at transplantation and conditioning regimen, 0.66 (95% CI 0.53-0.683), p<0.001 (OS) and 0.79 (CI 95% 0.65-0.95), p=0.01 (RFS), respectively. In cumulative incidence analyses of death from relapse with death from transplant-related-mortality as a competing event, patients with high concentrations of TCR γδ cells 56 days after transplantation had a significantly lower risk of dying from relapse compared to patients with low concentrations, p=0.003, figure 2a. Cumulative incidence of acute GVHD with death as a competing event furthermore showed that patients with high concentrations of TCR γδ cells 28 days after transplantation had significantly less acute GVHD compared with patients with low concentrations, p=0.02, figure 2b. All associations between TCR γδ cell concentrations and outcomes were independent of the total CD3 T cell concentrations. Conclusion: The results of this prospective study suggest a protective effect of early robust TCR γδ cell immune reconstitution on relapse and acute GVHD resulting in increased OS after HSCT, and support further research in adoptive TCR γδ cell therapy in transplant patients. Handgretinger, R. & Schilbach, K. The potential role of gd T cells after allogeneic HCT for leukemia. Blood131, 1063-1072 (2018). Scheper, W., Grunder, C., Straetemans, T., Sebestyen, Z. & Kuball, J. Hunting for clinical translation with innate-like immune cells and their receptors. Leukemia28, 1181-1190 (2014). Disclosures No relevant conflicts of interest to declare.

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Jacoby, Elad, Haiying Qin, Yinmeng Yang, Christopher Daniel Chien y Terry J. Fry. "CD19 CAR T Cells Maintain Efficacy in the Allogeneic Environment but Mediate Acute Graft-Versus-Host-Disease Only in the Presence CD19+ Acute Lymphoblastic Leukemia". Blood 124, n.º 21 (6 de diciembre de 2014): 1115. http://dx.doi.org/10.1182/blood.v124.21.1115.1115.

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Abstract A significant portion of patients with relapsed acute lymphoblastic leukemia (ALL) who are eligible for treatment with chimeric-antigen-receptor (CAR) T cells have undergone a previous hematopoietic stem cell transplantation. We and others have previously demonstrated that the allogeneic environment, even in the presence mild graft-versus-host disease (GVHD), severely impairs tumor-directed T-cell immunity. To study the behavior of CAR cells in the allogeneic setting we chose a murine model of minor mismatched allogeneic T-cell depleted bone marrow transplantation (BMT) followed by CAR T (CD19-28-z) cell infusion in recipients bearing a murine B-precursor ALL model (positive for CD19). Importantly, the leukemia persists following myeloablative radiation thus mimicking post-transplant minimal residual disease. Donor-derived, post-transplant injection of CD19 CAR T cells eliminated residual leukemia in the syngeneic as well as the allogeneic settings. CD19 CAR T cells harvested from allogeneic recipients maintained in-vitro ability to produce IFN-gamma and degranulate in the presence of ALL ex vivo, at levels comparable to syngeneic CD19 CAR T cells. However, CAR T cells administered in the allogeneic environment had the potential to mediate severe acute GVHD with early mortality of recipients not typically seen in this minor mismatch model. This occurred across multiple T cell doses capable of clearing leukemia (0.3e6-5e6), in transduced CD19 CAR T cells generated from donors tolerized to allogeneic antigens, and when CD19 CAR T cell infusion was delayed following BMT. In-vivo tracking of transferred cells showed comparable expansion and persistence of the CD19 CAR T cells in the allogeneic and syngeneic environments. However, syngeneic CAR T cells tended to develop later into central memory T cells (CD62L+CD44+), whereas the profile of allogeneic cells was significantly skewed toward effector T cells (CD62L-CD44+). Remarkably, the process of CAR-driven acute GVHD in this minor mismatch model was only seen in the presence of leukemia, indicating a CAR-target interaction influences the induction of GVHD. Indeed, pro-inflammatory cytokines IFN-gamma and IL-6 were elevated only in the presence of both ALL and CAR T cells, whereas TNF alpha levels were undetectable in all instances. We are currently testing whether neutralization of cytokines can prevent GVHD in these models. Altogether, these data demonstrate efficacy of CD19 CAR to clear residual leukemia in an immunocompetent mouse model, and maintain initial cytotoxicity despite the potentially suppressive allogeneic environment. However, we demonstrated potential risks of allogeneic CAR T cells aggravating GVHD in the presence of residual leukemia, likely via cytokine-mediated manner. Clinically, as IL-6 was shown to be significant in cytokine release syndrome, this may represent a murine model to study potential interventions. Disclosures No relevant conflicts of interest to declare.

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Qiao, Shukai, Hanyun Ren, Yongjin Shi, Wei Liu y Jing Yuan. "Allogeneic Compact Bone-Derived Mesenchymal Stem Cell Transplantation Attenuates The Severity Of Idiopathic Pneumonia Syndrome In a Murine Bone Marrow Transplantation Model". Blood 122, n.º 21 (15 de noviembre de 2013): 4466. http://dx.doi.org/10.1182/blood.v122.21.4466.4466.

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Introduction Idiopathic pneumonia syndrome (IPS) is a serious and life-threatening lung complication following allogeneic hematopoietic stem cell transplantation (allo- HSCT) and currently no effective therapies exist. The present study was designed to determine whether transplantation of allogeneic murine compact bone derived- mesenchymal stem cells (CB-MSCs) could prevent the development of IPS. Methods We tested the effects of allogeneic CB-MSCs transplantation on IPS using an established murine model of IPS, wherein lethally irradiated male BALB/c (H-2d) recipient mice received bone marrow and spleen cells from female C57BL/6(H-2b) donors. Survival rates, body weight change, clinical GVHD scores, lung histological changes and wet-dry lung ratios were assessed after IPS induction. Mechanistically, concentrations of cytokines (TNF-alpha, IFN-gamma and IL-4) and chemokines (CCL5, CXCL9 and CXCL10) in bronchoalveolar lavage fluid (BALF) from the recipient mice were measured at different time point post-transplantation. CD4+CD25+Foxp3+ regulatory T cell (Treg) percentage, CCR5, CXCR3 and CCR7 expression on CD3+ T cells, and lung CXCR3, CCR5, CCR7, T-bet and GATA-3 mRNA levels were also evaluated at different time point post-transplantation. Results In the IPS model, co-transplantation of CB-MSCs significantly attenuated the severity of lung injuries and increased the survival rate of mice compared to non-cotransplanted mice. Furthermore, a higher Treg percentages, reduced TNF-alpha, IFN-gamma, CCL5, CXCL9 and CXCL10 levels, CXCR3 and CCR5 down-regulation, as well as CCR7 up-regulation, were observed in MSCs co-transplantation mice. Additionally, the prophylactic effect of CB-MSCs was also associated with a shift of Th1/Th2 balance toward anti-inflammatory Th2 polarization. Conclusions Our present data suggested that allogeneic CB-MSCs attenuated the severity of IPS due to its profound immunomodulatory capacity in our murine model. This may offer a novel prophylactic approach for IPS patients after allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

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Melenhorst, J. Joseph, Ann M. Leen, Catherine M. Bollard, Máire F. Quigley, David A. Price, Cliona M. Rooney, Malcolm K. Brenner, A. John Barrett y Helen E. Heslop. "Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects". Blood 116, n.º 22 (25 de noviembre de 2010): 4700–4702. http://dx.doi.org/10.1182/blood-2010-06-289991.

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Adoptive transfer of viral antigen-specific memory T cells can reconstitute antiviral immunity, but in a recent report a majority of virus-specific cytotoxic T-lymphocyte (CTL) lines showed in vitro cross-reactivity against allo-human leukocyte antigen (HLA) molecules as measured by interferon-γ secretion. We therefore reviewed our clinical experience with adoptive transfer of allogeneic hematopoietic stem cell transplantation donor-derived virus-specific CTLs in 153 recipients, including 73 instances where there was an HLA mismatch. There was no de novo acute graft-versus-host disease after infusion, and incidence of graft-versus-host disease reactivation was low and not significantly different in recipients of matched or mismatched CTL. However, we found that virus-specific T cell lines recognized up to 10% of a panel of 44 HLA disparate targets, indicating that virus-specific T cells can have cross-reactivity with HLA-mismatched targets in vitro. These data indicate that the adoptive transfer of partially HLA-mismatched virus-specific CTL is safe despite in vitro recognition of recipient HLA molecules.

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Kochenderfer, James N., Mark E. Dudley, Robert O. Carpenter, Sadik H. Kassim, Jeremy J. Rose, William Telford, Frances T. Hakim et al. "Donor-Derived Anti-CD19 Chimeric-Antigen-Receptor-Expressing T Cells Cause Regression Of Malignancy Persisting After Allogeneic Hematopoietic Stem Cell Transplantation". Blood 122, n.º 21 (15 de noviembre de 2013): 151. http://dx.doi.org/10.1182/blood.v122.21.151.151.

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Abstract Progressive malignancy is a leading cause of death in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). To improve treatment of B-cell malignancies that persist despite alloHSCT, we conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Ten patients were treated on this trial. Four patients were recipients of human-leukocyte-antigen (HLA)-matched unrelated donor (URD) transplants and 6 patients were recipients of HLA-matched sibling transplants. T cells for genetic modification were obtained from each patient’s healthy alloHSCT donor. Patients received a single infusion of anti-CD19-CAR T cells. Cell doses ranged from 1x106 to 10x106 T cells/kg. A mean of 58% of the infused cells expressed the CAR. Patients did not receive chemotherapy or other anti-malignancy therapy with the CAR-T-cell infusions, so the responses observed in these patients are not confounded by the effects of chemotherapy. In contrast to other reports of successful treatment of B-cell malignancies with anti-CD19-CAR T cells, the patients on this study were not lymphocyte-depleted at the time of the CAR-T-cell infusions. Two patients with chronic lymphocytic leukemia (CLL) refractory to standard unmanipulated allogeneic donor lymphocyte infusions (DLIs) had regressions of large malignant lymph node masses after infusion of allogeneic anti-CD19-CAR T cells. One of these CLL patients obtained a complete remission that is ongoing 9 months after treatment with allogeneic anti-CD19-CAR T cells. This patient also had complete eradication of blood B cells within 9 days after her CAR-T-cell infusion. Another patient had tumor lysis syndrome requiring rasburicase treatment as his CLL dramatically regressed in lymph nodes, bone marrow, and blood within 2 weeks of his anti-CD19-CAR-T-cell infusion. A patient with mantle cell lymphoma obtained a partial remission that is ongoing 3 months after infusion of anti-CD19-CAR T cells. A fourth patient with diffuse large B-cell lymphoma has ongoing stable disease 11 months after infusion of anti-CD19-CAR T cells. The other 6 treated patients all had short periods of stable malignancy or progressive disease after their CAR-T-cell infusions. Specific eradication of blood B cells occurred after infusion of CAR T cells in 3 of 4 patients with measurable blood B cells pretreatment. None of the patients treated on this study developed GVHD after their anti-CD19-CAR-T-cell infusions, despite the fact that 6 of 10 treated patients had experienced GVHD at earlier time-points after their most recent alloHSCT. One patient, who had a history of cardiac dysfunction with prior acute illnesses, had temporary cardiac dysfunction after infusion of anti-CD19-CAR T cells. The most prominent toxicities experienced by patients were fever and hypotension; these peaked 5 to 12 days after CAR-T-cell infusions and resolved within 14 days after the T-cell infusions. Two patients had Grade 3 fever, and 2 patients had Grade 3 hypotension. No patients experienced Grade 4 toxicities that were attributable to the CAR-T-cell infusions. Elevated levels of serum interferon gamma were detected in 3 patients at the time that they were experiencing toxicities. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. The peak blood levels of CAR T cells varied from undetec to 2.8% of peripheral blood mononuclear cells. The persistence of the CAR T cells in the blood of patients was limited to one month or less. When we assessed T cells from the blood of patients ex vivo, we found elevated levels of the T-cell inhibitory molecule programmed cell death protein-1 (PD-1) on CAR+ T cells compared to CAR-negative T cells. These results show for the first time that small numbers of donor-derived allogeneic anti-CD19-CAR T cells can cause regression of highly treatment-resistant B-cell malignancies after alloHSCT without causing GVHD. Malignancies that were resistant to standard DLIs regressed after anti-CD19-CAR-T-cell infusions. Future goals for improving this approach include enhancing the persistence of anti-CD19-CAR T cells and reducing toxicities. Infusion of allogeneic T cells genetically modified to recognize malignancy-associated antigens is a promising approach for treating residual malignancy after alloHSCT. Disclosures: No relevant conflicts of interest to declare.

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Lee, Myoung Woo, Dae Seong Kim, Hye Jin Kim, Meong Hi Son, Soo Hyun Lee, Hye Lim Jung, Keon Hee Yoo, Ki Woong Sung y Hong Hoe Koo. "Induction of Indoleamine 2,3-Dioxygenase Expression by Interferon-g in Human Mesenchymal Stem Cells Inhibits Graft Versus Host Disease". Blood 118, n.º 21 (18 de noviembre de 2011): 4698. http://dx.doi.org/10.1182/blood.v118.21.4698.4698.

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Abstract Abstract 4698 Background: It is important to overcome the limitations such as graft rejection and graft versus host disease (GvHD) in allogeneic hematopoietic stem cell transplantation. Mesenchymal stem cells (MSCs), which evoke only minimal immune reactivity, may have anti-inflammatory and immunomodulatory effects. Purpose: In this study, we aimed to identify the immunomodulatory properties of human MSCs and to elucidate the possible mechanism of their properties for clinical treatment of allogeneic conflicts using MSCs. Materials & Methods: We conducted a comparative analysis about the immunomodulatory properties of MSCs derived from adult human tissues, including bone marrow (BM), adipose tissues (AT), umbilical cord blood (CB), and cord Wharton's jelly (WJ), in vitro and in vivo models. Results: AT-MSCs, CB-MSCs, and WJ-MSCs effectively suppressed phytohemagglutinin (PHA)-induced T-cell proliferation as effectively as did BM-MSCs. Levels of interferon (IFN)-g secreted from activated T-cells increased over time, but these levels were significantly reduced when cocultured with each type of MSCs. In addition, expression of indoleamine 2,3-dioxygenase (IDO) increased in MSCs treated with IFN-γ via JAK/STAT1 signaling pathways. Treatment with anti-IFN-g antibodies, JAK1/2 inhibitor or STAT1 siRNA restored PHA-induced T-cell proliferation. Use of an antagonist, 1-methyl-L-tryptophan, also restored PHA-induced T-cell proliferation, suggesting that IDO contributes to IFN-g-induced immunosuppression in MSCs. Moreover, infusion of IFN-g-treated MSCs decreased symptoms for human peripheral blood-derived mononuclear cells-induced GvHD in NOD/SCID mice, which resulted in an increase of survival rate of in vivo GvHD model. Conclusion: These data indicate that IFN-γ produced by activated T-cells is correlated with induction of IDO expression in MSCs by IFN-γ receptor/JAK/STAT1 pathway, which resulted in suppression of T-cell proliferation. Our findings suggest that MSCs derived from BM, AT, CB, or WJ could be used for clinical treatment of allogeneic conflicts. Disclosures: No relevant conflicts of interest to declare.

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Bader, Cameron S., Henry Barreras, Casey O. Lightbourn, Sabrina N. Copsel, Dietlinde Wolf, Jingjing Meng, Jeonghyun Ahn et al. "The Innate Immune Sensor Sting Promotes Donor CD8+ T Cell Activation and Recipient APC Death Early after Preclinical Allogeneic Hematopoietic Stem Cell Transplantation". Blood 134, Supplement_1 (13 de noviembre de 2019): 3202. http://dx.doi.org/10.1182/blood-2019-130197.

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Graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplants (aHSCTs). Pre-HSCT conditioning typically consists of irradiation and drug administration resulting in the death of rapidly dividing cells and release of endogenous danger signals. These molecules drive the activation of antigen presenting cells (APCs) and the differentiation of allo-reactive donor T cells, leading to damage of particular host tissues characteristic of GVHD. Cell death following conditioning has promoted the hypothesis that sensors of cytoplasmic DNA damage in GVHD target tissues contribute to pro-inflammatory cytokine production. We identified a role for Stimulator of Interferon Genes (STING), an innate immune sensor, in GVHD using pre-clinical MHC-matched unrelated donor (MUD) aHSCT models. Here we show that STING rapidly promotes donor CD8+ T cell activation and recipient APC death early after aHSCT. To assess STING involvement immediately post-HSCT, cytokine mRNA expression was examined 48 hrs after transplant of MUD C3H.SW bone marrow (BM) + T cells into irradiated B6 wildtype (WT) or STING-/- recipients. Colon tissue from STING-/- recipients had >2x reduction in IFNβ, TNFα and IL-6 mRNA vs WT. MUD STING-/- HSCT recipients also experienced decreased weight loss, GVHD scores and skin pathology 6 wks post-HSCT vs WT. Double chimerism studies showed that the absence of STING in non-hematopoietic cells was responsible for GVHD amelioration. Conversely, a single dose of the highly specific STING agonist DMXAA given in vivo increased IFNβ, TNFα and IL-6 mRNA expression in WT, but not STING-/-, colon tissue 48 hrs after transplant and increased GVHD scores and lethality post-HSCT. Post-transplant cytoxan treatment abolished the ability of DMXAA to augment GVHD, supporting the notion that STING signaling increases donor T cell activation during aHSCT. To evaluate the potential impact of STING in the clinical setting, we transplanted C3H.SW BM + T cells into mice homozygous for a murine homologue of a human allele associated with diminished STING activity (STINGHAQ/HAQ) and found that these mice also exhibited diminished GVHD. Interestingly, our findings that STING deficiency ameliorates GVHD in MUD aHSCT contrasts to reported observations that STING deficiency can exacerbate GVHD after MHC-mismatched (MMUD) aHSCT (Fischer J, et al, Sci. Transl. Med. 2017). Since CD4+ and CD8+ T cells are central in MMUD and MUD GVHD, respectively, we hypothesized that STING's effect on the predominant T cell subset in each model may explain these seemingly paradoxical results in STING-/- vs WT recipients. Therefore, we transplanted MMUD BALB/c BM + CD8+ T cells into B6-WT and STING-/- mice and found that - in contrast to MMUD recipients of combined CD4+ and CD8+ T cells - STING-/- recipients developed lower GVHD clinical scores, reduced skin pathology and had lower frequencies of activated T cells 8 wks post-HSCT vs WT, supporting a role for STING in the promotion of CD8+ T cell-mediated GVHD. Next, we investigated if recipient APCs played a role in STING's enhancement of CD8+ T cell-mediatedGVHD. We found that STING-/- mice had greater frequencies and numbers of recipient splenic CD11b+CD11c+ APCs 1 day after MMUD B6 into BALB/c aHSCT (Fig. A). BALB/c-STING-/- APCs also expressed reduced MHC class I protein levels (Fig. B). Moreover, STING-/- recipient spleens contained lower numbers of donor CD8+ T cells producing IFNγ and TNFα (Fig. C). These data support the hypothesis that STING contributes to early activation of donor CD8+ T cells and elimination of recipient APCs. Next, to identify if the loss of host MHC II+ APCs affected subsequent donor CD4+ T cell activation, B6-Nur77GFP transgenic donor T cells were used to explicitly monitor T cell receptor signaling. Consistent with increased numbers of host MHC II+ APCs in the spleens of STING-/- recipients 1 day post-aHSCT, we found greater frequencies and numbers of donor Nur77GFP CD4+ T cells expressing GFP, CD69 and IFNγ in STING-/- spleens 6 days after transplant (Fig. D). In summary, our studies demonstrate that STING plays an important role in regulating aHSCT and provide one potential mechanism by which STING could promote CD8+ T cell-mediated GVHD yet diminish CD4+-mediated GVHD. Overall, our studies suggest this pathway can provide a target for new therapeutic strategies to ameliorate GVHD. Disclosures Blazar: BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-Founder; Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Alpine Immune Sciences, Inc.: Research Funding; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding. Levy:Heat Biologics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pelican Therapeutics: Consultancy, Research Funding.

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Thakkar, Astha, Diego Adrianzen Herrera, Shafia Rahman, Zhu Cui, Angelica D'Aiello, Amanda Lombardo, Fariha Khatun et al. "Allogeneic Stem Cell Transplantation in a Large Urban Cohort of North-American Adult T-Cell Leukemia/Lymphoma". Blood 136, Supplement 1 (5 de noviembre de 2020): 21–22. http://dx.doi.org/10.1182/blood-2020-140812.

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Introduction: Adult T-cell leukemia lymphoma (ATLL) is a rare hematologic malignancy caused by human T-cell lymphotropic virus (HTLV-1) with dismal cure rates and poor response to conventional chemotherapy. Allogeneic Hematopoietic Stem Cell Transplantation (AlloSCT) is the only therapeutic option which may offer the chance of long-term remission and cures in a subset of patients. We sought to investigate the outcomes of transplantation in one of the largest cohorts in North America. Methods: A retrospective chart review study was conducted using the North-American ATLL and the Hematopoietic Precursor Cell transplantation databases at Montefiore Medical Center from 2011 to 2020. Variables collected include age, sex, ethnicity, ATLL subtype, molecular profile, previous treatments, conditioning regimens, type of transplant, immunosuppressive regimen, progression free survival (PFS) post-transplant and overall survival (OS) post-transplant. Results: Fourteen patients with ATLL who received an AlloSCT from 2011-2020 were identified. Fifty-seven percent (8/14) of patients were male. Seventy-one percent (10/14) of patients were African American and twenty-nine percent (4/14) were Hispanic. Median age was 51 years. Sixty-four percent (9/14) of patients had Stage IV disease at the time of diagnosis. Forty-three percent (6/14) patients had acute and fifty-seven percent (8/14) had lymphomatous ATLL. Almost all patients (92%) were treated initially with EPOCH combination chemotherapy. Twenty-eight percent (4/14) of patients received interferon/zidovudine as bridge-to-transplant. Fifty-seven percent (8/14) of patients achieved complete remission (CR) prior to AlloSCT, 7% (1/14) were in partial remission, and 28% (4/14) were relapsed or refractory. Forty-three percent (6/14) of patients received SCT from a matched-related donor (MRD), 36% (5/14) from a haplo-identical donor and 21% (3/14) from a matched-unrelated donor (MUD). Ninety-three percent (13/14) of patients received a reduced-intensity conditioning (RIC) regimen pre-transplantation. Seven percent (1/14) received a myeloablative conditioning (MAC) regimen. RIC regimens consisted of fludarabine with melphalan +/- anti-thymocyte globulin (ATG) or fludarabine with cyclophosphamide with total-body irradiation in doses less than 500 cGy. Patients receiving haplo-identical SCT also received post-transplant cyclophosphamide (PTCy) for prevention of graft vs host disease (GVHD). The MAC regimen used included busulfan with cyclophosphamide at myeloablative doses. Twenty-eight percent (4/14) of patients relapsed post-alloSCT with a median relapse-free survival of 6 months (range 4-18 months). The median OS of the whole cohort was 27 months (8-82 months). Graft-versus-host disease (GVHD) developed in 28% (4/14) percent of patients. The most common manifestation was skin GVHD. Fifty-percent (7/14) of the patients are surviving to-date. Transplant-related mortality (TRM) at day 100 was 21% (3/14) of patients. Causes of death were complex and included several diagnoses in certain patients. The most frequent diagnoses associated with death were infection (28%), graft failure (14%), GVHD (14%), veno-occlusive disease of the liver (VOD) (7%), disease progression (14%) and unknown due to patient lost to follow-up (14%). The main infectious events included fungal (2), bacterial (1), and COVID-19 (1) infection. Forty-three percent (6/14) of patients remain in complete remission to date. Conclusions: Allogeneic Stem Cell Transplantation offers long-term survival with a TRM of 21% in a disease with an inherently dismal prognosis. AlloSCT using several graft sources, is thus, a safe and well tolerated treatment modality and offers long term remissions. Disclosures Steidl: Pieris Pharmaceuticals: Consultancy; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Research Funding; Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; Medpacto: Research Funding; stelexis: Current equity holder in private company. Janakiram:ADC Therapeutics, FATE therapeutics, TAKEDA pharmaceuticals: Research Funding.

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Hubbard, Vanessa M., Jeffrey M. Eng, Teresa Ramirez-Montagut, Kartono H. Tjoe, Stephanie J. Muriglan, Adam A. Kochman, Theis H. Terwey et al. "Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation". Blood 106, n.º 9 (1 de noviembre de 2005): 3285–92. http://dx.doi.org/10.1182/blood-2005-01-0410.

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AbstractInducible costimulator (ICOS) is expressed on activated and memory T cells and is involved in the regulation of cytokine production. We studied the role of ICOS on alloreactive T cells in graft versus host disease (GVHD) and determined that ICOS expression was up-regulated on alloreactive T cells in recipients of an allogeneic hematopoietic stem cell transplantation (allo-HSCT) with GVHD. We compared ICOS-/- T cells with wild-type (WT) T cells in 2 GVHD models. In both models, recipients of ICOS-/- T cells demonstrated significantly less GVHD morbidity and mortality, which was associated with less intestinal and hepatic GVHD but increased cutaneous GVHD. In addition, recipients of ICOS-/- donor T cells displayed a slight decrease in graft versus leukemia (GVL) activity. Further analysis of alloreactive ICOS-/- T cells showed no defect in activation, proliferation, cytotoxicity, and target organ infiltration. Recipients of ICOS-/- T cells had decreased serum levels of interferon-γ (IFN-γ), while interleukin-4 (IL-4) and IL-10 levels were increased, suggesting that alloreactive ICOS-/- T cells are skewed toward T helper-2 (Th2) differentiation. These data suggest a novel role for ICOS in the regulation of Th1/Th2 development of activated T cells. In conclusion, alloreactive ICOS-/- donor T cells induce less GVHD due to a Th2 immune deviation while GVL activity is slightly diminished.

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Bader, Cameron S., Henry Barreras, Casey O. Lightbourn, Sabrina Copsel, Jeonghyun Ahn, Glen N. Barber, Lei Jin y Robert B. Levy. "The Innate Immune Sensor Sting Regulates Intestinal Inflammation and GVHD after Allogeneic Hematopoietic Stem Cell Transplantation in Knock-out and Human Allele Knock-in Recipient Mice". Blood 132, Supplement 1 (29 de noviembre de 2018): 65. http://dx.doi.org/10.1182/blood-2018-99-109999.

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Abstract Graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplants (allo-HSCTs). Pre-HSCT conditioning typically consists of irradiation and drug administration resulting in the death of rapidly dividing cells. Damage to host tissues initiates a cytokine storm, promoting activation and expansion of donor anti-host alloreactive T cells. Cell death following conditioning has promoted the hypothesis that sensors of cytoplasmic DNA damage in GVHD target tissues contribute to cytokine production. We identified a role for Stimulator of Interferon Genes (STING), an innate immune sensor, in GVHD using pre-clinical MHC-matched (MUD) allo-HSCT models. Our studies show that the STING pathway rapidly regulates cytokine production in the intestinal tract and non-hematopoietic cells can contribute to these responses. Using mice expressing a human STING allele associated with decreased STING activity (Patel S, et al, J Immunol. 2016), we demonstrate its potential clinical importance. To assess STING involvement immediately post-HSCT, cytokine mRNA expression was examined 48 hrs after transplant of C3H.SW bone marrow (BM) + T cells into irradiated B6-WT or STING-/- recipients. Colonic tissue from STING-/- recipients had >2x reduction in IFNβ, TNFα and IL-6 mRNA vs. WT. On day 10 post-transplant, colons from STING-/- recipients exhibited reduced inflammation and overall pathology scores than WT. MHC-matched STING-/- HSCT recipients also experienced decreased weight loss, GVHD scores and skin pathology 6 weeks post-HSCT vs. WT. Chimeric studies demonstrated that the absence of STING in non-hematopoietic cells was responsible for the amelioration of GVHD. Therefore, to test STING signaling in non-hematopoietic intestinal cells, we generated intestinal organoid cultures. Intestinal organoids upregulated IFNβ, TNFα, IL-6 and CXCL10 mRNA 6hrs after stimulation with the highly specific STING agonist DMXAA, supporting the notion that STING in intestinal tissues can contribute to inflammation in vivo. Interestingly, expression of these cytokines returned to baseline levels 24 hrs after stimulation (Fig. 1A). Next, we posited that if the absence of the STING pathway in recipients ameliorated GVHD after MHC-matched HSCT, pathway stimulation would exacerbate GVHD. B6-WT mice were injected with DMXAA immediately prior to HSCT with donor C3H.SW BM + T cells. Administration of a single dose of DMXAA increased expression of IFNβ, TNFα and IL-6 mRNA in colon tissue 48 hrs after transplant (Fig. 1B). Importantly, DMXAA treatment of WT - but not STING-/- - recipients significantly increased GVHD scores and lethality post-HSCT. To evaluate the potential impact of STING in the clinical setting, we evaluated recipients after transplant of C3H.SW BM + T cells into mice homozygous for a human allele associated with diminished STING activity (HAQ-MPYS knock-in mice, termed B6N-STINGHAQ/HAQ here) and found that STINGHAQ/HAQ mice contained a lower frequency of donor T cells expressing an activated phenotype (CD44hiCD62Llo) vs. WT recipients and the former also exhibited diminished GVHD (Fig. 1C,D). In contrast to STING knock-out recipients completely lacking protein, these results indicate that reduced STING activity can also affect GVHD. Interestingly, our findings that STING deficiency ameliorates GVHD in MHC-matched allo-HSCT contrast reported observations that STING activation can exacerbate GVHD after MHC-mismatched HSCT (Fischer J, et al, Sci. Transl. Med. 2017). We are currently investigating how the STING pathway regulates CD4+ and CD8+ T cell mediated GVHD and initial findings may provide insight into understanding the pathway's involvement in MHC-matched vs. mismatched allo-HSCT. In total, our studies demonstrate that STING plays an important role in regulating allo-HSCT and suggest this pathway can provide a target for new therapeutic strategies to ameliorate GVHD. Disclosures Levy: Allergan: Consultancy; Capricor Therapeutics: Consultancy; HEAT Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pelican Therapeutics: Consultancy; OccuRx: Research Funding; Shire: Research Funding.

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Herblot, Sabine, Valérie Paquin, Paulo Cordeiro y Michel Duval. "Adoptive Transfers of Plasmacytoid Dendritic Cells after Hematopoietic Stem Cell Transplantation Decrease the Risk Acute Lymphoblastic Leukemia Relapse without Increasing the Risk of Graft-Versus-Host-Disease". Blood 132, Supplement 1 (29 de noviembre de 2018): 2053. http://dx.doi.org/10.1182/blood-2018-99-111130.

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Abstract Despite advances in chemotherapy and hematopoietic stem cell transplantation (HSCT), the outcome of children with relapsed acute lymphoblastic leukemia (ALL) has not significantly improved over the last 2 decades. About 50% of children with relapsed leukemia still die from their disease and ALL is still the first cause of death by cancer in children. A new hope of cure for patients with chemo-resistant cancers has emerged with the development of cancer immunotherapy. However, the major risk of post-transplant immunotherapy is the exacerbation of life-threatening Graft-versus-Host Disease (GvHD) mediated by donor-derived T cells. We therefore explored the avenue of innate immune stimulation. Several reports have demonstrated that activated Natural Killer (NK) cells can control acute myeloid leukemia (AML) in transplanted patients, whereas ALL is deemed to be resistant to NK cell killing. We recently challenged this paradigm and demonstrated that the stimulation of NK cells with third-party activated plasmacytoid dendritic cells (pDC) killed most ALL cell lines and patient-derived ALL blasts. We further demonstrated the efficacy of pDC adoptive transfers to cure ALL in a humanized mouse model of HSCT. Collectively, these results uncovered for the first time the unique therapeutic potential of activated pDC as immunotherapeutic tools to stimulate NK cell anti-leukemic activity early after HSCT. The next step toward the clinical translation of pDC-based post-transplant immunotherapy is to verify that adoptive transfers of pDC do not stimulate T cells nor exacerbate GvHD in the presence of mature T cells. We designed a GMP-compliant method for in vitro expansion and differentiation of cord blood progenitors giving rise to sufficient numbers of pDC for adoptive transfers in patients. We showed that after Toll-like receptor (TLR) stimulation, these in vitro differentiated pDC displayed a phenotype of interferon producing cells (CD80neg PDL-1+) but not of antigen presenting cells (CD80+PDL-1neg). Accordingly, in vitro mixed lymphocyte reactions with purified allogeneic T cells demonstrated that TLR-activated pDC induced very low allogeneic T cell proliferation as compared with bona fide antigen presenting cells such as myeloid dendritic cells (mDC - CD11c+) or monocyte-derived dendritic cells (mo-DC) (Figure 1A). To test whether activated pDC could exacerbate GvHD in the presence of mature T cells, we used a xenoGvHD model in which human peripheral blood mononuclear cells (PBMC) were injected in immune-deficient mice (Nod/Scid/gRc-/-, NSG). We monitored GvHD 3-times a week according to a GvHD-assessment scale as previously described. Overt GvHD was characterized by cutaneous and intestinal lesions, weight loss and high numbers of human CD3+ cells in peripheral blood. Mice were sacrificed when endpoints were reached and GvHD was confirmed by immunohistochemistry and flow cytometry. Five weekly injections of TLR-activated in vitro differentiated pDC did not accelerate the GvHD onset and the severity of the lesions were not increased. We did not either observe any difference in survival between control and pDC-treated groups (Figure 1B). Collectively, our results indicate that TLR-activated pDC do not stimulate allogeneic T cells and do not increase the risk of acute GvHD in a mouse model of xenoGvHD. We therefore expect this novel pDC-based immunotherapy to be safe for transplanted patients. These data open the way for the next step: a Phase I clinical trial of in vitro differentiated pDC after transplantation for leukemia. Disclosures No relevant conflicts of interest to declare.

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Li, Jian-Ming, Kataryna A. Darlak, Ying Lu, Cynthia Giver, Wayne Harris, David L. Jaye y Edmund Waller. "CD11b− Donor Dendritic Cells Enhance Donor T-Cells’ Th1 Polarization and Graft Versus Leukemia Activity in Allogeneic Hematopoietic Stem Cell Transplantation". Blood 112, n.º 11 (16 de noviembre de 2008): 1252. http://dx.doi.org/10.1182/blood.v112.11.1252.1252.

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Abstract Background: Based on a clinical association of donor plasmacytoid dendritic cell (DC) content with leukemia relapses after allogeneic BMT (Waller, Blood 2001), we have previously reported that CD11b− donor DC added to a graft containing FACS-purified hematopoietic stem cells (HSC) and T-cells enhanced interferon-γ (IFN-γ) production and GvL activity in MHC-mismatched allogeneic transplant mouse models (Li, Blood 2007). Objective: In this study, we studied the mechanisms whereby donor DC in the graft modulate donor T-cell activity and the graft-versus-leukemia (GvL) effect in MiHA (C3H.SW → C57BL/6J)- and MHC (C57BL/6J → B10.BR)- mismatched models of allogeneic hematopoietic stem cell transplantation (HSCT). Methods: Mice irradiated to 11 Gy received 5 × 104 log-phase viable MMB3.19 myeloid lymphoma cells via intraperitoneal injection or intravenous injection of 1 x 105 LBRM T-cell lymphoma cells one day before transplant. Allografts consisted of 5 × 104 FACS-purified donor BM CD11b− DC or CD11b+ DC plus 3 × 103 FACS-purified c-kit+ sca-1+ lineage− hematopoietic stem cells (HSC) in combination with either 3 × 105 T-cells, 3 × 105 CD8+ T-cells or no additional T-cells transplanted via tail vein. Graft-versus-host disease (GvHD) clinical scores (based on body weight loss, posture, skin, fur texture, activity) were recorded twice weekly in non-tumor bearing recipients. In vitro proliferation and cytotoxic activity of donor-derived T-cells against tumor targets was assessed by CFSE staining and a caspase flow cytometry assay (CyToxiLux PLUS) using donor T-cells harvested from recipients on day 34 and day 82 post transplant. Serum and intracellular Th1 cytokines (IFN-γ, IL-2, and TNF-α) and Th2 cytokines (IL-4, IL-5, and IL-10) from recipients’ peripheral blood and spleens day 3 and day 10 post-transplant was measured by ELISA and flow cytometry. IFN-γ direct killing of leukemia cells was tested by in vitro IFN-γ exposure. Results: In non-tumor bearing mice, recipients of all combinations of donor DC subsets, with and without donor T-cells had equivalent survival (75% – 85%) at 3 months post transplant without significant clinical signs of GvHD. Transplantation of tumor cells to recipients of HSC alone, HSC plus donor T-cells, or HSC plus T-cells and CD11b+ DC in the MiHA- and the MHC-mismatched transplant models led to 0% or 5% 3 month survival, respectively. Strikingly, tumor-bearing mice transplanted with CD11b− DC had significantly enhanced 3 month survival (35% in the MiHA-mismatched model and 45% in the MHCmismatched model) without increased GvHD (p<0.001). There was no significant difference in survival between mice that received HSC plus CD11b− DC and a mixture of CD4+ and CD8+ donor T-cells versus mice that received HSC plus CD11b− DC and only CD8+ donor T-cells. Donor T-cells harvested from recipients of CD11b− DC 34 days after transplant in the MiHA-mismatched model as well as 82 days after transplant in the MHC-mismatched model displayed increased cell proliferation following co-culture with irradiated hosttype splenocytes as a source of alloantigen compared with donor T-cells harvested from recipients of CD11b+ DC or recipients of HSC plus T-cells without donor DC. Leukemia cell killing was greater following incubation of purified donor T-cells recovered from recipients of CD11b− DC with tumor targets compared to T-cells recovered from other treatment groups. Recipients of CD11b− DC had higher serum levels of Th1 cytokines IFN-γ and IL-2 and higher number of Th1 positive donor T-cells compared with recipients of other treatment groups. In contrast, recipients of CD11b+ DC had higher serum levels of Th2 cytokines IL-4, IL-5, and IL-10 and higher number of Th2 positive donor T-cells. IFN-γ added to in vitro cultures with MMB3.19, and LBRM, had no direct cell killing effect. Conclusion: CD11b− donor DC enhanced Th1 polarization of donor T-cells and GvL without increasing GvHD. Donor CD8+ T-cells mediated tumor killing effect. CD11b+ donor DC enhanced Th2 polarization of donor CD4+ T-cells and led to limited GvHD and GvL.

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Tang, XiaoWen, Qianlan Zhou, Zhengming Jin, Chengcheng Fu, Chunmei Ye, Xiaolan Shi, Xiaohui Hu et al. "Novel Therapy with Interferon-α in Combination with Donor Lymphocyte Infusion for High Risk Acute Leukemia Patients Who Relapsed After Allogeneic Hematopoietic Stem Cell Transplantation". Blood 118, n.º 21 (18 de noviembre de 2011): 658. http://dx.doi.org/10.1182/blood.v118.21.658.658.

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Abstract Abstract 658 Background Relapse remains a major cause of failure for allogeneic stem cell transplantation (allo-HSCT). Donor lymphocyte infusion (DLI) is routinely employed as salvage for patients who relapsed after allo-HSCT. In order to improve the graft versus leukemia (GVL) effect of DLI, we investigated the efficacy and safety of combining interferon-α with DLI (aDLI) in patients with high risk acute leukemia who relapsed after allo-HSCT, and compared the efficacy, toxicity and leukemia free survival (LFS) of aDLI and traditional donor lymphocyte infusion(tDLI)in our transplantation center. Methods Sixteen acute leukemia patients were enrolled in this study. All patients were treated with interferon-α-2b therapy at a dose of 3×106U/day subcutaneously for 5 days followed by G-CSF mobilized donor peripheral stem cell infusion. IFN-α treatment continued until complete remission or development of graft-versus-host disease (GVHD). We coined the term “aDLI” for this novel treatment protocol. The median duration of interferon-α treatment was 17 (range, 5–50) days, and the median CD3+ cells dose was 9.25×107/kg(range, 4–20×107/kg)of recipient weight. Bone marrow smear, real-time PCR, STR-PCR,FISH,cytogenetic analysis and flow cytometry were used to monitor engraftment and minimal residual disease. In parallel, we retrospectively analyzed the results of tDLI for 14 acute leukemia patients with hematological relapse post allo-HSCT treated in the same period in our transplantation center, and compared the efficacy, toxicity and LFS of tDLI with aDLI. Results Patients treated on the aDLI protocol included 9 ALL and 7 AML, with a median age of 26.5 years. Fourteen of 16 patients had high risk acute leukemia: 3 patients with Ph+ ALL, 6 patients relapsed after CR1, 4 patients had complicated chromosome abnormality, and 1 patient had testicular leukemia. The median relapse time was 5.5 (range, 1–25) months post transplant. Salvage chemotherapy was administrated in 7 patients before aDLI, with only 3 patients achieved CR. The overall complete remission (CR) rate for aDLI protocol was 75% (12/16), with CR rate of aDLI alone without chemotherapy at 66.7% (6/9). The median time from aDLI to bone marrow CR was 7(range, 6–14)days, and the median time to molecular complete remission (MCR) and full donor chemerism (median level was 96.3%) in responsive patients was 2 weeks post DLI. With a median follow-up of 5.5 (range, 1–34) months, 7 patients were alive with durable MCR. Two-year LFS was 50%. Treatment related toxicities included reversible episode of fever, GVHD and myelosuppression. The tDLI group had similar demographic characteristics with respect to age, disease subtypes, transplant and relapse history. Compared to tDLI, the aDLI protocol had higher CR rate (75.0% vs 14.3%, p =0.001), faster response (median time to obtain BM CR and full donor chimerism were 7 days vs 23 days, and 30 days vs 60 days respectively), higher incidence of acute GVHD (56.3 % vs 27.3%, p=0.05), and significant better 2-year LFS(50.0% vs 7.1%,p=0.05. Importantly, there was no significant difference between the two groups with respect to the incidence of pancytopenia (53.8% vs 75%, p>0.05) and treatment related mortality(18.8% vs 7.1%, p>0.05). Conclusion Interferon-α-2b in combination with donor lymphocyte infusion appears to induce rapid and durable remissions in high risk acute leukemia patients who relapsed following allo-HSCT, with acceptable treatment-related toxicity. This novel adoptive immunotherapeutic strategy warrants additional studies in allo-HSCT settings Disclosures: No relevant conflicts of interest to declare.

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Chen, Xiaochuan, Chien-Hsing Chang, Rhona Stein, Thomas M. Cardillo, David V. Gold y David M. Goldenberg. "Prevention of Acute Graft-Versus-Host Disease in Human/Mouse Xenogeneic SCID Mouse Model by Humanized Anti-CD74 Monoclonal Antibody, Milatuzumab". Blood 120, n.º 21 (16 de noviembre de 2012): 4105. http://dx.doi.org/10.1182/blood.v120.21.4105.4105.

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Abstract Abstract 4105 Introduction: Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation. Prevention and treatment of GVHD remains a major challenge, because current T-cell depletion and mainstay immunosuppressive therapies compromise preexisting T-cell immunity, leading to severe infections and disease relapse. Thus, novel anti-GVHD agents that can spare protective T-cell memory are critically needed. Milatuzumab (hLL1) is a humanized anti-CD74 antagonist IgG1κ monoclonal antibody (mAb) currently under clinical investigation as a therapeutic mAb for relapsed or refractory B-cell malignancies. Since CD74 is widely expressed in both hematopoietic and non-hematopoietic antigen-presenting cells (APCs), and because host APCs, especially non-hematopoietic APCs, play an important role in initiating GVHD, whereas donor APCs contribute and are required to maximize GVHD, we reasoned milatuzumab could affect recipient or donor APCs, thereby modulating GVHD. We report herein the in vitro effect of milatuzumab on the survival and function of human blood APCs and T cells, including CMV-specific T cells, and the in vivo therapeutic efficacy on preventing acute GVHD in a humanized SCID mouse model. Methods: The effects of milatuzumab on APCs and T cells in human peripheral blood mononuclear cells (PBMCs) were assessed by multi-color flow cytometry. The effect of milatuzumab on the proliferation of T cells and T cell subsets in allogeneic mixed lymphocyte reactions (allo-MLRs) was measured by CFSE labeling of allogeneic PBMCs that were mixed to each other and cultured for 11 days before flow cytometric analysis of the proliferating cells that lost fluorescence. The impact of milatuzumab on preexisting anti-viral T-cell immunity was evaluated by intracellular staining of CD3+CD8+IFN-γ+T cells in allo-MLRs upon stimulation with HLA-A2-restricted cytomegalovirus (CMV) pp65 peptide (NLVPMVATV). The therapeutic effect of milatuzumab on acute GVHD was evaluated in a human PBMC-transplanted SCID mouse model, in which GVHD is developed and mediated by engrafted human T cells and DCs. Results: Milatuzumab moderately reduces the number of myeloid DC type 1 (mDC1), myeloid DC type 2 (mDC2), and B cells in PBMCs, but has little effect on plasmacytoid DC (pDC), monocytes, or T cells, which correlates with the level of CD74 expression on these cells. As a consequence, milatuzumab inhibits the proliferation of total T cells, CD4 and CD8 T cell subsets in allo-MLRs. In a human/mouse xenogeneic SCID mouse model, milatuzumab effectively prevents the onset and manifestations of acute GVHD, suppresses the serum levels of human interferon-g and IL-5, eliminates the infiltration of human lymphocytes in GVHD target organs (lung, liver and spleen), and significantly promotes the survival of animals (90% versus 20% for controls, P=0.0012). Furthermore, exposure to milatuzumab does not affect the number of CMV-specific, IFN-γ-producing, human CD8+ T cells in allo-MLRs. Conclusion: CD74 is a potential target for antibody-mediated mitigation of GVHD, as demonstrated by the encouraging results obtained with milatuzumab. Further exploration of milatuzumab as a new therapeutic agent for GVHD is warranted. Disclosures: Cardillo: Immunomedics, Inc: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

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Elimelakh, Milena, Ted Eastlund, Mark Reding, Todd DeFor y Linda Burns. "Incidence and Outcomes of Immune Thrombocytopenia (ITP) Following Hematopoietic Stem Cell Transplantation (HCT)." Blood 110, n.º 11 (16 de noviembre de 2007): 1316. http://dx.doi.org/10.1182/blood.v110.11.1316.1316.

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Abstract While thrombocytopenia is common following HCT, and has been associated with delayed engraftment, disease relapse, infections and drugs, autoantibody mediated ITP is rarely observed. In one series of non-Hodgkin’s lymphoma patients, development of ITP following autologous HCT (autoHCT) was associated with long-term disease free survival (Hequet et al. Bone Marrow Transplant2003; 32:89). Limited data is available on occurrence and prognosis of ITP following allogeneic HCT (alloHCT). Here we report the incidence and outcomes of ITP in 1700 adults who underwent autoHCT (n=749) and alloHCT (n=951) between January 1990 and December 2004. Of the alloHCT recipients, 531 patients received stem cells from a sibling donor (SD), 268 from an unrelated donor (URD), and in 147 patients umbilical cord blood (UCB) was used as the stem cell source. ITP was defined according to the American Society of Hematology guidelines for diagnosis of ITP (Ann Intern Med1997; 126:319). In addition, a confirmatory bone marrow examination demonstrating adequate megakaryocyte numbers and morphology and absence of CMV viremia were required. Patients receiving interferon therapy around the time of ITP diagnosis were excluded. Recovery from ITP was defined as a sustained increase in platelet count to 140 x 109/liter (l). Ten patients (median age 37 years [range 25–51]), including 7 alloHCT and 3 autoHCT recipients developed ITP at a median 15 months (range 4–76) post transplant, with an overall cumulative incidence of 0.8% at 5 years (95% confidence interval [CI] 0.3–1.6%). Of the alloHCT recipients, four patients received one or two antigen mismatched UCB HCT, two received matched HCT from an URD and one a SD HCT. The overall cumulative incidence of ITP at 5 years was highest among UCB HCT recipients (3%; 95% CI 0–6%) as compared to SD (0.2%; 95%CI 0–0.5%) and URD (0.7%; 95% CI 0–1.7%) HCT recipients (p<0.01). Nine (7 alloHCT and 2 autoHCT) recipients were transplanted for hematologic malignancy and one autoHCT patient for metastatic breast cancer. Nine of ten patients received myeloablative conditioning regimen. Six of the seven alloHCT recipients received cyclosporin for graft versus host disease (GVHD) prophylaxis. ITP was severe, with a nadir platelet count of 10 x 109/l in all patients. Platelet antibodies were present in 50% (3 of 6) of patients tested. Nine of the ten patients were in complete remission from their underlying malignancy at the time of ITP diagnosis. ITP was steroid refractory in the majority of patients, and required multiple treatment modalities. All alloHCT recipients with ITP developed chronic GVHD and systemic viral infections. While nine patients recovered, one autoHCT recipient died of multi-organ hemorrhage at 76 months post HCT. At a median follow-up of 61 months, seven patients are still alive and disease free, while two additional patients died (one from relapsed acute myeloid leukemia 32 months and one from pulmonary Aspergillosis 154 months post HCT). In summary, we found ITP to be a rare complication of HCT, with the highest incidence in recipients of UCB HCT. While the majority of patients eventually recovered from ITP and achieved long-term overall survival, the illness was severe, associated with chronic GVHD and serious viral infections. Degree of antigenic disparity, immune dysregulation, development of autoimmunity and its contribution to maintenance of disease control after transplantation may be implicated in pathogenesis of ITP following HCT.

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Kuroda, Rie, Shintaro Mase, Toshihiro Fujiki, Hideaki Maeba, Raita Araki, Yasuhiro Ikawa, Masaki Fukuda, Shoichi Koizumi, Akihiro Yachie y Ryosei Nishimura. "Third Party Cytokine-Induced Killer Cells Protect from Murine Lethal Graft-Versus-Host Disease". Blood 126, n.º 23 (3 de diciembre de 2015): 3092. http://dx.doi.org/10.1182/blood.v126.23.3092.3092.

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Abstract Cell adoptive immunotherapy protect from lethal graft-versus-host disease (GVHD) while preserving graft-versus-tumor effects is ideal in allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. Moreover, the use of third party cells would open a huge source of availability and feasibility across major histocompatibility barriers. In fact, some studies demonstrated that infusion of third party derived cells such as whole bone marrow cells or iNKT cells could ameliorate lethal GVHD in a murine model. Cytokine-induced killer (CIK) cells are ex vivo-expanded T lymphocytes expressing both natural killer and T-cell markers. We have previously reported that donor-type CIK cells have potential to separate graft-versus-tumor effects from GVHD by eliminating host dendritic cells due to the enhanced killing activity by interferon-gamma. Actually, donor-typed CIKs infusion for refractory hematological malignancies after HSCT has been started in some clinical trails. In the present study, we examine the effect of third party cells against GVHD protection, in particular third party CIK cells for prevention from lethal GVHD in a murine model of allogeneic HSCT. To test this, lethally irradiated host Balb/c (H-2d) mice were given C3H (H-2k) or B6 (H-2b) bone marrow cells and splenocytes to induce lethal GVHD with/without third-party cells (C57/BL6 or C3H) such as CIK cells, whole splenocytes, or bone marrow derived dendritic cells (BMDCs) on day 0, which were cultured from bone marrow cells with GM-CSF. Mice receiving third party CIK cells showed much less GVHD and significant survival benefit compared those with third party splenocytes, or BMDCs as shown in the figure below. Interestingly, when infusion of third party splenocytes was delayed until day 4 after bone marrow transplantation, host mice receiving splenocytes survived much better compared with mice receiving splenocytes on day 0, even though reduced number of third party splenocytes was used. This result indicated that timing of third party cell infusion was quite important, especially when third party splenocytes were used. As expected, the mice given reduced number of third CIK cells also showed excellent survival with much less GVHD. Taken together, our results clearly demonstrated that third party CIK cells have strong potential to prevent lethal GVHD without attention to timing of cell infusion. Next, to further investigate the advantage of third party CIK cells rather than whole splenocytes, we compared the hematological reconstitution between the mice given third party CIK cells on day 4 after BMT and whole splenocytes. Both mice showed much less GVHD with the same level, however the recovery of white blood cell count on day 21 after BMT was significantly better in the mice receiving third party CIK cells. In conclusion, infusion of third party CIK cells has strong potential to prevent lethal GVHD with faster hematological recovery after HSCT. Disclosures No relevant conflicts of interest to declare.

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