Articles de revues : « GvL and GvHD »

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Litvinova, Elena, Sébastien Maury, Olivier Boyer, Sylvie Bruel, Laurent Benard, Gilbert Boisserie, David Klatzmann et José L. Cohen. « Graft-versus-leukemia effect after suicide-gene–mediated control of graft-versus-host disease ». Blood 100, n^o 6 (15 septembre 2002) : 2020–25. http://dx.doi.org/10.1182/blood-2002-01-0161.

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Abstract Clinical data indicate that after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies, the graft-versus-leukemia (GVL) effect is in large part mediated by the graft-versus-host reaction (GVHR), which also often leads to graft-versus-host disease (GVHD). Controlling alloreactivity to prevent GVHD while retaining GVL poses a true dilemma for the successful treatment of such malignancies. We reasoned that suicide gene therapy, which kills dividing cells expressing the thymidine kinase (TK) “suicide” gene using time-controlled administration of ganciclovir (GCV), might solve this dilemma. We have previously shown that after infusion of allogeneic TK T cells along with HSCT to an irradiated recipient, an early and short GCV treatment efficiently prevents GVHD by selectively eliminating alloreactive T cells while sparing nonalloreactive T cells, which can then contribute to immune reconstitution. Nevertheless, it remained to be established that this therapeutic strategy retained the desired GVL effect. Hypothesizing that a contained GVHR would be essential, we evaluated the GVL effect using different protocols of GCV administration. We were able to show that when the GCV treatment is initiated at, or close to, the time of grafting, GVHD is controlled but GVL is lost. In contrast, when the onset of GCV administration is delayed until day 6, a potent GVL effect is retained while GVHD is still controlled. These data emphasize that, by a time-optimized scheduling of the administration of GCV, this TK/GCV strategy can be tuned to efficiently treat malignant hemopathies.

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Johnson, B. D., C. McCabe, C. A. Hanke et R. L. Truitt. « Use of anti-CD3 epsilon F(ab')2 fragments in vivo to modulate graft-versus-host disease without loss of graft-versus-leukemia reactivity after MHC-matched bone marrow transplantation. » Journal of Immunology 154, n^o 10 (15 mai 1995) : 5542–54. http://dx.doi.org/10.4049/jimmunol.154.10.5542.

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Abstract The use of T cell-specific mAb in vivo for prevention and treatment of graft-vs-host disease (GVHD) and its impact on graft-vs-leukemia (GVL) reactivity was examined in a murine model of MHC-matched bone marrow transplantation (BMT). F(ab')2 fragments of a CD3 epsilon-specific mAb were administered to irradiated AKR (H-2k) hosts after transplantation of BM plus spleen cells from B10.BR donors (BMS chimeras). The effects on GVH and GVL reactivity were Ab dose- and schedule-dependent. A short course of mAb (qe2d, days 0 to 8) prevented clinical evidence of GVHD and mortality. Anti-CD3 F(ab')2 mAb reversed clinical symptoms of acute GVHD when delayed up to 18 days post-transplant. Anti-host (Mls-1a)-specific V beta 6+ cells were absent from the spleens of GVH-negative control mice, but persisted in Ab-treated BMS chimeras despite the absence of GVHD. Leukemic mice given 16.7 micrograms of Ab on days 0, 2, and 4 survived leukemia-free without developing severe GVHD. A longer course of Ab completely prevented GVHD, but led to leukemia relapse in tumor-bearing hosts, despite engraftment of donor T cells. The GVL effect was quantitatively stronger when Ab was used for GVH therapy as compared with GVH prevention. Some Ab-treated, GVH-free chimeras relapsed with lymphomas in unusual sites, suggesting that occult tumor cells may persist in nonlymphoid tissues. These experiments demonstrate that T cell-specific mAb can be used successfully in vivo to avoid severe GVHD, but that excessive or ill-timed administration of Ab may eliminate GVL reactivity.

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Jadi, Othmane, Hancong Tang, Junke Wang, Dante Bortone, Steven Vensko, Loreall Pooler, Xin Sheng et al. « Associations of Clinical Outcomes after Allogeneic Hematopoietic Cell Transplantation with Number of Predicted Class II Restricted mHA ». Blood 136, Supplement 1 (5 novembre 2020) : 2. http://dx.doi.org/10.1182/blood-2020-142017.

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Background: Leukemia relapse after allogeneic hematopoietic cell transplantation (alloHCT) has been associated with loss of heterozygosity of class II HLA, suggesting that T cells targeting leukemia via class II interactions may be critical for graft-vs-leukemia (GvL) effects and protection from relapse (Zeiser & Vago, 2019). Therefore, we aimed to determine whether the number of predicted class-II restricted minor histocompatibility antigens (mHAs) in alloHCT recipients associates with clinical outcome. Specifically, we investigated: (1) if the number of mHAs expressed on leukemia and bone marrow cells (GvL mHAs) is correlated with incidence of leukemia relapse, and/or (2) if mHAs expressed on acute graft versus host disease (GvHD) target organs (GvH mHAs) correlated with incidence of GvHD. We expected increased GvL mHAs to be associated with increased survival, and increased GvH mHAs to be associated with increased incidence of GvHD. Methods: The study population was derived from donor-recipient alloHCT pairs (DRPs) treated for Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), and Myelodysplastic Syndrome (MDS) from the CIBMTR and previously analyzed in DISCOVeRY-BMT. To predict HLA class II restricted mHAs in alloHCT recipients, we translated nonsynonymous single nucleotide variants present in each recipient, but absent in their respective donor, into all possible peptides 15-24 amino acids long. We used netMHCIIpan to score these peptides and select those most likely to be presented (Reynisson et al., 2020). Predicted mHAs highly expressed in skin, hepatobiliary, and bowel tissues were classified as GvH mHAs, and those highly expressed highly in, testis, and bone marrow were classified as GvL mHAs. The impact of mHA on disease related mortality (DRM), leukemia free survival (LFS), disease relapse and death due to GVHD were assessed with competing risk models. We next determined whether knowledge of the number of GvL and GvH mHAs improves the ability of models to predict clinical outcome. We fit optimal logistic regression models (elastic net regularization with Monte Carlo cross validation) to predict GvHD mortality and relapse mortality at 1 year after alloHCT using: (1) clinical data only, and (2) both clinical data and number of GvH/GvL mHAs. Lastly, using the same regularization and cross-validation procedures as above, we determined which variables contributed most to the Cox regression models of overall survival. Results: The number of GvL-restricted and GvH-restricted class-II mHAs were significantly correlated (Figure 1). Patients who died of disease before 1 year after alloHCT had significantly fewer GvL mHAs when controlling for covariates (HR=.89, 95% CI .89, .99, P= 0.04) (Figure 2). There was no association between GvL mHAs and LFS or relapse. Surprisingly, death due to GvHD by 1 year after alloHCT was lower for recipients with more GvL mHAs (HR=.88, 95% CI= .76, 1.01 , P=.08) (Figure 3), however, because GvH and GvL mHAs are highly correlated, we believe this reflects better overall survival associated with increased GvL mHAs. Neither the predictive models that included the number of GvH/GvL mHAs nor the Cox regression models fitted with GvL mHA numbers performed better than models trained on clinical data alone (Figure 4). Conclusions: GvL mHAs were inversely associated with DRM at 1-year post-alloHCT as expected. Contrary to our hypothesis, the number of GvH mHAs was inversely associated with GvHD mortality at 1 year. This may reflect better overall survival associated with increased GvL mHAs, as GvH and GvL mHAs are highly correlated. The potential association between class-II mHAs and DRM warrant further investigation and validation. If validated, this supports the development of class-II mHA targeted immunotherapies. Disclosures Pasquini: Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. Armistead:GeneCentric: Consultancy; Cell Microsystems: Patents & Royalties: Patent application U.S. 16/347,104 "Automated collection of a specified number of cells". Vincent:GeneCentric Therapeutics: Consultancy.

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Das, Rupali, Richard Komorowski, Martin J. Hessner, Hariharan Subramanian, Claudia S. Huettner, Daniel Cua et William R. Drobyski. « Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses ». Blood 115, n^o 25 (24 juin 2010) : 5249–58. http://dx.doi.org/10.1182/blood-2009-11-255422.

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Abstract Allogeneic stem cell transplantation is the most potent form of effective adoptive immunotherapy. The graft-versus-leukemia (GVL) effect mediated by the allogeneic graft, however, is typically coexpressed with graft-versus-host disease (GVHD), which is the major complication of allogeneic stem cell transplantation. In this study, we used genetic and antibody-based strategies to examine the effect that blockade of interleukin 23 (IL-23) signaling had on GVH and GVL reactivity in murine transplantation recipients. These studies demonstrate that the selective protection of the colon that occurs as a consequence of inhibition of IL-23 signaling reduces GVHD without loss of the GVL effect. The separation of GVH and GVL reactivity was noted in both acute and chronic hematologic malignancy models, indicating that this approach was not restricted by the kinetic profile of the underlying leukemia. Furthermore, a potent GVL response could be mounted in the colon under conditions where tumor cells migrated to this site, indicating that this organ did not serve as a sanctuary site for subsequent systemic relapse in GVHD-protected animals. These studies demonstrate that blockade of IL-23 signaling is an effective strategy for separating GVH and GVL responses and identify IL-23 as a therapeutic target for the regulation of alloresponses in humans.

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Lehmann, Percy. « Stärken der Graft-versus-Leukämie-Effekte durch richtig terminierte Photochemotherapie ». Kompass Dermatologie 6, n^o 3 (2018) : 149–50. http://dx.doi.org/10.1159/000489283.

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Background: Cure of acute leukemia after transplantation is mediated by the grafted cells. We investigated the graft-versus-leukemia effect (GVL) in patients with cutaneous acute graft-versus-host disease (GVHD) treated with photochemotherapy (psoralen and ultraviolet light type A). Method: Forty-seven patients with acute leukemia were followed 5,000 days after transplantation to assess survival and GVL by multivariate analysis. The primary predictor was time to treatment of cutaneous acute GVHD by photochemotherapy separated into treatment start during the first week of acute GVHD versus after the first week of acute GVHD. Results: Photochemotherapy started after the first week of acute GVHD predicted GVL with a hazard ratio (HR) of 3.94 (95% confidence interval, CI, 1.67-9.33, p = 0.0018) and survival with preserved GVL with an HR of 2.63 (95% CI 1.30-5.32, p = 0.007). The effects on GVL and survival with preserved GVL were present regardless of whether the patients were transplanted in remission or relapse (p < 0.05). Chronic GVHD came earlier in the group that started photochemotherapy after 1 week of acute GHVD, but chronic GVHD did not increase the GVL. Conclusion: The timing of photochemotherapy after cutaneous acute GVHD may direct the GVL and predict long-term leukemia-free survival.

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Matte-Martone, Catherine, Jinli Liu, Dhanpat Jain, Jennifer McNiff et Warren D. Shlomchik. « CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVL ». Blood 111, n^o 7 (1 avril 2008) : 3884–92. http://dx.doi.org/10.1182/blood-2007-11-125294.

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Abstract Whether T-cell antigen receptors (TCR) on donor T cells require direct interactions with major histocompatibility complex class I or class II (MHCI/MHCII) molecules on target cells to mediate graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) is a fundamental question in allogeneic stem-cell transplantation (alloSCT). In MHC-mismatched mouse models, these contacts were not required for GVHD. However, this conclusion may not apply to MHC-matched, multiple minor histocompatibility antigen-mismatched alloSCT, the most common type performed clinically. To address this, we used wild-type (wt)→MHCI−/− or wt→MHCII−/− bone marrow chimeras as recipients in GVHD experiments. For GVL experiments, we used MHCI−/− or MHCII−/− chronic-phase CML cells created by expressing the BCR-ABL cDNA in bone marrow from MHCI−/− or MHCII−/− mice. TCR/MHCI contact was obligatory for both CD8-mediated GVHD and GVL. In contrast, CD4 cells induced GVHD in wt→MHCII−/− chimeras, whereas MHCII−/− mCP-CML was GVL-resistant. Donor CD4 cells infiltrated affected skin and bowel in wt→MHCII−/− recipients, indicating that they mediated GVHD by acting locally. Thus, CD4 cells use distinct effector mechanisms in GVHD and GVL: direct cytolytic action is required for GVL but not for GVHD. If these noncytolytic pathways can be inhibited, then GVHD might be ameliorated while preserving GVL.

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Heinrichs, Jessica Lauren, Hung Nguyen, David Bastian, Yongxia Wu, Anusara Daenthanasanmak et Xue-Zhong Yu. « CD8 Tregs Promote Gvhd Prevention and Restore Impaired GVL Effect Mediated By CD4 Tregs in Mice ». Blood 126, n^o 23 (3 décembre 2015) : 1873. http://dx.doi.org/10.1182/blood.v126.23.1873.1873.

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Abstract Adoptive regulatory T-cell (Treg) therapy has enhanced the outcome of patients suffering from graft-versus-host (GVH) disease following allogeneic hematopoietic stem cell transplantation (allo-HCT); however, fear of broad immune suppression and subsequent dampening of the beneficial graft-versus-leukemic (GVL) responses remains a challenge. In order to subvert broad immune suppression, we generated alloantigen-specific induced Tregs (iTregs) from resting CD4 or CD8 T cells and tested the ability of iTregs to suppress GVH and maintain GVL responses. We utilized a clinically relevant murine model of haploidentical-HCT with the addition of host-original leukemia cell line to evaluate the effects of CD4 and CD8 iTregs in GVH and GVL responses. While alloantigen-specific CD4 iTregs were effective in preventing GVHD (Fig. 1 A and C), they completely abrogated the GVL effect against aggressive leukemia resulting in 100% tumor mortality (Fig. 1 B and D). Mechanistically, these CD4 iTregs were found to potently suppress the expansion of effector T cells (Teffs) and their ability to secrete IFNγ and granzyme B in the recipient spleen and liver, which may contribute to the impaired GVL activity. Using similar approach, we generated alloantigen-specific CD8 iTregs and found they express higher levels of granzyme B and CTLA-4 compared to nTreg and CD4 iTregs. In vivo studies showed these CD8 iTregs moderately attenuated GVHD (Fig. 1 A and C)while completely sparing the GVL effect (Fig. 1 B and D). We thus further reasoned that the combination of CD4 and CD8 iTregs could achieve the optimal goal of allo-HCT: GVHD suppression with GVL preservation. Indeed, the combination therapy potently suppressed GVHD resulting in increased survival and decreased pathological injury to target organs than either CD4 or CD8 iTreg singular therapy (Fig. 1 A and C). More importantly, the combination therapy maintained potent GVL responses reflected by significantly decreased tumor mortality and load (Fig. 1 B and D).Mechanistically, we observed addition of CD8 iTregs maintained the suppression of Teff expansion but restored the ability of Teffs in producing inflammatory cytokines (e.g. IFNγ and TFNα) and cytolytic effector molecules (e.g. granzyme B and TRAIL). To our knowledge the current findings are the first to support the use of combinational iTreg therapy to achieve optimal suppression of GVHD while maintaining GVL responses. This work was supported by NIH grants: R01 CA118116 and R01 CA169116 Disclosures No relevant conflicts of interest to declare.

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Hess, Allan D. « Separation of GVHD and GVL ». Blood 115, n^o 9 (4 mars 2010) : 1666–67. http://dx.doi.org/10.1182/blood-2009-11-254946.

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Li, Jian-Ming, Cynthia R. Giver, Ying Lu, Mohammad S. Hossain, Mojtaba Akhtari et Edmund K. Waller. « Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation ». Immunotherapy 1, n^o 4 (juillet 2009) : 599–621. http://dx.doi.org/10.2217/imt.09.32.

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Routine methods to maximize the graft-versus-leukemia (GvL) activity of allogeneic hematopoietic stem cell transplantation (HSCT) without the detrimental effects of graft-versus-host disease (GvHD) are lacking. Depletion or inhibition of alloreactive T cells is partially effective in preventing GvHD, but usually leads to decreased GvL activity. The current model for the pathophysiology of acute GvHD describes a series of immune pathways that lead to activation of donor T cells and inflammatory cytokines responsible for tissue damage in acute GvHD. This model does not account for how allotransplant can lead to GvL effects without GvHD, or how the initial activation of donor immune cells may lead to counter-regulatory effects that limit GvHD. In this review, we will summarize new findings that support a more complex model for the initiation of GvHD and GvL activities in allogeneic HSCT, and discuss the potential of novel strategies to enhance GvL activity of the transplant.

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Fanning, Stacey, Stephanie Berger, Robert Korngold et Thea Friedman. « Tumor-sensitized, Vβ spectratype-selected CD8+ T cells promote graft-versus-leukemia responses in the absence of severe lethal graft-versus-host disease in a murine model of allogeneic bone marrow transplantation. (145.20) ». Journal of Immunology 184, n^o 1_Supplement (1 avril 2010) : 145.20. http://dx.doi.org/10.4049/jimmunol.184.supp.145.20.

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Abstract The successful use of allogeneic blood and marrow transplantation (BMT) in the treatment of hematological malignancies is hampered by the fact that many donor T cells responsible for mediating graft-versus-leukemia (GVL) effects are also involved in development of graft-versus-host disease (GVHD). Optimizing outcomes for allo-BMT depends upon successful separation of GVHD and GVL responses. Our work focuses on identifying host reactive and tumor reactive T cells based on TCR Vβ CDR3-size spectratype analysis. In this study, we used a MHC-matched, miHA-mismatched murine model of BMT (B10.BR→CBA) and a CBA-derived myeloid leukemia, MMC6. Previous studies have shown this GVHD model to be mediated by CD4+-independent CD8+ T cells. Here, we show that the Vβ13 family is uniquely skewed in the B10.BR anti-MMC6 CD8+ T cell response. Transplantation of CD8+Vβ13+ T cells at the dose equivalent of 10x106 CD8+ T cells, the dose at which recipient mice develop severe lethal GVHD, did not mediate GVHD or GVL. Increased doses of Vβ13+ T cells led to increased GVL responses, however, recipient mice began to exhibit symptoms of GVHD. Of most interest, when recipients were given MMC6 presensitized Vβ13+ donor T cells, they displayed a significant GVL response in the absence of lethal GVHD. These results indicate that Vβ spectratyping can be used to identify T cells uniquely skewed in GVL responses and suggest that tumor-presensitized T cells can promote GVL in the absence of GVHD.

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Schmaltz, Cornelius, Onder Alpdogan, Kirsten J. Horndasch, Stephanie J. Muriglan, Barry J. Kappel, Takanori Teshima, James L. M. Ferrara, Steven J. Burakoff et Marcel R. M. van den Brink. « Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect ». Blood 97, n^o 9 (1 mai 2001) : 2886–95. http://dx.doi.org/10.1182/blood.v97.9.2886.

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Abstract In allogeneic bone marrow transplantation (BMT) donor T cells are primarily responsible for antihost activity, resulting in graft-versus-host disease (GVHD), and for antileukemia activity, resulting in the graft-versus-leukemia (GVL) effect. The relative contributions of the Fas ligand (FasL) and perforin cytotoxic pathways in GVHD and GVL activity were studied by using FasL-defective or perforin-deficient donor T cells in murine parent → F1 models for allogeneic bone marrow transplantation. It was found that FasL-defective B6.gld donor T cells display diminished GVHD activity but have intact GVL activity. In contrast, perforin-deficient B6.pfp−/− donor T cells have intact GVHD activity but display diminished GVL activity. Splenic T cells from recipients of B6.gld or B6.pfp−/− T cells had identical proliferative and cytokine responses to host antigens; however, splenic T cells from recipients of B6.pfp−/− T cells had no cytolytic activity against leukemia cells in a cytotoxicity assay. In experiments with selected CD4+ or CD8+ donor T cells, the FasL pathway was important for GVHD activity by both CD4+ and CD8+ T cells, whereas the perforin pathway was required for CD8-mediated GVL activity. These data demonstrate in a murine model for allogeneic bone marrow transplantation that donor T cells mediate GVHD activity primarily through the FasL effector pathway and GVL activity through the perforin pathway. This suggests that donor T cells make differential use of cytolytic pathways and that the specific blockade of one cytotoxic pathway may be used to prevent GVHD without interfering with GVL activity.

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Oka, Yoko, Ryosuke Shirasaki, Takuji Matsuo, Haruko Tashiro, Jun Ooi et Naoki Shirafuji. « T Cell Receptor Vbeta Repertoire Plays An Important Role In Graft-Versus-Leukemia Effect To Acute Lymphocytic Leukemia With TCF3-PBX1 ». Blood 122, n^o 21 (15 novembre 2013) : 5434. http://dx.doi.org/10.1182/blood.v122.21.5434.5434.

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Abstract Background and Aims We recently reported that graft-versus-leukemia (GVL) effect was observed in acute lymphocytic leukemia (ALL) with TCF3-PBX1 (53rd ASH, and 15th ASGCT). To understand better the mechanism of this GVL effect, we analyzed blood T cell receptors (TCRs) obtained from ALL patients with TCF3-PBX1. Materials and Methods The institutional ethical committee approved our study using clinical materials. Three informed ALL patients with TCF3-PBX1 were eligible. Leukemic blasts, blood lymphocytes after underwent allogeneic hematopoietic stem cell transplantation to achieve and keep complete remission, and cells from pathologically GVHD-diagnosed organs (liver, and skin) were collected. Lymphocytes were co-cultured with the patient-derived ALL blasts that were priory irradiated at 20 Gray (GVL model) or GVHD-related cells (GVHD model) for 14 days with recombinant human interleukin-2. Then, TCR Valpha (Va) and Vbeta (Vb) usages were analyzed with RT-PCR. When the preferential usage of Va and Vb was observed, T cells underwent single-cell culture, and the clones showing ALL blast-killing activity and not GVHD effect were selected, and their TCR nucleotide sequences were analyzed. Results In GVHD model and GVL one, TCR Va and Vb were oligoclonally used, in which Vb 6, 10, and 14 were preferentially used in GVL model but not in GVHD. On Va no selective usage was demonstrated between GVL model and GVHD one. Furthermore, the obtained single cells with GVL effect had specific TCR Vb nucleotide-sequences. Discussion In GVL model TCR Vbs were preferentially used. Currently we isolate tcf3-pbx1-specific oligopeptide-antigen recognized by the isolated TCRs, and observe cytotoxic GVL effect with the isolated TCRs in vitro. We also validate in vivo implications of the isolated GVL-specific T cells to treat leukemic non-obese diabetes/severe combined immunodeficiency mouse generated by the injection of ALL-blast with TCF3-PBX1. Disclosures: No relevant conflicts of interest to declare.

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Karimi, Mobin A., Mahinbanu Mahinbanu Mammadli, Weishan Huang, Rebecca Harris, Samuel Weeks, Adriana May, Teresa Gentile, Jessica L. Henty Ridilla, Avery August et Mobin Karimi. « Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT ». Journal of Immunology 206, n^o 1_Supplement (1 mai 2021) : 28.01. http://dx.doi.org/10.4049/jimmunol.206.supp.28.01.

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Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for relapsed hematological malignancies due to graft-versus-leukemia (GVL) activity mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) is also primarily mediated by the same donor T cells. Here we assessed the effect of attenuating TCR-mediated SLP76:ITK interaction in T cell-mediated GVL vs. GVHD effects after allo-HSCT. Neither CD8+ T cells nor CD4+ donor T cells from mice expressing a tyrosine to phenylalanine mutation at position 145 (Y145F) of the adapter protein SLP-76 caused GVHD, T cells cells preserved GVL effects after allogeneic transplantation. SLP76Y145FKI CD8+ and CD4+ donor T cells also produce less inflammatory cytokines and show decreased migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). We also report the development of a novel peptide that can specifically inhibit SLP76 and ITK interactions, which results in decreased phosphorylation of PLCγ1 and ERK, and decreased cytokine production in human T cells. This peptide inhibited donor T cell-mediated GVHD while maintaining GVL effects. Altogether, our data suggest that inhibiting SLP76:ITK interaction could be a therapeutic strategy to reduce GVHD while retaining the beneficial GVL effects after allo-HSCT treatment.

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Truitt, RL, et AA Atasoylu. « Impact of pretransplant conditioning and donor T cells on chimerism, graft-versus-host disease, graft-versus-leukemia reactivity, and tolerance after bone marrow transplantation ». Blood 77, n^o 11 (1 juin 1991) : 2515–23. http://dx.doi.org/10.1182/blood.v77.11.2515.2515.

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Abstract Graft rejection, mixed chimerism, graft-versus-host disease (GVHD), leukemia relapse, and tolerance are interrelated manifestations of immunologic reactivity between donor and host cells that significantly affect survival after allogeneic bone marrow transplantation (BMT). In this report, a mouse model of BMT, in which the donor and host were compatible at the major histocompatibility complex (MHC), was used (1) to examine the interrelationship of pretransplant conditioning and T- cell content of donor BM with regard to lymphoid chimerism and GVHD and (2) to determine how these factors affected graft-versus-leukemia (GVL) reactivity and donor-host-tolerance. AKR (H-2k) host mice were administered optimal or suboptimal total body irradiation (TBI) as pretransplant conditioning followed by administration of BM cells from B10.BR (H-2k) donor mice with or without added spleen cells as a source of T lymphocytes. Transplanted mice were injected with a supralethal dose of AKR leukemia cells 20 and 45 days post-BMT to assess GVL reactivity in vivo. The pretransplant conditioning of the host and T- cell content of the donor marrow affected the extent of donor T-cell chimerism and the severity of GVH disease. GVL reactivity was dependent on transplantation of mature donor T cells and occurred only in complete chimeras. Transplantation of T-cell-deficient BM resulted in the persistence of host T cells, ie, incomplete donor T-cell chimerism, even when lethal TBI was used. Mixed chimerism was associated with a lack of GVL reactivity, despite the fact that similar numbers of donor T cells were present in the spleens of mixed and complete chimeras. In this model, moderate numbers of donor T cells facilitated complete donor T-cell engraftment, caused only mild GVHD, and provided a significant GVL effect without preventing the subsequent development of tolerance after conditioning with suboptimal TBI. In contrast, severe, often lethal, GVHD developed when the dose of TBI was increased, whereas tolerance and no GVH/GVL reactivity developed when the T-cell content of the marrow was decreased.

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Truitt, RL, et AA Atasoylu. « Impact of pretransplant conditioning and donor T cells on chimerism, graft-versus-host disease, graft-versus-leukemia reactivity, and tolerance after bone marrow transplantation ». Blood 77, n^o 11 (1 juin 1991) : 2515–23. http://dx.doi.org/10.1182/blood.v77.11.2515.bloodjournal77112515.

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Graft rejection, mixed chimerism, graft-versus-host disease (GVHD), leukemia relapse, and tolerance are interrelated manifestations of immunologic reactivity between donor and host cells that significantly affect survival after allogeneic bone marrow transplantation (BMT). In this report, a mouse model of BMT, in which the donor and host were compatible at the major histocompatibility complex (MHC), was used (1) to examine the interrelationship of pretransplant conditioning and T- cell content of donor BM with regard to lymphoid chimerism and GVHD and (2) to determine how these factors affected graft-versus-leukemia (GVL) reactivity and donor-host-tolerance. AKR (H-2k) host mice were administered optimal or suboptimal total body irradiation (TBI) as pretransplant conditioning followed by administration of BM cells from B10.BR (H-2k) donor mice with or without added spleen cells as a source of T lymphocytes. Transplanted mice were injected with a supralethal dose of AKR leukemia cells 20 and 45 days post-BMT to assess GVL reactivity in vivo. The pretransplant conditioning of the host and T- cell content of the donor marrow affected the extent of donor T-cell chimerism and the severity of GVH disease. GVL reactivity was dependent on transplantation of mature donor T cells and occurred only in complete chimeras. Transplantation of T-cell-deficient BM resulted in the persistence of host T cells, ie, incomplete donor T-cell chimerism, even when lethal TBI was used. Mixed chimerism was associated with a lack of GVL reactivity, despite the fact that similar numbers of donor T cells were present in the spleens of mixed and complete chimeras. In this model, moderate numbers of donor T cells facilitated complete donor T-cell engraftment, caused only mild GVHD, and provided a significant GVL effect without preventing the subsequent development of tolerance after conditioning with suboptimal TBI. In contrast, severe, often lethal, GVHD developed when the dose of TBI was increased, whereas tolerance and no GVH/GVL reactivity developed when the T-cell content of the marrow was decreased.

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Emerson, Stephen G. « Punching holes in GVHD and GVL ». Blood 97, n^o 9 (1 mai 2001) : 2533–34. http://dx.doi.org/10.1182/blood.v97.9.2533b.

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Murphy, William J. « Drilling down interferon in GVHD/GVL ». Blood 141, n^o 8 (23 février 2023) : 821–23. http://dx.doi.org/10.1182/blood.2022019232.

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Eom, Hyeon-Seok, Ronjon Chakraverty, Jessica Sachs, Guiling Zhao et Megan Sykes. « Requirement for CD4 Help for Optimal GVL Effects of Alloreactive T Cells Given to Established Mixed Chimeras but Not Freshly Irradiated Mice. » Blood 104, n^o 11 (16 novembre 2004) : 3044. http://dx.doi.org/10.1182/blood.v104.11.3044.3044.

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Abstract Donor lymphocyte infusion (DLI) may lead to lymphohematopoietic graft-versus-host (GVH) reactions without graft-versus-host-disease (GVHD). The graft-versus-leukemia (GVL) effect of DLI is greater in mixed chimeras than in full chimeras following fully MHC-mismatched bone marrow transplantation (BMT). Some studies showed, following MHC-mismatched BMT, that only CD8+ T cells are involved in GVL effects of DLI against MHC class I+ class II− tumors, but others showed that the GVL effect of DLI is dependent on both CD8+ and CD4+ T cells. Previously, we have observed that GVL against EL4 is mediated by CD8+ T cells but not CD4+ T cells following DLI in freshly irradiated mice treated with cytokines to reduce GVHD mortality in fully MHC-mismatched BMT. The exact contribution of CD4+ and CD8+ T cells to the GVL effects of DLI in established mixed chimeras is not known. We hypothesized that lethal conditioning leads to the production of many proinflammatory cytokines which may help to generate a CD4 cell-independent, CD8 cell-mediated anti-tumor effect. However, in delayed DLI recipients, CD4+ helper T cells might be needed to induce CD8+ anti-tumor effector cells. We evaluated the role of T-cell subsets in GVL effects of DLI following fully major histocompatibility complex (MHC)-mismatched BMT in freshly irradiated mice and mixed chimeric delayed DLI recipients. While GVL effects of delayed DLI given to established mixed chimeras were dependent on both CD4+ and CD8+ T cells, CD4+ T cells did not contribute to GVL effects in freshly irradiated mice. Consistent with this, MHC class II expression on host antigen-presenting cells (APCs) was needed to optimize GVL effects of DLI in established mixed chimeras. To address whether cross-presentation of tumor antigens (Ag) via class I would permit GVL responses in full chimeras, we generated full chimeras in which donor and recipient shared a class I locus. However, there were no GVL effects of delayed DLI in full chimeras, providing no evidence that cross-presentation of tumor Ag through class I molecules shared by donor and the tumor led to anti-tumor effects in this model. We conclude that following delayed DLI to established mixed chimeras, the GVL response requires extensive MHC disparity, MHC class II expression on host APCs and the presence of CD4+ T cells. In contrast, the requirement for CD4+ T cells can be bypassed in freshly irradiated recipients, but this occurs at the expense of a greater risk of GVHD. Administration of delayed DLI to mixed chimeras permits achievement of optimal GVL effects because large numbers of GVH-reactive T cells can be administered without inducing GVHD.

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Kim, Sena, Srikanth Santhanam, Sora Lim et Jaebok Choi. « Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia ». International Journal of Molecular Sciences 21, n^o 12 (16 juin 2020) : 4281. http://dx.doi.org/10.3390/ijms21124281.

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL.

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20

Negrin, Robert S. « Graft-versus-host disease versus graft-versus-leukemia ». Hematology 2015, n^o 1 (5 décembre 2015) : 225–30. http://dx.doi.org/10.1182/asheducation-2015.1.225.

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Abstract Graft-versus-host disease (GVHD) is a significant clinical problem after allogenic hematopoietic cell transplantation (HCT) associated with substantial morbidity and mortality that limits the potential utility of transplantation. Associated with GVHD is the well-recognized phenomenon of the graft-versus-leukemia (GVL) effect that results in reduced risk of disease relapse. GVL effects have been observed after treatment for a broad range of hematological malignancies. Both GVHD and GVL are the results of T cell–effector functions that frames a major question in the field of how linked are these two phenomena. A major goal of basic science and translational research has been to develop strategies to reduce the risk of GVHD while maintaining or enhancing GVL. In this review, a number of different strategies developed from preclinical animal models will be explored with a focus on those approaches that have been extended to the clinic in an attempt to achieve this goal. Needless to say, there is no proven strategy; however, with the use of modern technology and clinical translation, there has been substantial progress toward this goal of reducing the risks of GVHD while promoting and enhancing GVL responses.

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Ghosh, Arnab, Wolfgang Koestner, Martin Hapke, Verena Schlaphoff, Florian Länger, Rolf Baumann, Christian Koenecke et al. « Donor T cells primed on leukemia lysate-pulsed recipient APCs mediate strong graft-versus-leukemia effects across MHC barriers in full chimeras ». Blood 113, n^o 18 (30 avril 2009) : 4440–48. http://dx.doi.org/10.1182/blood-2008-09-181677.

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Abstract Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cells (ETCs) mediate anti-leukemia effects only when primed on recipient-derived APCs. Loading of APCs in vitro with leukemia cell lysate, chimerism status of the recipient, and timing of adoptive transfer after HCT are important factors determining the outcome. Delayed transfer of ETCs resulted in strong GVL effects in leukemia-bearing full chimera (FC) and mixed chimera (MC) recipients, which were comparable with the GVL/GVHD rates observed after the transfer of naive donor lymphocyte infusion (DLI). Upon early transfer, GVL effects were more pronounced with ETCs but at the expense of significant GVHD. The degree of GVHD was most severe in MCs after transfer of ETCs that had been in vitro primed either on nonpulsed recipient-derived APCs or with donor-derived APCs.

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Yang, Yong-Guang, Justin J. Sergio, Denise A. Pearson, Gregory L. Szot, Akira Shimizu et Megan Sykes. « Interleukin-12 Preserves the Graft-Versus-Leukemia Effect of Allogeneic CD8 T Cells While Inhibiting CD4-Dependent Graft-Versus-Host Disease in Mice ». Blood 90, n^o 11 (1 décembre 1997) : 4651–60. http://dx.doi.org/10.1182/blood.v90.11.4651.

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Abstract We have recently demonstrated that a single injection of 4,900 IU of interleukin-12 (IL-12) on the day of bone marrow transplantation (BMT) markedly inhibits acute graft-versus-host disease (GVHD) in a fully major histocompatibility complex plus minor antigen-mismatched BMT model (A/J → B10, H-2a → H-2b), in which donor CD4+ T cells are required for the induction of acute GVHD. We show here that donor CD8-dependent graft-versus-leukemia (GVL) effects against EL4 (H-2b) leukemia/lymphoma can be preserved while GVHD is inhibited by IL-12 in this model. In mice in which IL-12 mediated a significant protective effect against GVHD, marked GVL effects of allogeneic T cells against EL4 were observed. GVL effects against EL4 depended on CD8-mediated alloreactivity, protection was not observed in recipients of either syngeneic (B10) or CD8-depleted allogeneic spleen cells. Furthermore, we analyzed IL-12–treated recipients of EL4 and A/J spleen cells which survived for more than 100 days. No EL4 cells were detected in these mice by flow cytometry, tissue culture, adoptive transfer, necropsies, or histologic examination. Both GVL effects and the inhibitory effect of IL-12 on GVHD were diminished by neutralizing anti–interferon-γ (IFN-γ) monoclonal antibody. This study demonstrates that IL-12–induced IFN-γ production plays a role in the protective effect of IL-12 against GVHD. Furthermore, IFN-γ is involved in the GVL effect against EL4 leukemia, demonstrating that protection from CD4-mediated GVHD and CD8-dependent anti-leukemic activity can be provided by a single cytokine, IFN-γ. These observations may provide the basis for a new approach to inhibiting GVHD while preserving GVL effects of alloreactivity.

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Yang, Yong-Guang, Justin J. Sergio, Denise A. Pearson, Gregory L. Szot, Akira Shimizu et Megan Sykes. « Interleukin-12 Preserves the Graft-Versus-Leukemia Effect of Allogeneic CD8 T Cells While Inhibiting CD4-Dependent Graft-Versus-Host Disease in Mice ». Blood 90, n^o 11 (1 décembre 1997) : 4651–60. http://dx.doi.org/10.1182/blood.v90.11.4651.4651_4651_4660.

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We have recently demonstrated that a single injection of 4,900 IU of interleukin-12 (IL-12) on the day of bone marrow transplantation (BMT) markedly inhibits acute graft-versus-host disease (GVHD) in a fully major histocompatibility complex plus minor antigen-mismatched BMT model (A/J → B10, H-2a → H-2b), in which donor CD4+ T cells are required for the induction of acute GVHD. We show here that donor CD8-dependent graft-versus-leukemia (GVL) effects against EL4 (H-2b) leukemia/lymphoma can be preserved while GVHD is inhibited by IL-12 in this model. In mice in which IL-12 mediated a significant protective effect against GVHD, marked GVL effects of allogeneic T cells against EL4 were observed. GVL effects against EL4 depended on CD8-mediated alloreactivity, protection was not observed in recipients of either syngeneic (B10) or CD8-depleted allogeneic spleen cells. Furthermore, we analyzed IL-12–treated recipients of EL4 and A/J spleen cells which survived for more than 100 days. No EL4 cells were detected in these mice by flow cytometry, tissue culture, adoptive transfer, necropsies, or histologic examination. Both GVL effects and the inhibitory effect of IL-12 on GVHD were diminished by neutralizing anti–interferon-γ (IFN-γ) monoclonal antibody. This study demonstrates that IL-12–induced IFN-γ production plays a role in the protective effect of IL-12 against GVHD. Furthermore, IFN-γ is involved in the GVL effect against EL4 leukemia, demonstrating that protection from CD4-mediated GVHD and CD8-dependent anti-leukemic activity can be provided by a single cytokine, IFN-γ. These observations may provide the basis for a new approach to inhibiting GVHD while preserving GVL effects of alloreactivity.

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Mapara, Markus Y., Yong-Mi Kim, Sheng-Ping Wang, Roderick Bronson, David H. Sachs et Megan Sykes. « Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras : a critical role for host antigen–presenting cells ». Blood 100, n^o 5 (1 septembre 2002) : 1903–9. http://dx.doi.org/10.1182/blood-2002-01-0023.

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In mice, donor leukocyte infusion (DLI) given to established mixed allogeneic chimeras can mediate powerful graft-versus-host (GVH) reactions confined to the lymphohematopoietic system without inducing graft-versus-host disease (GVHD). In a clinical trial attempting to capture this approach to achieve graft-versus-leukemia/lymphoma (GVL) effects without GVHD, we have observed surprisingly powerful antitumor effects of DLI in patients achieving mixed chimerism after nonmyeloablative bone marrow transplantation. This observation led us to hypothesize that host antigen–presenting cells in mixed chimeras might be required to optimally present recipient antigens to the donor lymphocytes, leading to maximal graft-versus-tumor effects. To test this hypothesis, we established mixed and fully allogeneic hematopoietic chimeras in B6 mice and evaluated the effect of DLI on EL4 T-cell lymphoma. DLI administration to mixed chimeras produced dramatically improved leukemia-free survival compared to administration of DLI to full donor chimeras. DLI also converted mixed chimeras to full chimeras without causing GVHD. The magnitude of the GVL effect was dependent on the level of major histocompatibility complex class I expression on recipient hematopoietic cells in mixed chimeras. Thus, the induction of mixed chimerism followed by delayed DLI provides an approach to inhibiting GVHD that optimizes GVL effects.

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Mammadli, Mahinbanu, Rebecca Harris, Sara Mahmudlu, Anjali Verma, Adriana May, Rohan Dhawan, Adam T. Waickman, Jyoti Misra Sen, Avery August et Mobin Karimi. « Human Wnt/β-Catenin Regulates Alloimmune Signaling during Allogeneic Transplantation ». Cancers 13, n^o 15 (28 juillet 2021) : 3798. http://dx.doi.org/10.3390/cancers13153798.

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adoptive immunotherapy for the treatment of hematological malignancies. Detrimental graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we evaluated the role of β-catenin in this process. Using a unique mouse model of transgenic overexpression of human β-catenin (Cat-Tg) in an allo-HSCT model, we show here that T cells from Cat-Tg mice did not cause GVHD, and surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing revealed changes in the expression of 1169 genes for CD4, and 1006 genes for CD8+ T cells involved in essential aspects of immune response and GVHD pathophysiology. Altogether, our data suggest that β-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

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Vaeth, Martin, Carina A. Bäuerlein, Tobias Pusch, Janina Findeis, Martin Chopra, Anja Mottok, Andreas Rosenwald, Andreas Beilhack et Friederike Berberich-Siebelt. « Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity ». Proceedings of the National Academy of Sciences 112, n^o 4 (12 janvier 2015) : 1125–30. http://dx.doi.org/10.1073/pnas.1409290112.

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Graft-versus-host disease (GvHD) is a life-threatening immunological complication after allogenic hematopoietic stem cell transplantation (allo-HCT). The intrinsic graft-versus-leukemia (GvL) effect, however, is the desirable curative benefit. Patients with acute GvHD are treated with cyclosporine A (CsA) or tacrolimus (FK506), which not only often causes severe adverse effects, but also interferes with the anticipated GvL. Both drugs inhibit calcineurin, thus at first suppressing activation of the nuclear factor of activated T cells (NFAT). Therefore, we explored the specific contribution of individual NFAT factors in donor T cells in animal models of GvHD and GvL. Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GvHD, due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In contrast, the frequency of Foxp3+ regulatory T (Treg) cells was increased and NFAT-deficient Tregs were fully protective in GvHD. CD8+ T-cell recall response and, importantly, the beneficial antitumor activity were largely preserved in NFAT-deficient effector T cells. Thus, specific inhibition of NFAT opens an avenue for an advanced therapy of GvHD maintaining protective GvL.

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Fanning, Stacey L., Stephanie A. Berger, Kristin Vazzana, Loise N. Gichuru, Robert Korngold et Thea M. Friedman. « Vβ Spectratype-guided Separation of Graft-Versus-Host Disease and Graft-Versus-Leukemia Effects in a MHC-Matched miHA-Mismatched Mouse Model of Hematopoietic Stem Cell Transplantation ». Blood 112, n^o 11 (16 novembre 2008) : 3517. http://dx.doi.org/10.1182/blood.v112.11.3517.3517.

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Abstract Allogeneic hematopoietic stem cell transplantation has been proven to be one of few curative treatment options for patients with hematological malignancies. One drawback to this procedure is the development of graft-versus-host disease (GVHD), which can lead to high rates of morbidity and mortality. It is well established that donor T cells are primarily responsible for anti-host activity. Removal or delayed-administration of donor T cells reduces the incidence or severity of GVHD, but is often associated with an increased risk of tumor relapse due to lack of donor T cells that mediate graft-versus-leukemia (GVL) effects. Utilizing CDR3-size spectratype analysis we have focused on identifying host- and tumor-reactive T cells. In this study, a MHC-matched, miHA-mismatched murine transplantation model (B10.BR→CBA) was used to characterize CD8+ T cell repertoire anti-host responses as well as anti-tumor responses to a host-derived myeloid leukemia cell line (MMC6). This model is particularly relevant in that it mimics matched-sibling donor transplants for AML. Spectratype analysis has shown that 14 of 20 Vβ families exhibit biased CDR3-size usage in the B10.BR anti-CBA CD8+ T cell repertoire. In response to MMC6, 7 of 20 Vβ families exhibit biased CDR3-size usage, with Vβ4 and Vβ13 uniquely skewed in the anti-tumor response. We sought to test the ability of spectratype-identified Vβ families, uniquely skewed in the B10.BR CD8+ T cell anti-MMC6 response, to mediate GVL effects in the absence of GVHD in tumor challenged transplant recipients. To this end lethally irradiated (11Gy;split dose) CBA recipients were transplanted with B10.BR ATBM alone, ATBM + B10.BR CD8+ T cells, or ATBM + either B10.BR CD8+ Vβ4+ or Vβ13+ T cells. Duplicate groups of mice received the same transplant conditions and were challenged with MMC6 on day +1 post-transplant. All mice were monitored for symptoms of GVHD and tumor growth. Mice receiving MMC6 in the absence of T cells succumbed to tumor within 30 days post-transplant. Tumor challenged mice receiving CD8+ T cells displayed a statistically significant GVL effect (p<0.0001), however, all eventually succumbed to GVHD. Mice receiving either Vβ4+ or Vβ13+ T cells along with MMC6 displayed minimal GVL effects, with all mice succumbing to tumor challenge. As expected based on the spectratype analysis, mice receiving either Vβ4+ or Vβ13+ T cells in the absence of tumor challenge did not develop any signs of GVHD and survived until termination of the experiment. In order to test the possibility of enhancing the GVL potential, duplicate groups of mice received the same transplant conditions and MMC6 tumor challenge, as above with an additional group that was co-transplanted with CD8+Vβ4+ and Vβ13+ T cells. This combined transplantation of CD8+Vβ4+ and Vβ13+ T cells did not mediate severe lethal GVHD (80% survival). However, together, CD8+Vβ4+ and Vβ13+ T cells significantly prolonged survival (p=0.001) of tumor challenged recipients. Taken together, the results of this study provide proof of principle to support the hypothesis that Vβ spectratype analysis can be used to identify the donor GVH- and GVL-reactive T cells. Furthermore, manipulation of the donor inoculum to enrich for the GVL-reactive and/or deplete the GVH-reactive Vβ families can provide an effective way to separate GVHD from GVL effects.

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Ramadan, Abdulraouf, Brad Griesenauer, Djamilatou Adom, Reuben Kapur, Helmut Hanenberg, Chen Liu, Mark H. Kaplan et Sophie Paczesny. « Specifically differentiated T cell subset promotes tumor immunity over fatal immunity ». Journal of Experimental Medicine 214, n^o 12 (16 octobre 2017) : 3577–96. http://dx.doi.org/10.1084/jem.20170041.

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Allogeneic immune cells, particularly T cells in donor grafts, recognize and eliminate leukemic cells via graft-versus-leukemia (GVL) reactivity, and transfer of these cells is often used for high-risk hematological malignancies, including acute myeloid leukemia. Unfortunately, these cells also attack host normal tissues through the often fatal graft-versus-host disease (GVHD). Full separation of GVL activity from GVHD has yet to be achieved. Here, we show that, in mice and humans, a population of interleukin-9 (IL-9)–producing T cells activated via the ST2–IL-33 pathway (T9IL-33 cells) increases GVL while decreasing GVHD through two opposing mechanisms: protection from fatal immunity by amphiregulin expression and augmentation of antileukemic activity compared with T9, T1, and unmanipulated T cells through CD8α expression. Thus, adoptive transfer of allogeneic T9IL-33 cells offers an attractive approach for separating GVL activity from GVHD.

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Gillissen, Marijn Aletta, Sophie E. Levie, Greta de Jong, Etsuko Yasuda, Arjen Q. Bakker, Pauline M. van Helden, Douglas M. Jefferson, Cynthia Huisman, Hergen Spits et Mette D. Hazenberg. « AML Relapse after Rituximab Treatment for Graft-Versus-Host Disease : Crucial Role for B Cells in Graft-Versus-Host and Graft-Versus-Leukemia ». Blood 126, n^o 23 (3 décembre 2015) : 5473. http://dx.doi.org/10.1182/blood.v126.23.5473.5473.

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Abstract Patients with hematologic malignancies that develop graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT) have a reduced risk of disease relapse compared to patients that do not develop GvHD, suggesting that GvHD and graft-versus-leukemia (GvL) responses are co-dependent. T cells are important in these processes, as T cell depletion from the graft reduces the risk of GvHD at the expense of disease relapse. Much less is known about the effect of B cell depletion on GvHD and GvL responses. Small patient series have demonstrated variable efficacy of Rituximab in the treatment of steroid-refractory chronic GvHD but the effect of depleting allo-reactive B cells on disease relapse remains to be determined. We here report on a patient with steroid-refractory GvHD whose AML relapsed after Rituximab treatment. This 39-year old male received an allogeneic HSCT for chemotherapy-related AML (AML-t) that however relapsed 8 weeks after the transplantation. Upon rapid cessation of immunosuppressive therapy (cyclosporine, mycophenolic acid) and without additional chemotherapy he obtained full remission, at the expense of severe GvHD of the skin, liver and intestine that was corticosteroid-refractory. B cell depletion with Rituximab was successful as second-line treatment for GvHD but eliminated the GvL response and the patient died of AML relapse several months after. To evaluate the B cell repertoire of this patient at the moment of maximal GvH and GvL responses, we isolated peripheral blood B lymphocytes that were transduced with Bcl-xL and Bcl-6 to create clonal B cell lines. These B cells were screened for binding to AML and host tissues. One clone was retrieved that specifically bound to AML cell lines and AML blasts freshly isolated from newly diagnosed AML patients. Antibodies from this clone induced antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of AML cells in vitro. Several other clones were retrieved that were specific for host tissues such as liver (HepG2 and H69 cell lines), skin (primary fibroblasts) and/or colon (CaCo cell line). These data demonstrate the pivotal role of B lymphocytes in anti-leukemia and anti-host immune responses in an allogeneic HSCT recipient with relapsed AML-t. Disclosures No relevant conflicts of interest to declare.

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Weiss, L., I. Lubin, I. Factorowich, Z. Lapidot, S. Reich, Y. Reisner et S. Slavin. « Effective graft-versus-leukemia effects independent of graft-versus-host disease after T cell-depleted allogeneic bone marrow transplantation in a murine model of B cell leukemia/lymphoma. Role of cell therapy and recombinant IL-2. » Journal of Immunology 153, n^o 6 (15 septembre 1994) : 2562–67. http://dx.doi.org/10.4049/jimmunol.153.6.2562.

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Abstract After allogeneic bone marrow transplantation (BMT) for leukemia, beneficial graft-vs-leukemia (GVL) effects are usually accompanied by potentially serious graft-vs-host disease (GVHD). Because T cell depletion is the only effective way to prevent GVHD it seems important to understand whether effective GVL can develop after BMT with T cell depletion in GVHD-free recipients. Well-established C57BL/6-->BALB/c chimeras that were free of GVHD, reconstituted with T cell-depleted allogeneic bone marrow cells, and inoculated 3 mo after BMT with a high inoculation of murine B cell leukemia (BCL1) showed no evidence of disease, whereas all control mice developed leukemia and died within 58 days. Results from adoptive transfer experiments in secondary naive BALB/c recipients indicated that all BCL1 cells were eliminated in the chimeras within 14 days. Hence, complete resistance to BCL1 developed in the chimeras despite complete tolerance to host alloantigens. The GVL effects observed in tolerant chimeras were further amplified by administration of immunocompetent allogeneic C57BL/6 spleen cells, low dose rIL-2, or both for 5 days. Our data suggest that GVL effects can develop even after T cell depletion in the absence of clinically overt GVHD and that GVL can be further amplified by rIL-2, either with or without use of additional immunocompetent donor T cells. Our data may provide the basis for new approaches to induce effective GVL after allogeneic BMT with cell therapy and rIL-2 at the stage of minimal residual disease, while avoiding early GVHD induced by the BMT procedure.

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Liang, Yaming, et Xue-Zhong Yu. « CD18 Separates GVHD and GVL effect (50.9) ». Journal of Immunology 178, n^o 1_Supplement (1 avril 2007) : S91—S92. http://dx.doi.org/10.4049/jimmunol.178.supp.50.9.

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Abstract Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. Migration of donor-derived T cells into GVHD target organs plays an essential role in the development of GVHD. β2 integrins, a group of heterodimeric molecules including CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), CD11c/CD18 and CD11d/CD18, are of critical importance for leukocyte extravasation through vascular endothelia and for T cell activation. We asked whether CD18-deficient T cells would induce less GVHD while sparing graft-versus-leukemia (GVL) effect. In murine allogeneic BMT models, we found that recipients of CD18−/− donor T cells had significantly less GVHD morbidity and mortality compared with recipients of WT donor T cells. A cell-dose titration experiment indicated that the ability of CD18−/− T cells had more than 4-fold reduction compared to that of WT T cells in the induction of GVHD. Analysis of alloreactive showed that CD18−/− and WT T cells had comparable activation, expansion and cytokine production in vivo. Reduced GVHD was associated with a significant decrease in donor-T cell infiltration of recipient intestine and with an overall decrease in pathologic scores in intestine and liver. Finally, we found that in vivo GVL effect of CD18−/− donor T cells was largely preserved, because mortality of the recipients transplanted with CD18−/− T cells plus tumor cells was greatly delayed or prevented. Our data suggest that strategies to target β2 intergrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.

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Sykes, M., V. S. Abraham, M. W. Harty et D. A. Pearson. « IL-2 reduces graft-versus-host disease and preserves a graft-versus-leukemia effect by selectively inhibiting CD4+ T cell activity. » Journal of Immunology 150, n^o 1 (1 janvier 1993) : 197–205. http://dx.doi.org/10.4049/jimmunol.150.1.197.

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Abstract We have recently demonstrated, in a fully MHC-mismatched murine bone marrow transplantation model, that administration of a short course of high dose IL-2 markedly diminishes graft-vs-host disease (GVHD) without compromising alloengraftment or the graft-vs-leukemia (GVL) effect of allogeneic T cells. We have now evaluated the mechanism of the dissociation of GVL and GVHD observed in this model. We demonstrate that CD4+ T cells were required to produce severe, acute GVHD in the fully MHC-mismatched plus minor histocompatibility Ag-mismatched A/J-->B10 strain combination. The GVHD-producing activity of A/J CD4+ T cells administered without CD8+ T cells was inhibited by IL-2 treatment. In contrast, CD8+ T cells alone mediated the GVL effect observed in the EL4 leukemia/lymphoma model, and CD4+ cells did not contribute to this effect. This CD8-mediated GVL activity was not inhibited by IL-2 treatment. Because naive A/J CD8+ T cells administered without CD4+ T cells did not produce acute GVHD, we were unable to evaluate the effect of IL-2 in this model. However, when A/J donors were presensitized with B10 skin grafts, CD4-depleted A/J spleen cells were capable of causing acute GVHD in B10 recipients. This CD8-mediated GVHD was not inhibited by treatment with IL-2. However, IL-2 did partially inhibit the GVHD produced by nondepleted presensitized A/J spleen cells, probably due to selective inhibition of the function of presensitized A/J CD4+ T cells. The dissociation of GVHD and GVL against the EL4 leukemia/lymphoma in IL-2-treated mice can therefore be explained by selective inhibition by IL-2 of CD4 activity.

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Billiau, An D., Sabine Fevery, Omer Rutgeerts, Willy Landuyt et Mark Waer. « Transient expansion of Mac1+Ly6-G+Ly6-C+ early myeloid cells with suppressor activity in spleens of murine radiation marrow chimeras : possible implications for the graft-versus-host and graft-versus-leukemia reactivity of donor lymphocyte infusions ». Blood 102, n^o 2 (15 juillet 2003) : 740–48. http://dx.doi.org/10.1182/blood-2002-06-1833.

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AbstractA murine model of minor histocompatibility antigen (miHCag)–mismatched bone marrow transplantation (BMT) was used to study the development of immunoregulatory cells in the posttransplantation period and their possible involvement in the dissociated graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity of posttransplantation donor lymphocyte infusions (DLIs). DLI, applied immediately after BMT, induced GVH disease (GVHD), but when DLI was delayed for 3 weeks, GVHD was avoided while a distinct GVL response was allowed to develop. A population of Mac1+Ly6-G+Ly6-C+ immature myeloid cells, found in small numbers in normal mice, strongly expanded in spleens of chimeras, reaching a maximum level at week 3 and returning to base level by week 12. Upon isolation, these cells exhibited interferon-γ (IFN-γ)–dependent, nitric oxide (NO)–mediated suppressor activity toward in vitro alloresponses, suggesting that, after in vivo DLI, they are activated by IFN-γ to produce NO and suppress GVH reactivity. Because not only alloactivated T-cell proliferation but also leukemia cell growth was found susceptible to inhibition by exogenous NO, in vivo activation of these cells after DLI may explain the occurrence of a GVL effect despite suppression of GVHD. This suggested sequence of events was supported by the finding that the ex vivo antihost proliferative response of spleen cells, recovered shortly after in vivo DLI, was characterized by strong mRNA production of the monokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) and of inducible nitric oxide synthase (iNOS). Our data suggest that transiently expanding Mac1+Ly6-G+Ly6-C+ immature myeloid cells (probably as a result of extramedullary myelopoiesis) may play a role in controlling GVH while promoting GVL reactivity of DLI after allogeneic BMT.

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Karimi, Mobin, Martha Jordon et Taku Kambayashi. « Separation of Gvhd from GVL Responses By Modulation of TCR Signaling ». Blood 124, n^o 21 (6 décembre 2014) : 3822. http://dx.doi.org/10.1182/blood.v124.21.3822.3822.

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Abstract In allogeneic hematopoietic stem cell transplantation (HSCT), devising new strategies to separate GVHD and GVL responses is of critical importance. However, this is a difficult task, as GVHD and GVL rely on the same recognition of allogeneic MHC by donor-derived T cells. CD8+ T cells are key effector cells that mediate both GVHD and GVL. In mouse models of allogeneic HSCT, the infusion of donor-derived CD8+ T cells eliminates tumor growth but also causes severe GVHD. The activation of CD8+ T cells can be potentially manipulated by perturbing the signaling pathways downstream of the T cell receptor (TCR). TCR signaling depends on the formation of a proximal multimolecular complex, which is nucleated by adaptor proteins such as SLP-76. The phosphorylation of the Y145 residue of SLP-76 is critical for activation of the downstream enzyme PLCg1. As such, a YàF mutation at Y145 of SLP-76 (Y145F) causes decreased TCR-mediated signaling and attenuated T cell function. Here, we investigated how the SLP-76 Y145F mutation in CD8+T cells may impact GVHD and GVL responses in a mouse model of allogeneic HSCT. We employed a major MHC-mismatch mouse model of GVHD involving the transplantation of C57BL/6 (B6)-derived bone marrow (BM) into lethally irradiated Balb/c mice (B6àBalb/c). BM-transplanted mice were also injected with FACS-sorted CD8+ T cells either B6 wildtype (WT) mice or Y145F mice. Recipients of Y145F CD8+ T cells showed significantly (p<0.001) less weight loss, lower clinical score, and improved survival compared to mice injected with WT CD8+ T cells. Next, to determine whether the Y145F CD8+ T cells could mediate GVL effects, BM-transplanted Balb/c mice were additionally challenged intravenously with 1 x 105 luciferase-positive A20 leukemia cells. As expected, BM-transplanted Balb/c mice succumbed from A20 tumor growth, whereas mice injected with WT CD8+ T cells cleared the tumor but developed GVHD. Surprisingly, mice receiving Y145F CD8+ T cells eradicated the leukemic cells but did not develop GVHD. These data suggest that the Y145F mutation in CD8+T cells may be able to separate GVHD from GVL effects. In addition to defective TCR signaling observed in peripheral T cells of Y145F mice, a majority of Y145F KI CD8+ T cells adopt a memory-like CD44hi phenotype through exposure to high levels of IL-4 produced in the thymus of these mice. To test whether the CD44hi CD8+ T cell phenotype was necessary and/or sufficient for the separation of GVHD and GVL effects, BM-transplanted Balb/c mice were injected with FACS-sorted CD44hi or CD44lo CD8+ T cells from WT or Y145F KI mice and challenged with A20 leukemia cells. While BM-transplanted mice receiving CD44hi CD8+ T cells from Y145F mice displayed intact GVL responses without causing GVHD, mice injected with CD44lo CD8+ T cells from Y145F mice displayed impaired ability to clear the tumor cells. Moreover, recipients of CD44hi or CD44lo CD8+ T cells from WT mice cleared the tumor but exhibited severe GVHD. These findings were corroborated with data obtained with an inducible system, whereby CD8+ T cells are affected by the Y145F mutation only after full maturation and thus do not display a CD44hi phenotype (Y145F conditional knock-in mice). Bone marrow-transplanted recipients receiving Y145F conditional knock-in CD8+ T cells developed GVHD and exhibited an attenuated GVL response, suggesting that the Y145F mutation needed to be present during T cell development. Together, these data suggest that either the Y145F mutation or CD44hi phenotype alone in CD8+T cells is insufficient to separate GVHD from GVT. Our data demonstrate that perturbation of the TCR signaling pathway downstream of Y145 of SLP-76 in CD8+ T cells results in separation of GVHD from GVL effects. Experiments to mechanistically test how the Y145F signaling mutation synergizes with the CD44hi phenotype of CD8+ T cells to allow for the separation of the GVHD and GVL effects are currently underway. Our novel and unexpected finding could lead to a novel therapeutic strategy for treatment of acute GVHD after allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

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Zheng, Hong, Catherine Matte-Martone, Hongmei Li, Britt E. Anderson, Srividhya Venketesan, Hung Sheng Tan, Dhanpat Jain, Jennifer McNiff et Warren D. Shlomchik. « Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease ». Blood 111, n^o 4 (15 février 2008) : 2476–84. http://dx.doi.org/10.1182/blood-2007-08-109678.

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Much of the efficacy of allogeneic hematopoietic stem cell transplantation (alloSCT) in curing hematologic malignancies is due to a graft-versus-leukemia (GVL) effect mediated by donor T cells that recognize recipient alloantigens on leukemic cells. Donor T cells are also important for reconstituting immunity in the recipient. Unfortunately, donor T cells can attack nonmalignant host tissues and cause graft-versus-host disease (GVHD). We previously reported that donor CD4+ effector memory T cells (TEMs) do not cause GVHD but transfer functional T-cell memory. In the present work, we demonstrate in an MHC-mismatched model that CD4+ TEMs (unprimed to recipient antigens) mediate GVL against clinically relevant mouse models of chronic phase and blast crisis chronic myelogenous leukemia, without causing GVHD. By creating gene-deficient leukemias and using perforin-deficient T cells, we demonstrate that direct cytolytic function is essential for TEM-mediated GVL, but that GVL is retained when killing via FasL, TNF-α, TRAIL, and perforin is individually impaired. However, TEM-mediated GVL was diminished when both FasL and perforin pathways were blocked. Taken together, our studies identify TEMs as a clinically applicable cell therapy for promoting GVL and immune reconstitution, particularly in MHC-mismatched haploidentical alloSCTs in which T cell–depleted allografts are commonly used to minimize GVHD.

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Li, Nainong, Ying Chen, Wei He, Tangsheng Yi, Dongchang Zhao, Chunyan Zhang, Chia-Lei Lin, Stephen Forman et Defu Zeng. « Anti-CD3 Preconditioning Separates GVL from GVHD Via Modulating Host Dendritic and Donor T Cell Migration in TBI-Conditioned Recipients ». Blood 112, n^o 11 (16 novembre 2008) : 4611. http://dx.doi.org/10.1182/blood.v112.11.4611.4611.

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Abstract Host dendritic cells (DCs) play a critical role in initiating graft versus host disease (GVHD) and graft versus leukemia (GVL), and separation of GVL from GVHD remains a major challenge in the treatment of hematological malignancies by allogeneic hematopoietic cell transplantation (HCT). Here, we show that preconditioning with anti- CD3 mAb before conditioning with total body irradiation prevents GVHD but retains GVL in a HCT model of MHC-mismatched C57BL/6 donor to BALB/c host. Prevention of GVHD is associated with inhibition of donor T expression of homing and chemokine receptors and inhibition of GVHD target tissue expression of chemokines. Furthermore, inhibition of donor T expression of gut homing a4b7 and chemokine receptor CCR9 by anti-CD3 preconditioning results from reduction of CD103+ DCs in draining mesenteric lymph nodes, which is associated with downregulation of DC expression of CCR7, a receptor required for tissue DC migration to draining LN. These results indicate that anti-CD3 preconditioning reduces not only tissue release of chemokines but also prevents tissue DC migration to draining LN and subsequently reduces draining LN DC’s capacity in imprinting donor T tissue tropism. Therefore, modulation of host DCs by anti-CD3 preconditioning before HCT represents a new approach for separating GVL from GVHD. (Li and Chen contribute equally.

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Yu, Yu, Dapeng Wang, Chen Liu, Kane Kaosaard, Kenrick Semple, Claudio Anasetti et Xue-Zhong Yu. « Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice ». Blood 118, n^o 18 (3 novembre 2011) : 5011–20. http://dx.doi.org/10.1182/blood-2011-03-340315.

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Abstract Allogeneic hematopoietic cell transplantation (HCT) is effective therapy for hematologic malignancies through T cell–mediated GVL effects. However, HCT benefits are frequently offset by the destructive GVHD, which is also induced by donor T cells. Naive Th can differentiate into Th1 and Th17 subsets and both can mediate GVHD after adoptive transfer into an allogeneic host. Here we tested the hypothesis that blockade of Th1 and Th17 differentiation is required to prevent GVHD in mice. T cells with combined targeted disruption of T-bet and RORγt have defective differentiation toward Th1 and Th17 and skewed differentiation toward Th2 and regulatory phenotypes, and caused ameliorated GVHD in a major MHC-mismatched model of HCT. GVL effects mediated by granzyme-positive CD8 T cells were largely preserved despite T-bet and RORγt deficiency. These data indicate that GVHD can be prevented by targeting Th1 and Th17 transcription factors without offsetting GVL activity.

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Zheng, Hong, Catherine C. Matte, Srividhya Venkatesan, Britt E. Anderson, Mark J. Shlomchik et Warren D. Shlomchik. « CD4+ Effector Memory and Naive T Cells Mediate Graft-Versus-Leukemia Via Direct Recognition of MHCII on Leukemic Cells. » Blood 106, n^o 11 (16 novembre 2005) : 579. http://dx.doi.org/10.1182/blood.v106.11.579.579.

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Abstract One of the major challenges in allogeneic stem cell transplantation (alloSCT) is to separate graft-versus-host-disease (GVHD) from graft-versus-leukemia (GVL). We and others have previously demonstrated, in both major histocompatibility complex (MHC)-compatible/multiple minor histocompatibility antigen-mismatched and MHC-mismatched murine models of alloSCT, that spontaneous effector memory (EM) CD4+T cells depleted of regulatory CD25+ cells (CD4+CD44+CD62L-CD25-) do not cause GVHD. We have also shown that these EM CD4+ T cells can mediate GVL against a model of murine chronic phase of CML (mCP-CML) induced via retroviral transduction of BM cells with the bcr-abl fusion cDNA without causing GVHD (Zheng, et al ASH meeting 2004). In the present study we analyzed the effector mechanisms of these EM CD4+ cells in the B6bm12 → B6 MHCII disparate bone marrow transplantation (BMT) model. First, we demonstrated that the GVL activity of both EM and naïve CD4+ T cells required cognate interactions with CML targets as GVL was ineffective against mCP-CML induced in bone marrow from B6.I-Ab−/− (MHCII−) mice. Recipients of MHCII− mCP-CML died from mCP-CML between day 15-20 post BMT, regardless of whether they received EM or naïve CD4+ cells or no T cells at all. In light of data in the same model that parenchymal MHCII expression is not required for GVHD (Teshima et al, 2002), these data demonstrate distinct mechanisms for the cytotoxicity by CD4+ cells in GVL and GVHD—direct in the former and indirect in the latter. To further investigate the specific mechanisms of T cell killing, we tested the effectiveness of EM CD4+ cells in eradicating mCP-CML induced in bone marrow cells from Fas−/− and TNFR1/R2−/− mice. Both EM and naïve CD4+ cells mediated GVL against these gene deficient leukemias that was similar to that against wild type mCP-CML. In summary, these results suggest that EM and naive CD4+ cells mediate GVL via direct cognate engagement with targets. Their killing, however, does not depend on either FasL or TNF-α which suggests a dominant role for perforin, TRAIL, or both. Interestingly, although the mechanisms of recognition and killing of mCP-CML by either naïve or EM CD4+ T cells are so far indistinguishable, whereas only the naïve cells cause GVHD. Whereas a number of investigators have been able to separate mechanisms of killing in GVHD vs. GVL, this is to our knowledge the first clear demonstration of a difference in the mechanism of recognition between GVHD and GVL.

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Lu, Ying, Cynthia R. Giver, Akshay Sharma, Jian Ming Li, Katarzyna A. Darlak, Lauren M. Owens, John D. Roback, Jacques Galipeau et Edmund K. Waller. « IFN-γ and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity ». Blood 119, n^o 4 (26 janvier 2012) : 1075–85. http://dx.doi.org/10.1182/blood-2010-12-322891.

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Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) can eradicate chemorefractory leukemia through the graft-versus-leukemia (GVL) activity of donor T cells. However, the clinical success of allo-HSCT is limited by the graft-versus-host disease (GVHD) activity of donor T cells. We have reported previously that donor bone marrow precursors of plasmacytoid dendritic cells (pre-pDCs) can activate donor T cells toward T-helper 1 immune polarization in murine allogeneic HSCT. To optimize the GVL activity of these activated donor T cells and limit their graft versus host activity, we engineered the cellular constituents of an allogeneic hematopoietic stem cell graft with highly purified hematopoietic stem cells, T cells, and pre-pDCs and studied their GVL and GVHD activities in a murine model of allogeneic HSCT. Transplanted donor pre-pDCs expanded in vivo for 2 weeks after transplant, and they markedly augmented the activation and GVL activity of donor T cells while attenuating their GVHD activity, leading to an improved therapeutic index. Bidirectional signaling between donor T cells and donor pDCs with IFN-γ synthesis by donor T cells inducing indoleamine 2,3-dioxygenase synthesis by donor pDCs limited GVHD by altering the balance between donor T-reg and inflammatory T cells. Manipulating the content of donor DC precursors in allogeneic HSCT is a novel method to optimize the balance between GVL and GVHD.

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Perruche, Sylvain, Adrien Chauchet, Romain Vallion, Francis Bonnefoy et Philippe Saas. « Apoptotic cell injection-induced tolerance preserved graft versus leukemia effect (P2206) ». Journal of Immunology 190, n^o 1_Supplement (1 mai 2013) : 69.41. http://dx.doi.org/10.4049/jimmunol.190.supp.69.41.

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Abstract Allogeneic hematopoietic cell transplantation (AHCT) is a curative therapy for hematological malignancies unfortunately limited by graft-versus-host-disease (GvHD) occurrence. We have demonstrated that apoptotic cell injection can favor tolerance due to their immunomodulatory properties and thus increase engraftment and limit GvHD, through TGF-β and regulatory T cell dependent mechanisms. However, since apoptotic cell injection favors tolerance we evaluated whether graft-versus-leukemia (GvL) was preserved. In an experimental mouse model of T cell-depleted bone marrow transplantation (TCD BMT), leukemic A20 luciferase+ cells were injected at d0 and allogeneic donor T cell infusion was given on d6. Apoptotic cells were injected either on d0 or d6. Eradication of leukemic cells was observed in all mice receiving T cells, as attested by tumor growth evaluated by luminescence. Mice not receiving T cells died from leukemia within 27 days. Mice demonstrating GvL also developed GvHD according to Ferrara's score, and only 27% survived at d27. In contrast, 50% of mice receiving apoptotic cells on d0 or d6 survived at d27 and demonstrated long-term GvL with the complete absence of leukemic cell growth. Our data clearly demonstrated that GvHD suppression by apoptotic cell injection does not abrogate GvL activity. Thus, apoptotic cell injection should be considered in clinic to favor engraftment, prevent GvHD, conserving high GvL therapeutic activity.

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Zhang, Lingling, Shuting Zhao, Steven M. Devine, Xiaoming He et Jianhua Yu. « Nanoparticle-Encapsulated Allogeneic T Cells Mitigate Graft-Versus-Host Disease but Retain Graft-Versus-Leukemia Activity ». Blood 124, n^o 21 (6 décembre 2014) : 3820. http://dx.doi.org/10.1182/blood.v124.21.3820.3820.

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Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) has curative potential for hematological malignancies, but is often associated with life-threatening complications including graft-versus-host disease (GVHD). The graft-versus-leukemia (GVL) activity which accompanies HSCT is responsible for eradication of tumor cells and prevention of relapse. GVHD and GVL are usually associated with each other and the separation of the two activities occurs in limited circumstances. In this study, we aimed to mitigate GVHD but retain GVL through transplantation of allogeneic T cells encapsulated with bio-degradable nanoparticle materials. For the above purpose, donor T cells were encapsulated with chitosan and alginate through layer-by-layer coating using electrostatic deposition. Encapsulated donor T cells were characterized in vitro, and their ability to inhibit GVHD and retain GVL was determined in vivo after being transplanted together with non-encapsulated donor bone marrow (BM) cells in a C57BL/6 → BALB/c HSCT mouse model. We found 85.7% of donor T cells were successfully encapsulated by the above method (Fig 1A). In vitro studies showed that the encapsulation did not change the phenotype of T cells as defined through the following parameters: size, viability, proliferation, antibody binding, cytokine secretion, and cytotoxicity of T cells (Fig. 1B and data not shown). Mice transplanted with encapsulated allogeneic T cells exhibited less severe acute GVHD and prolonged survival (Fig. 1 C-E). The mice showed a lower GVHD score, less liver damage, a smaller CD8/CD4 T cell ratio, and a higher number of donor BM-derived cells following transplantation with encapsulated donor T cells (Fig. 1 C-E and data not shown). When this GVHD model was combined with implantation of A20 lymphoma cells, GVL of encapsulated T cells was not compromised, while GVHD was still suppressed and the mouse survival also prolonged (Figure 2). In summary, nanoencapsulation of T cells with bio-degradable materials attenuated the severity of GVHD but retained GVL, presenting a novel and potentially safer and effective approach of allogeneic HSCT for future clinical application. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Hanash, Alan M., Marcel R. M. Van Den Brink, Guoqiang Hua, Richard Kolesnick et Bruce R. Blazar. « Effect of IL-22 on intestinal stem cells, GVHD-related tissue damage, and GVL. » Journal of Clinical Oncology 30, n^o 15_suppl (20 mai 2012) : 6539. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.6539.

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6539 Background: Intestinal graft vs. host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (allo-BMT). Strategies to limit GVHD by selective promotion of epithelial regeneration in the absence of immunosuppression are largely unknown. Methods: We investigated the role of IL-22 in allo-BMT by utilizing wild type and IL-22 knockout (KO) mice as donors or recipients in allo-BMT. Results: We found that administration of an anti-IL-22 neutralizing antibody to allo-BMT recipients during the first month post-BMT led to increased GVHD mortality, indicating that IL-22 functioned to reduce GVHD severity post-BMT. In contrast, use of IL-22 KO donor T cells did not impair their ability to eliminate A20 lymphoma cells upon tumor challenge, thus indicating that IL-22 was not essential for donor T cells to mediate graft vs. lymphoma (GVL) responses. BMT with WT donors and recipients indicated that IL-22 levels in small and large intestine were increased after BMT and after radiation injury (RI) without BMT. IL-22 upregulation after RI was dependent on the presence of IL-23p40. Although intestinal IL-22 levels were increased after T cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 production was mediated by host-derived innate lymphoid cells (ILC) that were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in IL-22 KO mice led to increased apoptosis in epithelial crypts where the intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry and immunofluorescence demonstrated IL-22 receptor expression on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ reporter mice indicated that ISC were targeted by GVHD, and GVHD in IL-22 KO mice led to dramatic ISC depletion. Conclusions: IL-22 is critical for protection of host epithelium during GVHD and critical for protection of ISC, and it does not contribute to donor T cell GVL responses. These findings may have broad relevance for protection of ISC and intestinal epithelium in clinical GVHD and other inflammatory intestinal diseases, and may be useful for clinical separation of pathologic GVH and therapeutic GVL responses.

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Yang, Yong-Guang, Jin Qi, Min-Guang Wang et Megan Sykes. « Donor-derived interferon γ separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells ». Blood 99, n^o 11 (1 juin 2002) : 4207–15. http://dx.doi.org/10.1182/blood.v99.11.4207.

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The graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD)–inducing activity of CD8 T cells was compared in murine recipients of wild-type (WT) or interferon γ (IFN-γ)–deficient (GKO) allogeneic donor cells. CD8 T cells (or CD4-depleted splenocytes) from GKO donor mice induced more severe GVHD in lethally irradiated allogeneic recipients compared to the same cell populations from WT donors. Consistent with GVHD severity, donor CD8 T-cell expansion in allogeneic recipients was augmented in the absence of IFN-γ. These results demonstrate that IFN-γ does not stimulate but instead down-modulates GVHD induced by donor CD8 T cells. Remarkably, antihost lymphohematopoietic reactions, including GVL effects against host leukemia/lymphoma cells, of CD8 T cells correlated inversely with their GVHD-inducing activity, and those of GKO donors were markedly weaker than those mediated by WT donor CD8 T cells. These data show for the first time that GVHD-inducing activity and GVL effects of allogeneic CD8 T cells can be separated by a single cytokine, IFN-γ.

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Stern, Martin, Liesbeth C. de Wreede, Ronald Brand, Anja van Biezen, Peter Dreger, Mohamad Mohty, Theo M. de Witte, Nicolaus Kröger et Tapani Ruutu. « Impact of Graft-Versus-Host Disease On Relapse After Allogeneic Hematopoietic Stem Cell Transplantation, an EBMT Megafile Study ». Blood 120, n^o 21 (16 novembre 2012) : 469. http://dx.doi.org/10.1182/blood.v120.21.469.469.

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Abstract Abstract 469 Background: After allogeneic HSCT, graft-versus-host disease (GvHD) occurs through recognition of minor or major histocompatibility mismatches by donor derived T lymphocytes. The same mechanism also operates in the elimination of residual malignant cells (the graft-versus-leukemia or GvL effect). Earlier studies have already shown reduced relapse risks for patients developing GvHD (Weiden et al, NEJM 1979; Horowitz et al, Blood 1990). In particular, a large study in CML patients (Gratwohl et al, Blood 2002) showed that increasing grades of acute and chronic GvHD are associated with a proportional decrease in relapse risk. Incidence and severity of acute and chronic GvHD might therefore be used as surrogate markers for GvL effects. Transplant procedures have changed significantly since these publications. Increased use of unrelated donors, peripheral blood as stem cell source, and the introduction of reduced intensity conditioning regimens might affect the relationship between GvHD and GvL. Furthermore, previous studies have only analyzed transplants for AML, ALL and CML, the prevailing transplant indications at the time. Today, many patients receive transplants for MDS, plasma cell disorders (PCD) or lymphoma. We hypothesized that comparing the effect GvHD on relapse incidence might provide a useful surrogate marker for the susceptibility of different diseases to allo-immune effects. Methods: We studied 48,111 first allogeneic transplants carried out and reported to EBMT between 1998 and 2007. The impact of GvHD on relapse risk was assessed by including acute and chronic GvHD as time-dependent covariates in Cox models for cause-specific hazards adjusted for patient age, year of transplant, donor type, stem cell source, and type of conditioning regimen. Results: Diseases were CML (N=7,711), AML (14,539), ALL (6,802), MDS/MPN (6,958), lymphoma (N=8,231), or PCD (3,870). Donors were HLA identical family donor (N=28,030), and HLA-identical unrelated donors (N=14,422) or mismatched donors (N=5,659). Stem cell source was bone marrow (N=13,273), peripheral blood (N=34,022), or cord blood (N=816). Conditioning intensity was myeloablative (N=28,843), reduced intensity (15,889) or unknown (N=3,379). 14,764 (31%) of grafts were T-cell depleted. Incidence of grade I-IV acute GvHD was 49%, that of grade II-IV acute GvHD 30%. Limited chronic GvHD was diagnosed in 17% and extensive chronic GvHD in 20% of patients. Incidence of disease relapse was 22%, 28%, and 31% at 1, 2, and 4 years respectively. As shown previously, development of GvHD was associated with a reduced risk of relapse in our data. In CML, a clear reduction of relapse risk occurred with hazard ratios declining proportionally to severity of both acute and chronic GvHD (Figure 1). The protective effect of severe acute (grade III-IV) GvHD was similar to that of extensive chronic GvHD, whereas the protective effect of mild acute (grade I-II) GvHD was comparable to that of limited extensive GvHD. ALL was almost equally sensitive to GvHD as CML, whereas MDS/MPN and lymphomas showed intermediate sensitivity (Figure 1). Acute and limited chronic GvHD were only associated with modest reductions in relapse risk in AML and PCD. The limited sensitivity of PCD to allo-immune effects was also evident in Kaplan-Meier curves of disease-free survival where – in contrast to other diseases – no plateau developed during follow-up (Figure 2, upper panel). Similarly, hazard rates of disease relapse failed to drop to values near zero in patients with PCD (Figure 2, lower panel). Interestingly, despite a comparatively poor association of GvHD and relapse in AML patients, a plateau in the survival curve occurred and hazard rates dropped in parallel to other diseases, suggesting that curative GvL effects operating independently of GvHD might occur in this disease. Discussion: These data confirm earlier observations of a potent GvL effect associated with GvHD. While GvHD and GvL are significantly associated in all diseases, the strength of this association strongly differs between disease entities (strongest correlation in CML and ALL, weakest correlation in AML and PCD). A poor correlation might point to either insensitivity of a particular disease to GvL effects, to GvL effects operating in the absence of and independent from GvHD, or to a significant fraction of patients already cured before allogeneic SCT. Disclosures: No relevant conflicts of interest to declare.

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Sykes, M., MW Harty, GL Szot et DA Pearson. « Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects ». Blood 83, n^o 9 (1 mai 1994) : 2560–69. http://dx.doi.org/10.1182/blood.v83.9.2560.2560.

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Abstract We have recently shown that a short course of high-dose interleukin-2 (IL-2) can markedly inhibit the graft-versus-host disease (GVHD)- promoting activity of donor CD4+ T cells. The difficulty in dissociating GVHD-promoting from graft-versus-leukemia (GVL) effects of alloreactive donor T cells currently prevents clinical bone marrow transplantation (BMT) from fulfilling its full potential. To test the capacity of IL-2 treatment to promote such a dissociation, we have developed a new murine transplantable acute myelogenous leukemia model using a class II major histocompatibility complex-positive BALB/c Moloney murine leukemia virus-induced promonocytic leukemia, 2B-4–2. BALB/c mice receiving 2.5 x 10(5) 2B-4–2 cells intravenously 1 week before irradiation and syngeneic BMT died from leukemia within 2 to 4 weeks after BMT. Administration of syngeneic spleen cells and/or a 2.5- day course of IL-2 treatment alone did not inhibit leukemic mortality. In contrast, administration of non-T-cell-depleted fully allogeneic B10 (H-2b) spleen cells and T-cell-depleted B10 marrow led to a significant delay in leukemic mortality in IL-2-treated mice. In these animals GVHD was inhibited by IL-2 treatment. GVL effects were mediated entirely by donor CD4+ and CD8+ T cells. Remarkably, IL-2 administration did not diminish the magnitude of the GVL effect of either T-cell subset. This was surprising, because CD4-mediated GVHD was inhibited in the same animals in which CD4-mediated GVL effects were not reduced by IL-2 treatment. These results suggest a novel mechanism by which GVHD and GVL effects of a single unprimed alloreactive T-cell subset can be dissociated; different CD4 activities promote GVHD and GVL effects, and the former, but not the latter activities are inhibited by treatment with IL-2.

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Sykes, M., MW Harty, GL Szot et DA Pearson. « Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects ». Blood 83, n^o 9 (1 mai 1994) : 2560–69. http://dx.doi.org/10.1182/blood.v83.9.2560.bloodjournal8392560.

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We have recently shown that a short course of high-dose interleukin-2 (IL-2) can markedly inhibit the graft-versus-host disease (GVHD)- promoting activity of donor CD4+ T cells. The difficulty in dissociating GVHD-promoting from graft-versus-leukemia (GVL) effects of alloreactive donor T cells currently prevents clinical bone marrow transplantation (BMT) from fulfilling its full potential. To test the capacity of IL-2 treatment to promote such a dissociation, we have developed a new murine transplantable acute myelogenous leukemia model using a class II major histocompatibility complex-positive BALB/c Moloney murine leukemia virus-induced promonocytic leukemia, 2B-4–2. BALB/c mice receiving 2.5 x 10(5) 2B-4–2 cells intravenously 1 week before irradiation and syngeneic BMT died from leukemia within 2 to 4 weeks after BMT. Administration of syngeneic spleen cells and/or a 2.5- day course of IL-2 treatment alone did not inhibit leukemic mortality. In contrast, administration of non-T-cell-depleted fully allogeneic B10 (H-2b) spleen cells and T-cell-depleted B10 marrow led to a significant delay in leukemic mortality in IL-2-treated mice. In these animals GVHD was inhibited by IL-2 treatment. GVL effects were mediated entirely by donor CD4+ and CD8+ T cells. Remarkably, IL-2 administration did not diminish the magnitude of the GVL effect of either T-cell subset. This was surprising, because CD4-mediated GVHD was inhibited in the same animals in which CD4-mediated GVL effects were not reduced by IL-2 treatment. These results suggest a novel mechanism by which GVHD and GVL effects of a single unprimed alloreactive T-cell subset can be dissociated; different CD4 activities promote GVHD and GVL effects, and the former, but not the latter activities are inhibited by treatment with IL-2.

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Choi, Sung Won, Gerhard C. Hildebrandt, Ines Silva, Krystyna M. Olkiewicz, Stephen W. Chensue, Chen Liu, Meghana Chaudhary, Jacki Fisher, Thomas E. Lane et Kenneth R. Cooke. « Critical Role for CCR1:CCL5 (RANTES) Receptor Ligand Interactions in Modulating Allogeneic T Cell Responses Following Bone Marrow Transplantation. » Blood 106, n^o 11 (16 novembre 2005) : 3107. http://dx.doi.org/10.1182/blood.v106.11.3107.3107.

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Abstract Acute graft versus host disease (GVHD) and leukemic relapse are the most serious complications of allogeneic (allo) stem cell transplantation (SCT), and separating desirable graft-versus-leukemia (GVL) effects from GVHD remains the ultimate challenge to successful outcomes. The recruitment of activated T cells to host target tissues (GVHD) or sites of leukemic infiltration (GVL) is likely mediated by chemokine receptor:ligand interactions. CCR1 is a chemokine receptor that binds to CC chemokines including RANTES (CCL5), and is expressed on a variety of cells including activated T cells, monocytes, and macrophages. We have previously shown that mRNA expression of both CCR1 and RANTES is increased in GVHD target tissues following allo-SCT. Using a well established murine SCT model (B6->B6D2F1) and mice deficient in CCR1, we examined the contribution of CCR1 expression to allo T cell responses in vitro and to GVH and GVL effects in vivo. Lethally (1100cGy) irradiated B6D2F1 mice received SCT either from syngeneic (B6D2F1) or allogeneic (B6) CCR1+/+ or CCR1−/− donors. The severity of GVHD was assessed by survival and a well described clinical scoring system. Syngeneic SCT recipients all survived and were indistinguishable from naïve, untransplanted controls, whereas animals receiving allo-SCT from CCR1+/+ donors developed significant GVHD. By contrast, allo-SCT with CCR1−/− donor cells resulted in significantly improved survival (92% vs. 50%) and less severe clinical GVHD (p<0.01) by day 35 compared to allo-CCR1+/+ controls. GVL effects were next assessed by adding 500 P815 tumor cells (H-2d and syngeneic to host) to the bone marrow inoculum on day 0. F1 recipients of syngeneic BMT all died from tumor infiltration by day +15. Although all allo-SCT recipients effectively rejected their tumor, mice receiving CCR1-/− SCT had significantly improved leukemia free survival (45% vs. 5%) by day 60 compared to allo controls. At higher tumor doses, significant GVL activity remained in CCR1−/− SCT recipients, but the survival advantage was lost. Further examination of allo T cell responses in vivo revealed that day 7 splenic T cell expansion and serum IFNγ levels were significantly lower following CCR1−/− SCT (p < 0.01). Surprisingly, proliferation and IFNγ secretion were also reduced by ~70% when CCR1−/− T cells were stimulated with host antigens in vitro, whereas CTL activity remained equivalent to CCR1+/+ controls. The reduction in proliferation was not secondary to a migration defect, but was dependent on interactions between CCR1 and RANTES; neutralization of RANTES with a monoclonal antibody significantly reduced proliferation of CCR1+/+ T cells in a dose dependent manner. Finally, we found that GVHD mortality was also less when RANTES−/− mice were used as recipients in a second, MHC-disparate, SCT model (p = 0.03). Collectively these data demonstrate a critical role for CCR1 in donor T cell alloreactivity following SCT. These responses contribute to both GVHD and GVL effects in vivo and are likely dependent upon interactions between CCR1 and the chemokine ligand RANTES.

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Tsukada, Nobuhiro, Tetsuji Kobata, Yoshifusa Aizawa, Hideo Yagita et Ko Okumura. « Graft-Versus-Leukemia Effect and Graft-Versus-Host Disease Can Be Differentiated by Cytotoxic Mechanisms in a Murine Model of Allogeneic Bone Marrow Transplantation ». Blood 93, n^o 8 (15 avril 1999) : 2738–47. http://dx.doi.org/10.1182/blood.v93.8.2738.408k30_2738_2747.

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Allogeneic bone marrow transplantation (allo-BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect. In the present study, we examined the contribution of cytotoxic effector mechanisms, which are mediated by tumor necrosis factor- (TNF-), Fas ligand (FasL), or perforin, to GVHD and GVL effect in a murine BMT model. Bone marrow cells plus spleen cells (BMS) from wild-type, FasL-defective, or perforin-deficient donors were transferred into lethally irradiated recipients in the parent (C57BL/6) to F1 (C57BL/6 × DBA/2) BMT model with or without prior inoculation of DBA/2 leukemia L1210 or P815 mast cytoma cells. The effect of anti–TNF- antibody administration was also examined. Whereas the defect or blockade of each cytotoxic pathway could ameliorate lethal acute GVHD, the GVL effect was differentially affected. The wild-type BMS recipients died of acute GVHD within 50 days without residual leukemia cells. The FasL-defective BMS recipients showed 60%< survival over 80 days without acute GVHD or residual leukemia cells. Administration of anti–TNF- antibody resulted in early leukemia relapse and the recipients died within 25 days with massive leukemia infiltration in the liver. The perforin-deficient BMS recipients died within 60 days with residual leukemia cells. These results suggest that blockade of the Fas/FasL pathway could be used for ameliorating GVHD without impairing GVL effect in allo-BMT.

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Li, Nainong, Ying Chen, Wei He, Tangsheng Yi, Dongchang Zhao, Chunyan Zhang, Chia-Lei Lin et al. « Anti-CD3 preconditioning separates GVL from GVHD via modulating host dendritic cell and donor T-cell migration in recipients conditioned with TBI ». Blood 113, n^o 4 (22 janvier 2009) : 953–62. http://dx.doi.org/10.1182/blood-2008-06-165522.

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Abstract Host dendritic cells (DCs) play a critical role in initiating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL), and separation of GVL from GVHD remains a major challenge in the treatment of hematologic malignancies by allogeneic hematopoietic cell transplantation (HCT). Here, we show that preconditioning with anti-CD3 monoclonal antibody before conditioning with total body irradiation (TBI) prevents GVHD but retains GVL in a HCT model of major histocompatibility complex (MHC)–mismatched C57BL/6 donor to BALB/c host. Prevention of GVHD is associated with inhibition of donor T-cell expression of homing and chemokine receptors, and inhibition of GVHD target tissue expression of chemokines. Furthermore, inhibition of donor T-cell expression of gut homing α4β7 and chemokine receptor (CCR)9 by anti-CD3 preconditioning results from a reduction of CD103+ DCs in draining mesenteric lymph nodes (LNs), which is associated with down-regulation of DC expression of CCR7, a receptor required for tissue DC migration to draining LNs. These results indicate that anti-CD3 preconditioning reduces not only tissue release of chemokines but also prevents tissue DC migration to draining LNs and subsequently reduces the capacity of DCs of draining LNs to imprint donor T-cell tissue tropism. Therefore, modulation of host DCs by anti-CD3 preconditioning before HCT represents a new approach for separating GVL from GVHD.

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Park, Minhwa, Kyung-Ah Cho, So-Youn Woo et Kyung-Ha Ryu. « Macrophage Inflammatory Protien-2/CXCR2 Blockade Attenuates Acute Graft-versus-Host Disease while Preserving Graft-versus-Leukemia Activity (126.16) ». Journal of Immunology 188, n^o 1_Supplement (1 mai 2012) : 126.16. http://dx.doi.org/10.4049/jimmunol.188.supp.126.16.

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Abstract Graft-versus-host disease (GVHD) is the principal complication after allogeneic bone marrow transplantation (BMT). Strategies that effectively separate the beneficial GVL effects from GVHD toxicity are necessary for enhanced survival after BMT. GVHD mice were induced by infusion of both donor BM cells and spleen cells into BU-CY conditioned recipient female BALB/c mice. Tumor-bearing GVHD mice were also made adding A20 cells. A total of 31 cytokines and chemokines were measured in the liver, intestine, and skin in GVHD mice by Luminex Multiplex assay. Four cytokines, G-CSF, KC, MIP-2, and IL-23, were commonly unregulated in target organs at the initial GVHD stage and were reduced by neutralizing MIP2/CXCR2 axis ligation. CXCR2 blockade on donor T cells and systemic administration of anti-MIP-2 neutralizing antibodies to BMT recipients caused a significant decrease in both systemic GVHD and target organ histopathology. GVL responses (BCL2 expression or B220+/CD19+ cells in BM and PB) after MIP-2/CXCR2 blockade were largely preserved and mortality was significantly delayed compared to control allogeneic BMT recipients. These data suggest that blocking the MIP-2/CXCR2 axis represents a novel strategy to separate the toxicity of GVHD from the beneficial GVL effects after allogeneic BMT.

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