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1
Tan, Peng H., John B. Yates, Shao-An Xue, Cliburn Chan, William J. Jordan, Jennifer E. Harper, Martin P. Watson, et al. "Creation of tolerogenic human dendritic cells via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression." Blood 106, no. 9 (November 1, 2005): 2936–43. http://dx.doi.org/10.1182/blood-2005-05-1826.
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AbstractActivation of T lymphocytes requires the recognition of peptide–major histocompatibility complexes (MHCs) and costimulatory signals provided by antigen-presenting cells (APCs). It has been shown that T-cell activation without costimulation can lead to anergy. In this study, we developed a novel strategy to inhibit expression of B7 molecules (CD80/86) by transfecting APCs with a gene construct encoding a modified cytotoxic T lymphocyte antigen 4 (CTLA4) molecule (CTLA4-KDEL) that is targeted to the endoplasmic reticulum (ER). APCs expressing this construct failed to express CD80/86 on their surface, were unable to stimulate allogeneic and peptide-specific T-cell responses, and induced antigen-specific anergy of the responding T cells. Cells expressing CTLA4-KDEL do not up-regulate the indoleamine 2, 3-dioxygenase enzyme, unlike cells treated with soluble CTLA4-immunoglobin (Ig). This gene-based strategy to knock out surface receptors is an attractive alternative to using immature dendritic cells for preventing transplant rejection and treating of autoimmune diseases.
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Kay, NE, and RT Perri. "Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regulate B-cell immunoglobulin synthesis [published erratum appears in Blood 1989 Jun;73(8):2232]." Blood 73, no. 4 (March 1, 1989): 1016–19. http://dx.doi.org/10.1182/blood.v73.4.1016.bloodjournal7341016.
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B-chronic lymphocytic leukemia (CLL) patients frequently suffer from moderate to severe hypogammaglobulinemia. This complication is a serious cause of morbidity and mortality in this disorder. There is recent evidence that natural killer (NK) cells modulate B-cell immunoglobin (Ig) synthesis/secretion. The authors therefore evaluated the circulating NK cells from B-CLL patients on their ability to regulate mitogen-induced B-cell Ig synthesis. Blood, NK cells (CD16+, CD3-) from three B-CLL patients with hypogammaglobulinemia were able to clearly down-regulate the pokeweed mitogen (PWM)-induced-B-cell Ig secretion. In contrast, CD16+, CD3- cells from age-sex-matched controls or B-CLL patients with normal Ig were either nonregulatory or enhanced mitogen-induced B-cell Ig secretion. An alternative explanation for hypogammaglobulinemia in B-CLL patients is the immunomodulation of B- cell Ig production/secretion by CD16+, CD3- blood cells.
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Kay, NE, and RT Perri. "Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regulate B-cell immunoglobulin synthesis [published erratum appears in Blood 1989 Jun;73(8):2232]." Blood 73, no. 4 (March 1, 1989): 1016–19. http://dx.doi.org/10.1182/blood.v73.4.1016.1016.
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Abstract B-chronic lymphocytic leukemia (CLL) patients frequently suffer from moderate to severe hypogammaglobulinemia. This complication is a serious cause of morbidity and mortality in this disorder. There is recent evidence that natural killer (NK) cells modulate B-cell immunoglobin (Ig) synthesis/secretion. The authors therefore evaluated the circulating NK cells from B-CLL patients on their ability to regulate mitogen-induced B-cell Ig synthesis. Blood, NK cells (CD16+, CD3-) from three B-CLL patients with hypogammaglobulinemia were able to clearly down-regulate the pokeweed mitogen (PWM)-induced-B-cell Ig secretion. In contrast, CD16+, CD3- cells from age-sex-matched controls or B-CLL patients with normal Ig were either nonregulatory or enhanced mitogen-induced B-cell Ig secretion. An alternative explanation for hypogammaglobulinemia in B-CLL patients is the immunomodulation of B- cell Ig production/secretion by CD16+, CD3- blood cells.
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Karkhanis, Vrajesh, Warren Fiskus, Christopher Peter Mill, Abhishek Maiti, Bernardo H. Lara, James V. Maher, Isean Bhalla, et al. "Efficacy of Targeted Therapy in Novel Pre-Clinical in Vitro and In Vivo Models of Richter Transformation-Diffuse Large B-Cell Lymphoma (RT-DLBCL)." Blood 134, Supplement_1 (November 13, 2019): 3961. http://dx.doi.org/10.1182/blood-2019-132041.
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Richter Transformation (RT) is defined as the development of aggressive DLBCL (mostly ABC-type) in up to ~15% of patients with antecedent or concurrent diagnosis of CLL. Based on the comparison of immunoglobin gene rearrangements, approximately 80% of RT-DLBCL arise due to a direct clonal evolution of the underlying CLL clone, i.e., clonally related (CLR) RT-DLBCL, which exhibit poor median survival (MS) of one year. Approximately 20% of RT-DLBCLs are clonally unrelated (CUR) to the underlying CLL, arising most likely due to branched clonal evolution from a common pre-CLL progenitor. CUR RT-DLBCLs exhibit a better MS of 5 years. Although chemo-immunotherapy and treatment with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib or anti-apoptotic BCL2 inhibitor venetoclax can induce remissions, they fail to induce prolonged disease-free survival in RT-DLBCL. Majority of patients relapse with therapy-refractory disease. Lack of availability of in vitro cultured RT-DLBCL cells or PD xenograft models has prevented pre-clinical testing and development of novel targeted agents against RT-DLBCL. Here, we report the establishment of 3 patient-derived xenograft (PDX) models of RT-DLBCL. Based on immunoglobulin heavy chain (IGH) clonality testing by NGS, the RT-DLBCL RT17 was CLR, RT15 was CUR and RT5 was of indeterminate clonality. The PDXs were generated by tail-vein infusion and engraftment of luciferase-transduced CD19+ RT-DLBCL cells in NSG mice. The RT-DLBCL PDXs grew in the bone marrow and spleen, causing marked splenomegaly, requiring euthanasia 4 to 6 weeks after engraftment. All three RT-DLBCL PDX cells were EBV-negative by genomic and EBNA2 protein expression analyses. NextGen DNA sequencing of RT17, RT15, and RT5 cells showed large numbers of genetic mutations, including mutations in TP53, ATM, NOTCH2, TET2 and MLL3 genes with a high variant allelic frequencies. Array-CGH showed DNA copy gains or losses in multiple chromosomes, including 3, 8, 9, 11, 12, 17 and 18. A 5'-MYC amplification was detected by FISH analysis in RT5 DLBCL cells. ATAC-Seq showed increased signal intensity representing increased chromatin accessibility in the RT-DLBCL cells compared to CD34+ normal progenitors. High peak numbers were detected in specific loci, including TCF4, PAX5, IRF4, MYB, MYC, BCL2L1 and BCL-2. Anti-H3K27Ac ChIP-Seq analysis showed increased average, normalized read-densities at super-enhancers/enhancers (SEs/Es), including those of TCF4, PAX5, IRF4, BCL2 (RT17 and RT15) and MYC (RT5). Western analyses showed that all three RT-DLBCL PDX cells expressed TCF4, c-Myc, and BRD4, with highest expression in RT5 cells. Accordingly, RT5 cells were more sensitive than cells RT17 and RT15 cells to the BET protein inhibitor (BETi) OTX015-induced apoptosis. This was associated with greater, OTX015-mediated, depletion of c-Myc in RT5 cells. RT17 and RT15 expressed high levels of BCL2, Bcl-xL and MCL1, whereas RT5 lacked BCL2 expression. Consistent with this, RT17 and RT15 cells were significantly more sensitive than RT5 cells to venetoclax-induced apoptosis (p < 0.01). RT17 and RT15, but not RT5 cells, expressed NFkB2 (p52), consistent with activation of non-canonical NFkB signaling. This was associated with resistance of RT17 and RT15 cells to ibrutinib-induced apoptosis (p < 0.001). However, co-treatment with OTX015 and ibrutinib or venetoclax induced synergistic lethality in all RT-DLBCL cells (combination indices < 1.0). BET-PROTAC ARV-825 and ARV-771 treatment depleted BRD4, leading to marked reduction in c-Myc levels and apoptosis of all RT-DLBCL cells. Treatment with the ATP-competitive, CDK9 inhibitor NVP2 also dose-dependently induced apoptosis in RT-DLBCL cells associated with depletion of c-Myc, Bcl-xL, and MCL1 protein levels. These findings highlight the activity and support further in vitro and in vivo evaluation of BETi, BET-PROTAC or CDK9i-based combinations with ibrutinib or venetoclax against genetically-profiled RT-DLBCL cells that are clonally-related or clonally-unrelated to the antecedent CLL. Disclosures Maiti: Celgene: Other: research funding. Bhalla:Beta Cat Pharmaceuticals: Consultancy. Khoury:Angle: Research Funding; Stemline Therapeutics: Research Funding; Kiromic: Research Funding.
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Wang, Jing, Shuang Geng, Yuping Zhong, Mingyi Chen, Wenming Wang, Yuhong Pang, Jiajia Zhang, Yuanyuan Liu, Yanyi Huang, and Hongmei Jing. "Detection of Circulating Plasma Cells in Multiple Myeloma with Extramedullary Plasmacytoma." Blood 126, no. 23 (December 3, 2015): 5328. http://dx.doi.org/10.1182/blood.v126.23.5328.5328.
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Abstract Objective: To detect the circulating plasma cells (cPCs) in patients of multiple myeloma (MM) with or withoutextramedullary plasmacytoma (EMP). Methods: The 21 patients of MM samples were collected from April 2014 to April 2015. There were 12 males, 9 females, with a median age of 60 (49 to 76 years old). Peripheral blood and bone marrow were examined before treatment or after EMP. Multi parameter flow cytometry (MFC) was used to analyze abnormal plasma cells (tumor cells) in samples of bone marrow and CD138 MACS positive sorting peripheral blood. The antibodies used in the flow cytometry were CD38-APC, CD138-PE, CD81-PE-Cy7, CD45-PacBlue, CD19-Percp-Cy5.5, CD56-mCherry-PE-ef610, CD117-AmCyan, CD16, Zombie-APC-Cy7. Results: In these 21 patients, he ratio of sex is 1.33:1, the median age is 60 (49-76). The immunoglobin type is as follows: IgG κ 7 cases, IgG λ 5 cases, IgG 2 cases, IgA κ 3 cases, IgA λ 2 cases, λ light chain 1 cases. The morphology of bone marrow aspiration showed more than 15% plasma cells and abnormal plasma cells can be seen in bone marrow in cytometry. 9 of 21 patients diagnosed MM with EMP, 2 of them find EMP when initial diagnosis and 7 of them find EMP in the course of disease (6 months to 8 years). The sites of the EMP included head, jaw, chest wall, side of the rib, the soft tissue of the sacral region and the vertebral body and all patients had bone involvement. In 17 patients with complete clinical data, bone marrow and peripheral blood specimens, the cPCs negative rate was 87.5%(7/8) in EMP negative patients, while the cPCs positive rate was 66.7% (6/9) in EMP positive patients, the difference among groups was statistically significant (chi square values: 5.13, p = 0.024). Conclusion: MFC has been widely used in diagnosis and minimal residual disease surveillance of MM, here we established the detection method of cPCs in MM patients, and it is valuable for clinical diagnosis and prognosis judgment. Disclosures No relevant conflicts of interest to declare.
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Gilbreath, Tyler, Samantha Swenson, and Shannon M. Buckley. "Role of Ubiquitin E3 Ligase UBR5 in B-Cell Development and Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 2794. http://dx.doi.org/10.1182/blood-2019-128747.
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Mantle Cell Lymphoma (MCL) is a non-Hodgkin's lymphoma (NHL) that typically affects older adults. In MCL, there is uncontrolled growth of B cells within the mantle zone of lymph node and spleen germinal centers. The vast majority of MCL cases have a translocation of chromosome 11 and 14 which juxtaposes the cyclin D1 gene, CCND1, with the immunoglobin heavy chain gene promoter (Eµ) and leads to the overexpression of CCND1. This translocation of CCND1 is not enough to cause MCL by itself and additional mutations are needed for MCL to develop. Although MCL only represents ~5% of NHL patients, it has the poorest survival rate among NHL sub-types due to a lack of successful therapeutic treatments. As such, it is important to identify potential targets for treatment. Recently published data shows that in 18% of all MCL patients have a mutation in the gene encoding the E3 ubiquitin ligase, UBR5. UBR5 is part of the ubiquitin proteasome system, a degradation/recycling pathway in which proteins are tagged with a ubiquitin protein and degraded by the proteasome. Of the identified UBR5 mutations, over 60% of the mutations are truncations at the carboxy terminus that cut off the cysteine residue linked to ubiquitin transfer in exon 59 suggesting a catalytic dead mutant protein is produced. Interestingly, UBR5HECT mutations are specific to MCL and are not found in other sub-types of NHL. By studying UBR5, we can determine the role of UBR5 mutations in MCL, elucidate molecular mechanism of UBR5 in B cell development, and identify potential therapeutic targets. In order to study the role of UBR5 in B cell development and MCL, we generated a conditional mouse model targeting exon 58 similar to mutations in MCL patients and crossed the mice with Mb1CRE/WT mice to delete exon 58 specifically in B cells at the pro-pre B cell stage of B cell development. Mb1CRE/WT; Ubr5fl/fl mice shows that mice lacking the carboxy terminus of UBR5 have a block in B cell differentiation at the mature B cell IgM+ IgD+ stage within the spleen. Mb1CRE/WT; Ubr5fl/fl mice showed a marked decrease of mature IgM+ IgD+ B cells in the BM and spleen. Specifically, within the spleen, Mb1CRE/WT; Ubr5fl/fl mice produce abnormal follicular B cells (higher IgM and CD23 expression and lower IgD and CD22 expression) and significant reductions in marginal zone B cells, plasma cells, size of germinal centers, and number of germinal centers. Mass spectrometry comparing mouse B220+ splenocytes in Mb1CRE/WT; Ubr5fl/fl compared to Mb1CRE/WT; Ubr5+/+ mice showed that UBR5 in B cells in Mb1CRE/WT; Ubr5fl/fl mice has over two-fold more expression. Additionally, IgD was the most downregulated protein, B cell specific proteins were downregulated, and proteins involved with mRNA splicing were upregulated within the mass spectrometry. The loss of the UBR5 HECT domain leads to increased UBR5 half-life and upregulation of spliceosome proteins. Coupled together, this suggests that the loss of the carboxy terminus of UBR5 impedes B cell maturation by disrupting IgD expression, potentially by interfering with mRNA splicing. Finally, we have crossed and are currently aging our Mb1CRE/WT; Ubr5fl/fl mice with an EµCCND1 mouse model to determine if Ubr5 mutations lead to tumorigenesis. These studies aim to identify the role of UBR5 in the context of normal B cell development and lymphomagenesis with the goal of identifying therapeutic targets for drug discovery. Disclosures No relevant conflicts of interest to declare.
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Hasipek, Metis, Dale Grabowski, Yihong Guan, Anand D. Tiwari, Xiaorong Gu, Jason Valent, Jaroslaw Maciejewski, Frederic Joel Reu, James G. Phillips, and Babal K. Jha. "A Novel Therapeutic Strategy for Preferential Elimination of Multiple Myeloma Cells By Targeting Protein Disulfide Isomerase." Blood 136, Supplement 1 (November 5, 2020): 32–33. http://dx.doi.org/10.1182/blood-2020-142847.
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Multiple myeloma (MM) is a genetically complex hematological disease which is characterized by clonal proliferation of plasma cells in the bone marrow and secretion of monoclonal antibodies and cytokines that can damage bone, bone marrow, and kidney function1. MM cells constantly operate at the limit of their unfolded protein response (UPR) in the face of a secretory load of immunoglobin (Ig) and cytokines that is unparalleled by any other mammalian cell 2,3 and microenvironmental factors that aggravate the degree of physiologic misfolding that occurs during synthesis of secreted proteins. The endoplasmic reticulum (ER) resident protein disulfide isomerases (PDIs) are indispensable for folding of secreted proteins that require intramolecular disulfide-bond arrangement 4 like antibodies and many cytokines. As the main PDI family member, near-complete function of PDIA1 is essential for survival of MM cells while its inhibition should be manageable by the UPR in normal cells creating an opportunity for a large therapeutic window for PDI inhibitors in MM. Previously, we discovered and characterized an irreversible PDI inhibitor (CCF642) that induced cell death in MM cells at doses that did not affect survival of normal bone marrow cells. However, CCF642 has poor solubility and suboptimal selectivity precluding clinical translation. Using structure guided medicinal chemistry, we developed and characterized a highly potent and selective PDI inhibitor, with 10-fold higher potency (Fig 1B) and selectivity. CCF642-34 showed remarkable selectivity against PDIA1 and off-target bindings were eliminated when compared to CCF642 (Fig 1C). In addition to improved selectivity and in vitro PDI inhibition, CCF642-34 demonstrated more than 3-fold higher potency compared to CCF642 against MM1.S and bortezomib resistant MM1.S cells remained sensitive to CCF642-34. Importantly, the novel analogue CCF642-34 has 18-fold better potency in restricting the colony forming abilities of RPMI1640 cells while at no effect on the clonogenic potential of CD34+ cells derived from healthy bone marrow was observed at equivalent doses. CCF642-34 induces ER stress in MM1.S cells as observed in dose and time dependent cleavage of XBP1, IRE1α oligomerization and the profound induction of programmed cell death reflected by PARP and caspase 3 cleavage. To further analyze the modes of action of CCF642-34 and CCF642 we performed RNAseq after treatment of MM1.S cells and found exclusive induction of genes associated with UPR and downstream cell cycle and apoptotic responses for CCF642-34 while additional genes affecting were detected after CCF642 treatment. There were 362 and 568 differentially expressed genes in CCF642-34 and CCF-642 (compared to controls) treated MM1.S cells, respectively. Among these differentially expressed genes 87 down regulated and 142 upregulated were common to both, including downregulation of cell division and mitotic cell cycle process, and upregulation of response to ER stress, unfolded protein response, and apoptotic process gene sets. Results confirm that both CCF642 and CCF642-34 treatment act by inducing lethal ER-stress with greater selectivity for CCF642-34. Accordingly, hierarchical clustering showed distinct gene expression profiles in 642-34 and 642 treated MM1S cells (Fig. 2). CCF642-34 is orally bioavailable and highly efficacious in against established multiple myeloma in a syngeneic 5TGM1-luc/C57BL/KaLwRij model of myeloma. All vehicle control animals were dead by 52 days while 3 out of 6 mice lived beyond 6 months with no sign of relapse. In summary, we synthesized and characterized a novel lead PDIA1 inhibitor based on structure-guided medicinal chemistry that has improved pharmacologic properties to act as novel lead for clinical translation. References: 1. Manier S, Salem KZ, Park J, et al. Genomic complexity of multiple myeloma and its clinical implications. Nat. Rev. Clin. Oncol. 2017; 2. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: Spotlight review. Leukemia. 2009; 3. Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer. 2014; 4. Freedman RB, Hirst TR, Tuite MF. Protein disulphide isomerase: building bridges in protein folding. Trends Biochem. Sci. 1994; Disclosures Valent: Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau; Amgen Inc.: Other: Teaching, Speakers Bureau.
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Edwards, Donna R., Pei-yu Kuo, Alessandro Lagana, Seongjee Park, Pavithra Nedumaran, Violetta Leshchenko, Stephanie Christie, Shashidhar Jatiani, Julie Teruya-Feldstein, and Samir Parekh. "Aberrant Cell Cycle Programming Confers Rapid Lethality in the EuSOX11+ CCND1 MCL Mouse Model." Blood 136, Supplement 1 (November 5, 2020): 6–7. http://dx.doi.org/10.1182/blood-2020-143038.
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Mantle Cell Lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation. This hallmark oncogenic event transposes CCND1 (11q13) under the control of the immunoglobin heavy chain (IGH) locus (14q32) resulting in constitutive cyclin D1 expression. Although Cyclin D1 (CCND1) overexpression is a key hallmark of MCL, CCND1 overexpressing murine models do not effectively recapitulate the MCL phenotype. Our published data demonstrated that SOX11 binds and regulates components in multiple oncogenic pathways in MCL (Kuo et. al., Oncogene 2015). Furthermore, we recently demonstrated that SOX11 promotes BCR signaling to drive MCL-like pathogenesis utilizing a SOX11 overexpressing (Eu-SOX11) murine model (Kuo et. al., Blood 2018). Given that the majority of classic human MCL co-express CCND1 and SOX11, we hypothesize that these oncogenes may cooperate to drive the pathogenesis of classical MCL. To study in vivo cooperation between CCND1 and SOX11, we crossed Eu-SOX11 mice with Eu-CCND1 mice to generate Eu-SOX11:CCND1 double transgenic (DT) mice. We have previously reported an significant increase in the fraction of CD5+CD19+CD23- MCL cells in the peripheral blood, spleens, lymph nodes and bone marrow of Eu-SOX11 mice and this fraction was further enhanced in DT mice (Fig.1A). We have now conducted a 2-year survival analysis on all 4 genotypes and found significantly reduced survival in DT as compared to Eu-SOX11 mice (Fig.1B). Median survival in DT mice is 16.5 months as compared to 19.7 months in Eu-SOX11 mice. Taken together, our results demonstrate a B-cell specific in vivo cooperation between SOX11 and CCND1 towards promoting a lethal MCL phenotype. RNA sequencing of splenocytes from DT versus SOX11-Tg mice showed significant enrichment of E2F1 target genes (p<.02) as a top oncogenic pathway (Fig.1C). Our previous results with CDK4/6 inhibition demonstrate a profound reduction in S phase in MCL cells (Divakar et. al., Leukemia 2016). We have developed small molecule SOX11 inhibitors using a SOX11-DNA homology model we built using the crystal structure of the SOX4-DNA binding domain as a template. SOX11 small molecular inhibitors in combination with CDK4 inhibitors will be used to further dissect the mechanism of cooperation between SOX11 and CCND1 and develop a therapeutic strategy for MCL that is mechanistically distinct from BTK or Bcl-2 inhibition. Disclosures Teruya-Feldstein: Edge Anthem: Consultancy. Parekh:Karyopharm: Research Funding; Celgene: Research Funding; Foundation Medicine: Consultancy.
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Bu, Yongqian, Caiwen Jia, Xiaowei Tian, Kalibixiati Aimulajiang, Muhammad Ali Memon, Ruofeng Yan, Xiaokai Song, Lixin Xu, and Xiangrui Li. "Immunization of Goats with Recombinant Protein 14-3-3 Isoform 2(rHcftt-2) Induced Moderate Protection against Haemonchus contortus Challenge." Pathogens 9, no. 1 (January 6, 2020): 46. http://dx.doi.org/10.3390/pathogens9010046.
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A previous study identified that isoform 2 (Hcftt-2) of the 14-3-3 protein of Haemonchus contortus (H. contortus) could suppress immune functions of goat peripheral blood mononuclear cells (PBMCs) and might be a potential vaccine target, as neutralization of the protein function may enhance anti-parasite immunity. In this research, the recombinant Hcftt-2 was evaluated for its immunoprotective efficacy against H. contortus infection in goats. Five experimental goats were immunized twice with rHcftt-2 along with Freund’s adjuvant. The five immunized goats and five nonimmunized goats (adjuvant only) were challenged with 5000 L3-stage H. contortus larvae after 14 days of second immunization. Five nonimmunized and uninfected goats (adjuvant only) were set as the uninfected group. A significant increase in the serum immunoglobin G(IgG) and serum IgA levels were identified in the rHcftt-2 immunized animals. The mean eggs per gram in feces (EPG) and the worm burdens of rHcftt-2 immunized group were reduced by 26.46% (p < 0.05) and 32.33%, respectively. In brief, immunization of goats with rHcftt-2 induced moderate protection against H. contortus challenge.
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Wake, Matthew, Jonathan Papworth, Luke Bayliss, Benjamin Grimshaw, Natalie Rynkiewicz, Jemima Paterson, Alicia Poindron, et al. "Generation and Characterisation of KY1066, a Fully Human Antibody Targeting the Enzymatic Activity of Matriptase-2 for the Treatment of Iron Overload in Beta Thalassemia." Blood 134, Supplement_1 (November 13, 2019): 3532. http://dx.doi.org/10.1182/blood-2019-124075.
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Beta thalassemia is an inherited hemoglobinopathy caused by a genetic defect in beta-globin gene and characterised by ineffective erythropoiesis, iron overload, splenomegaly and anemia. Excessive EPO production, resulting from the anemia, has a suppressive effect on the iron regulator hepcidin leading to increased iron absorption from the gut and release from internal stores. This in turn leads to tissue iron overload in transfusion independent (NTDT) patients and exacerbates the situation in transfusion dependent (TDT) patients. Primary standard of care treatment for TDT patients involves regular blood transfusions resulting in secondary iron overload and toxic tissue damage caused by non-transferrin bound iron (NTBI), which requires iron chelator treatment. Although transfusions and iron chelation have improved TDT patient prognosis, the iron overload experienced by some patients today still represents an unmet clinical need. The role of TMPRSS6 in iron regulation is already well established and reducing Tmprss6 expression was shown to increase hepcidin expression, correcting the iron overload, splenomegaly and anemia in Hbbth3/+ mice (Guo et al, JCI, 2013). Here we describe a first-in-class antibody targeting MTP-2, termed KY1066, for the treatment of diseases of iron overload, such as beta thalassemia. Through immunising mice transgenic for human immunoglobin heavy and light chain variable regions with purified human MTP-2 extra-cellular domain (ECD) and full-length human MTP-2 expressed on cells, we were able to obtain cross-reactive, MTP-2-specific monoclonal antibodies (mAbs). Our lead molecule, KY1066, was found to be a cross-reactive neutraliser of MTP-2 enzymatic activity both in vitro and in vivo and mechanistically blocks MTP-2 through binding to the serine protease (SP) domain active site, preventing cleavage of substrates. As a result, it was seen to increase BMP/SMAD signalling and elevate levels of hepcidin expression from hepatocyte cells following a single I.P. dose (10 mg/kg) in C57BL/6J mice. The elevation of hepcidin decreased serum iron and transferrin saturation through increased internalisation and degradation of ferroportin. In Hbbth3/+ mice, a single I.P. dose (10 mg/kg) showed a decrease of 52% and 47% in serum iron and transferrin saturation (TSAT) respectively, at the 2-week timepoint. Furthermore, with repeat dosing, we were able to show consistent iron restriction in a Hbbth3/+ mice over multiple weeks. Together this provides evidence KY1066 has the potential to treat iron overloaded patients, such as in beta thalassemia, to improve the anemia and reduce the transfusion and iron chelation need. Disclosures Wake: Kymab Ltd: Employment, Equity Ownership. Papworth:Kymab Ltd: Employment, Equity Ownership. Bayliss:Kymab Ltd: Employment, Equity Ownership. Grimshaw:Kymab Ltd: Employment, Equity Ownership. Rynkiewicz:Kymab Ltd: Employment, Equity Ownership. Paterson:Kymab Ltd: Employment, Equity Ownership. Poindron:Kymab Ltd: Employment, Equity Ownership. Carter:Kymab Ltd: Employment. Hudson:Kymab Ltd: Employment, Equity Ownership. Theurl:Kymab Ltd: Consultancy, Equity Ownership. Germaschewski:Kymab Ltd.: Employment, Equity Ownership. Meynard:Kymab Ltd: Research Funding.
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Bakke, Anne Flore, Håvard Bjørgen, Erling Olaf Koppang, Petter Frost, Sergey Afanasyev, Preben Boysen, Aleksei Krasnov, and Hege Lund. "IgM+ and IgT+ B Cell Traffic to the Heart during SAV Infection in Atlantic Salmon." Vaccines 8, no. 3 (August 31, 2020): 493. http://dx.doi.org/10.3390/vaccines8030493.
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B cells of teleost fish differentiate in the head kidney, and spleen, and either remain in the lymphatic organs or move to the blood and peripheral tissues. There is limited knowledge about piscine B cell traffic to sites of vaccination and infection and their functional roles at these sites. In this work, we examined the traffic of B cells in Atlantic salmon challenged with salmonid alphavirus (SAV). In situ hybridization (RNAScope) showed increased numbers of immunoglobin (Ig)M+ and IgT+ B cells in the heart in response to SAV challenge, with IgM+ B cells being most abundant. An increase in IgT+ B cells was also evident, indicating a role of IgT+ B cells in nonmucosal tissues and systemic viral infections. After infection, B cells were mainly found in the stratum spongiosum of the cardiac ventricle, colocalizing with virus-infected myocardial-like cells. From sequencing the variable region of IgM in the main target organ (heart) and comparing it with a major lymphatic organ (the spleen), co-occurrence in antibody repertoires indicated a transfer of B cells from the spleen to the heart, as well as earlier recruitment of B cells to the heart in vaccinated fish compared to those that were unvaccinated. Transcriptome analyses performed at 21 days post-challenge suggested higher expression of multiple mediators of inflammation and lymphocyte-specific genes in unvaccinated compared to vaccinated fish, in parallel with a massive suppression of genes involved in heart contraction, metabolism, and development of tissue. The adaptive responses to SAV in vaccinated salmon appeared to alleviate the disease. Altogether, these results suggest that migration of B cells from lymphatic organs to sites of infection is an important part of the adaptive immune response of Atlantic salmon to SAV.
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Du, Juan, Jing Lu, Wanting Qiang, Lu Li, Jin Liu, Hua Jiang, Ziliang Qian, Baoan Chen, and Weijun Fu. "Cell-Free DNA Analysis Demonstrates Comprehensive Genomic Profiling and a Facile Method to Sensitively in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 5603. http://dx.doi.org/10.1182/blood-2018-99-116260.
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Abstract Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by complex cytogenetic and molecular abnormalities including translocations involving the immunoglobin heavy chain locus and mutations involving numerous oncogenic signaling pathways. Fluorescence in situ hybridization (FISH) has emerged as the most useful current cytogenetic assessment and provide a new level of insight into the correlation of myeloma prognosis risk model. However, the identification or sorting of malignant cells is required before FISH probes and only involved expansion of the types of probe and number of detectable targets is reached. Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with cancer precision medicine and patient prognosis. Methods: In this retrospective cohort study, we identified 37 patients from 9 relapsed/refractory (RR) and 33 newly diagnosed (ND) patients were analyzed for chromosomal copy number imbalance using the ultrasensitive chromosomal aneuploidy detector (UCAD) platform. Results: Chromosome copy number aberration (CNA) were frequently (82.6%, N=46) detected in MM plasma cell free DNA. Applying UCAD to cfDNA, FISH in CD138 purified bone marrow aspirates, and some matched bone marrow biopsies, we find concordance in copy number alterations (~81%) between liquid and tumor biopsies. Significant copy number changes, including 1q gains, 13q deletion and 17p deletion could be found in 57.89%, 54.05%, and 16.67% in plasma of MM, which is higher percentage than FISH assay (46.81%, 28.26%, and 8.89%), respectively. Besides, chromosome 6p and 6q were determined the higher frequency aberration from UCAD. Moreover, a higher frequency of copy number aberrations and variations was detected in RR patients than ND (100% vs 78.4%, respectively), obviously CNAs heterogeneity displayed in advanced disease. In the inconsistent some samples, UCAD from the plasma and bone marrow showed the similar results, which indicated the FISH is underdetermined and insensitivity in some patients' routine inspection. Conclusion: We conclude that cfDNA analysis as an adjunct to BM biopsy represents a noninvasive and broaden the applicability strategy for comprehensive genomic profiling and therapeutic monitoring of MM. Disclosures No relevant conflicts of interest to declare.
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Rieder, Mark J., David Williamson, Anna Sherwood, Ryan O. Emerson, Cindy Desmarais, Moon Chung, Harlan Robins, and Christopher S. Carlson. "Frequency Of Gene Usage and Copy Number Variation Within The Rearranged Immunoglobin Heavy-Chain Variable Locus Based On Immune Repertoire Sequencing." Blood 122, no. 21 (November 15, 2013): 3486. http://dx.doi.org/10.1182/blood.v122.21.3486.3486.
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Abstract The human adaptive immune system is composed of both B and T cells that undergo somatic recombination at specific loci to create rearrangements of Variable (V), Diversity (D) and Joining (J) gene segments. For the B-cell immunoglobin receptor heavy-chain (IGH), the CDR3 regions are defined by the VDJ gene segments and nucleotide insertions/deletions at these junctions that create the vast sequence diversity of the IGH repertoire. Characterizing the germline DNA in these regions is impeded by the high sequence similarity between gene segments, mutation and copy-number variation (i.e. large insertions/deletions). Currently, there is a fundamental lack of information about the baseline IGH immune repertoire V gene usage and diversity within healthy human controls. To provide an estimate of this, we sequenced functionally recombined gene segments to infer the underlying gene structure. From a set of 132 healthy controls we sorted C19+/CD27+ B-cells from whole blood and amplified genomic DNA using a highly multiplexed PCR assay that targeted the rearranged IGH receptor locus. Following DNA sequencing and data processing to assign V, D and J gene families and names, we examined the usage frequency of IGHV gene segments across all individuals. We found that of the 98 V gene segments only 56 (57%) were used at a frequency > 0.1%, and ∼10 showed little to no usage (present in<1% of individuals). This data also allowed us to identify two IGHV genes currently annotated as orphons (pseudogenes assigned to an alternate chromosomal location) that had unambiguous functional usage (IGHV4/OR15-8; IGHV3/OR16-09) and therefore must reside at the IGH locus on chromosome 14. Finally, by taking this functional approach we were able to screen all V gene segments for germline copy-number variation (e.g. large insertion/deletion events encompassing individual genes) by looking for an excess of deletion events or modal changes in gene usage. We confirmed that existence of 12 of 15 previously identified deleted IGHV gene segments. Strong deletion evidence was observed for an additional six IGHV genes (IGHV3-NL1, IGHV3-33, IGHV1-24, IGHV4-04, IGHV3-41, IGHV3-35) and ten with highly likely germline deletion events. These data suggest that functional immune profiling of rearranged immune receptors provides a more robust method of identifying individual structural variation and provides insight into the immune repertoire of healthy controls. Disclosures: Rieder: Adaptive Biotechnologies: Employment, Equity Ownership. Williamson:Adaptive Biotechnologies: Employment, Equity Ownership. Sherwood:Adaptive Biotechnologies: Employment, Equity Ownership. Emerson:Adaptive Biotechnologies: Employment, Equity Ownership. Desmarais:Adaptive Biotechnologies: Employment, Equity Ownership. Chung:Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Carlson:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties.
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McBride, Patrick, Houry Leblebjian, Paul Richardson, Jacob Laubach, and Hillary Prescott. "Evaluation of Infusion Reactions in Patients Receiving Daratumumab Post-Implementation of an Augmented Pre- and Peri-Medication Regimen." Blood 132, Supplement 1 (November 29, 2018): 3234. http://dx.doi.org/10.1182/blood-2018-99-111361.
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Abstract Introduction: Daratumumab is a first in class immunoglobin G1 kappa human monoclonal antibody that targets the CD38 antigen on the exterior of myeloma cells. Daratumumab provides an important treatment option and has become standard of care for patients with relapsed/refractory multiple myeloma (MM). While generally well tolerated, daratumumab is associated with a high incidence of IRRs (42-56% of patients; grade 3/4: 2-9%) (Palumbo A et al. New England Journal of Medicine 2016; 375: 754-766, Voorhees P et al. Blood 2015; 126: 1829, Lonial S et al. The Lancet 2016; 387: 1551-60). These reactions predominately occur during the first two infusions. The manufacturer recommends both pre- and post-medications for daratumumab, including steroids, antipyretics, and antihistamines with or without other supplementary agents. Dana-Farber Cancer Center (DFCI) implemented an augmented pre- and peri-infusion medication regimen in November 2015, meant to reduce the occurrence of daratumumab-associated IRRs (table 1). Methods: We conducted an observational, retrospective, single center, medical chart review of MM patients who received at least one dose of daratumumab between November 2015 and October 2017 at DFCI. Data were collected on patient characteristics (age, gender, number of previous treatment regimens, immunoglobulin subtype, and baseline disease burden), pre-/peri-/post-medications, daratumumab infusions (infusion duration and dose), and IRRs (grade of reaction and treatment of reaction). Data was collected for the first two daratumumab infusions (Cycle 1 Day 1 and Cycle 1 Day 8 (C1D1 and C1D8) for each eligible patient. The primary objective was to determine the incidence of IRRs in patients treated with daratumumab post-implementation of an augmented pre- and peri-medication regimen. Secondary objectives were to determine the infusion time of daratumumab and to characterize the use of infusion pre-and peri-infusion medications in patients receiving daratumumab at DFCI. Results: A total of 105 patients who received ≥1 dose of daratumumab during the 2-year study period were identified. Eighty-six patients met inclusion criteria and received a total of 165 evaluable infusions. Twenty-three of the 86 patients (26.7%) experienced any grade IRRs. All IRRs were ≤ grade 3 in severity (grade 1-2: 23.2%; grade 3: 3.5%). Figure 1 highlights categorization of IRRs in the study population based on the total number of infusions. IRRs were managed by supportive care medications and/or briefly stopping the infusion per prescribing information and institutional practice. All reactions occurred during the first dose of daratumumab. The differences in baseline characteristics between the patients with and without reactions are outlined in table 2. More patients that received combination therapy experienced an IRR compared those on monotherapy (65.1 vs 56.5%). Patient comorbidities did not appear to influence IRR incidence (26.1% without IRR vs 41.3% with IRR). Of the patients that received >3 previous treatment regimens, none experienced an IRR. The mean duration of infusion for daratumumab was longer in patients who experienced an IRR compared with those who did not (505.9 vs 355.3 minutes). Seventy-one pre- and peri-infusion medications were omitted during the study period, representing a 95.2% adherence rate to the 9 medications contained within the institutional standard regimen. Details on omitted medications can be found in table 3. Peri-infusion diphenhydramine had the highest incidence of omission and was not given in 36 (21.8%) daratumumab infusions. Rates of medication omission were higher during C1D8, where no IRRs were observed. Conclusions: An augmented regimen of pre- and peri-medications appears to lower the incidence of grade 1-2 IRRs with daratumumab, compared to previously published data. The results also support that most IRRs occur during the first dose of daratumumab. This suggests the benefit of an augmented pre- and peri-medication regimen for at least the first dose of daratumumab. Disclosures Richardson: Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Kohn, Donald B., Kit L. Shaw, Elizabeth Garabedian, Denise Ann Carbonaro-Sarracino, Theodore B. Moore, Satiro N. De Oliveira, Gay M. Crooks, et al. "Lentiviral Gene Therapy with Autologous Hematopoietic Stem and Progenitor Cells (HSPCs) for the Treatment of Severe Combined Immune Deficiency Due to Adenosine Deaminase Deficiency (ADA-SCID): Results in an Expanded Cohort." Blood 134, Supplement_1 (November 13, 2019): 3345. http://dx.doi.org/10.1182/blood-2019-123432.
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Background: Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) is a rare disorder caused by ADA gene mutations, leading to lymphotoxic build-up of purine metabolites and profound immunodeficiency. Historically, enzyme replacement therapy (ERT) has been used as a bridge therapy until patients can receive an allogeneic hematopoietic stem cell transplantation (HSCT), ideally from a matched related donor (MRD) or, if none is identified, a non-matched and/or unrelated donor. We developed a self-inactivating lentiviral vector (LV), denoted EFS-ADA LV, encoding the human ADA cDNA sequence under the control of a shortened human elongation factor 1α gene promoter. A fresh or cryopreserved formulation of a drug product (OTL-101), composed of autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with EFS-ADA LV, was evaluated in 2 prospective, non-randomized Phase I/II clinical trials at 2 USA centers. We report on safety and efficacy of OTL-101 in 30 ADA-SCID pediatric gene therapy (GT) subjects treated from 2013-2017 with a median follow up (FU) of 24 months (mo; range 12-26 mo), compared to a historical cohort of 26 ADA-SCID patients treated with HSCT. Methods: UCLA Fresh Study (NCT01852071): Autologous CD34+ HSPCs were isolated from bone marrow and pre-stimulated with cytokines before transduction with EFS-ADA LV to yield OTL-101, which was infused as a fresh formulation in 20 subjects (9 male, 11 female; aged 4 mo-4.3 yrs). Single dose busulfan (4 mg/kg) was administered prior to infusion of OTL-101. Subjects were followed for 24 mo. UCLA Cryo Study (NCT02999984): 10 subjects (4 male, 6 female; aged 5-15 mo) received a cryopreserved formulation of OTL-101, which allowed for an extended shelf-life and full quality control prior to infusion. Busulfan was administered in 2 doses, the first at 3 mg/kg and the second adjusted to target a total area under the curve of 4,900 µM*min (20 ng/mL*hr). At the time of analysis, all subjects reached 12 mo FU (except 1 subject who was withdrawn from the study due to lack of engraftment); 7 subjects reached 18 mo of FU. Historical Control Group: 26 patients (aged 0.2 mo-9.8 yrs) were treated with allogeneic HSCT (MRDs n=12, non-MRDs n=14) at Great Ormond Street Hospital, UK (n=16) or Duke University Children's Hospital, USA (n=10) from 2000-2016. Results: Sustained engraftment of genetically modified HSPCs was observed in 29/30 GT subjects by 6-8 mo and persisted through FU in both studies, based on vector gene marking in granulocytes and CD3+ T cell reconstitution (Figure). Subjects who engrafted maintained long-term metabolic detoxification from deoxyadenosine nucleotides after stopping ERT approximately 1 mo post-GT. At last FU (median 24 mo; range 12-24 mo) in the GT group, overall survival (OS) was 30/30 (100%) and event-free survival (survival in the absence of ERT reinstitution or rescue allogeneic HSCT; EvFS) was 29/30 (97%). OS and EvFS were higher in the GT group at last FU compared with HSCT controls (with or without an MRD) at 2 years (Table). One of 30 OTL-101 subjects (3%) did not engraft and was restarted on ERT; the subject was withdrawn from the study at 5.9 mo and subsequently received a rescue HSCT, whereas 42% of HSCT patients required rescue HSCT, PEG-ADA ERT or died. Among the 20 OTL-101 subjects in the UCLA Fresh Study who reached 2 years FU, 18 (90%) stopped immunoglobin replacement therapy (IgRT), compared to 52% of HSCT patients. Preliminary results were observed in 5/7 (71%) OTL-101 subjects in the UCLA Cryo Study with more limited (18 mo) FU. Twelve OTL-101 subjects experienced one or more serious adverse events, most frequently infections and gastrointestinal events; only 1 of which was considered treatment-related (bacteremia due to product contamination). In the GT group, there were no events of autoimmunity with ≤24 mo FU. Due to the autologous nature of OTL-101, there was no incidence of graft vs host disease (GvHD); in contrast, 8 HSCT patients experienced GvHD events (5 acute, 3 chronic events), 1 of which resulted in death. Conclusions: Based on sustained gene correction and restoration of immune function in all subjects who engrafted, treatment of ADA-SCID with OTL-101 has a favorable benefit-risk profile. Key correlates of engraftment were consistent across the expanded cohort. Importantly, higher rates of OS and EvFS compared with HSCT (with or without an MRD) were observed. Disclosures Kohn: Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor on IP licensed from UC Regents to Orchard Therapeutics. Future royalties may occur., Research Funding; NIH: Research Funding. Shaw:Orchard Therapeutics: Consultancy, Other: Personal fees and non-financial support; NIH: Research Funding. Carbonaro-Sarracino:NIH: Other: Salary while working on project at UCLA 2013-2016, Research Funding; Orchard Therapeutics: Consultancy, Employment. De Oliveira:National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London: Research Funding; CIRM: Research Funding; National Gene Vector Repository: Research Funding; NIAID, NHI: Research Funding; Medical Research Council: Research Funding. Terrazas:California Institute for Regenerative Medicine: Research Funding; Gene Therapy Resource Program, NHLBI/NIH: Research Funding. Hollis:Curative Therapeutics: Consultancy, Other: Personal fees. Trevisan:Orchard Therapeutics: Research Funding. Arduini:Orchard Therapeutics: Employment, Equity Ownership. Lynn:Orchard Therapeutics: Employment, Equity Ownership. Kudari:Orchard Therapeutics: Employment, Equity Ownership. Spezzi:Orchard Therapeutics: Employment, Equity Ownership. Buckley:Duke University: Research Funding. Booth:SOBI: Consultancy; GSK: Honoraria; NovImmune: Consultancy. Thrasher:Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gaspar:Orchard Therapeutics: Employment, Equity Ownership, Patents & Royalties: Lentiviral vector for gene therapy of ADA-SCID.
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Cicconi, Paola, Claire Jones, Esha Sarkar, Laura Silva-Reyes, Paul Klenerman, Catherine de Lara, Claire Hutchings, et al. "First-in-Human Randomized Study to Assess the Safety and Immunogenicity of an Investigational Respiratory Syncytial Virus (RSV) Vaccine Based on Chimpanzee-Adenovirus-155 Viral Vector–Expressing RSV Fusion, Nucleocapsid, and Antitermination Viral Proteins in Healthy Adults." Clinical Infectious Diseases 70, no. 10 (July 24, 2019): 2073–81. http://dx.doi.org/10.1093/cid/ciz653.
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Abstract Background Respiratory syncytial virus (RSV) disease is a major cause of infant morbidity and mortality. This Phase I, randomized, observer-blind, placebo- and active-controlled study evaluated an investigational vaccine against RSV (ChAd155-RSV) using the viral vector chimpanzee-adenovirus-155, encoding RSV fusion (F), nucleocapsid, and transcription antitermination proteins. Methods Healthy 18–45-year-old adults received ChAd155-RSV, a placebo, or an active control (Bexsero) at Days (D) 0 and 30. An escalation from a low dose (5 × 109 viral particles) to a high dose (5 × 1010 viral particles) occurred after the first 16 participants. Endpoints were solicited/unsolicited and serious adverse events (SAEs), biochemical/hematological parameters, cell-mediated immunogenicity by enzyme-linked immunospot, functional neutralizing antibodies, anti RSV-F immunoglobin (Ig) G, and ChAd155 neutralizing antibodies. Results There were 7 participants who received the ChAd155-RSV low dose, 31 who received the ChAd155-RSV high dose, 19 who received the placebo, and 15 who received the active control. No dose-related toxicity or attributable SAEs at the 1-year follow-up were observed. The RSV-A neutralizing antibodies geometric mean titer ratios (post/pre-immunization) following a high dose were 2.6 (D30) and 2.3 (D60). The ratio of the fold-rise (D0 to D30) in anti-F IgG over the fold-rise in RSV-A–neutralizing antibodies was 1.01. At D7 after the high dose of the study vaccine, the median frequencies of circulating B-cells secreting anti-F antibodies were 133.3/106 (IgG) and 16.7/106 (IgA) in peripheral blood mononuclear cells (PBMCs). The median frequency of RSV-F–specific interferon γ–secreting T-cells after a ChAd155-RSV high dose was 108.3/106 PBMCs at D30, with no increase after the second dose. Conclusions In adults previously naturally exposed to RSV, ChAd155-RSV generated increases in specific humoral and cellular immune responses without raising significant safety concerns. Clinical Trials Registration NCT02491463.
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Korde, Neha, Jane Trepel, Mattias Carlsten, Adriana Zingone, Rene Costello, Mary Ann Yancey, Marcia Mulquin, et al. "A Phase II Trial of IPH2101 (anti-KIR mAb) in Smoldering Multiple Myeloma." Blood 118, no. 21 (November 18, 2011): 2944. http://dx.doi.org/10.1182/blood.v118.21.2944.2944.
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Abstract Abstract 2944 Emerging evidence suggests multiple myeloma (MM) may be susceptible to components of the innate immune system including natural killer (NK) cells. In vitro studies have shown that allogeneic and autologous NK cells have the ability to kill CD138-purified primary MM cells. A recent study focusing on allogeneic hematopoietic stem cell transplantation for MM showed recipients who lacked MHC class I ligands for donor KIR (so called KIR incompatible transplants) had markedly reduced relapse rates, indicating NK cell KIR may exert significant control over clinical NK cell-mediated anti-MM responses. In this two-stage phase II study, we evaluated the response rate, toxicity, pharmacokinetic parameters and biological activity of IPH2101 in smoldering myeloma (SMM). IPH2101 is a fully human IgG4 monoclonal antibody (mAb) that facilitates natural killer (NK) cell-mediated killing of myeloma cells by blocking the interaction of inhibitory killer cell immunoglobin (Ig)-like receptor (KIR) 2D on NK cells with their human leukocyte antigen-C (HLA-C) ligands on target cells. This interim analysis was planned when all patients in the first stage (n=9/21) were recruited. Nine SMM patients meeting eligibility criteria were prospectively enrolled (median 59 yrs; 8 males and 1 female). Patients received a single dose of IPH2101 1mg/kg by intravenous route every other month (for a total of 6 cycles). A pre-treatment bone marrow biopsy was obtained for confirmation of diagnosis and for correlative studies. Peripheral blood mononuclear cells were obtained on days 1, 8, 18, 22 for cycle one then monthly thereafter for subsequent cycles for correlative studies to assess KIR 2D blockade and the effects of mAb therapy on NK cytotoxic function against K562 cells and MM cells matched for recipient KIR ligands. Routine blood work, serum/urine protein electrophoresis and immunofixation, and serum free light chain assays were conducted monthly. At the end of study, a post-treatment bone marrow biopsy will be obtained for clinical evaluation and correlative studies. To date, of the 9 patients enrolled on trial, 1 patient has received 5 cycles, 2 patients have received 4 cycles, and 4 patients have received 2 cycles. After an average of 3 (range 2–5) cycles of IPH2101, no patients have yet achieved a 50% reduction of their baseline M-spike (target for the study). Toxicities have been minimal and no grade 3–4 toxicities have been observed to date. Occupancy of KIR2D by IPH2101 has been assessed on peripheral blood NK cells taken at baseline, 24 hrs after the first infusion, and prior to each subsequent infusion using a flow based KIR occupancy assay that measures the binding of a labeled immunofluorescent anti-KIR relative to standard fluorescent beads. The interim results are consistent with a very high KIR occupancy of >90% at 24 hr post the first infusion and the maintenance of a high level of occupancy of available IPH2101 binding sites at 2 months post-infusion. In vitro studies measuring the cytotoxic function of patient's NK cells against K562 cells and KIR ligand matched myeloma cells before and after IPH2101 treatment are ongoing and will be reported at the meeting. In conclusion, this first interim analysis based on 9 SMM patients treated with IPH2101 are consistent with a very high KIR2D occupancy on NK cells by this mAb up to 2 months post-infusion. To date, none of the patients treated have had 50% reduction of their baseline M-spike. mAb infusions have been well tolerated with no grade 3–4 toxicities observed to date. Updated clinical data and functional in vitro studies measuring the cytotoxic function of patient's NK cells before and after mAb therapy will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.
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Leung, Nelson, David R. Barnidge, Angela Dispenzieri, Marin-Argany Marta, Dick J. Christopher, Cooper A. Shawna, Nasr H. Samih, Ward J. Christopher, and Ramirez-Alvarado Marina. "Urinary Exosomes Detect Amyloidogenic Light Chain in Patients Who Have Renal Progression Despite a Hematologic Complete Response." Blood 128, no. 22 (December 2, 2016): 3268. http://dx.doi.org/10.1182/blood.v128.22.3268.3268.
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Abstract Background: Immunoglobulin light chain (AL) amyloidosis is a fatal complication of B-cell clonal proliferation. Currently, the best biomarker for treatment monitoring is serum free light chain (FLC) assay. Despite its higher sensitivity, it cannot distinguish clonality thus ultralow levels of monoclonal gammopathy can be missed. Urinary exosomes (UExs) are the smallest members of the extracellular vesicle family that are excreted in the urine. They exhibit different characteristics in patients with AL amyloidosis vs multiple myeloma. This study was undertaken to determine if urinary exosomes have different characteristics in patients AL amyloidosis who progress despite being in complete response (CR) vs those who have a renal response. Methods: UEx were extracted from 4 patients at different stages of AL (Table 1). Immunoglobin light chains (LC) were identified in the UEx using western blotting. Intact immunoglobulin light chains were identified in plasma, UEx, and kidney biopsy amyloid deposits using mass spectrometry (MS). cDNAs from bone marrow plasma cells (BMPC) collected at the time of diagnosis from patient 4 were sequened. Results: Oligomeric LC (250 kd) were identified in the UEx of patient 1 (newly diagnosed, Fig 1a) and 4 (renal progression in CR, Fig 1d) but only monomeric LC (25 kd) were detected in patient 2 (Fig 1b) and 3 (CR and renal response, Fig 1c). MS of the UEx and plasma of patient 4 detected 2 monoclonal λ LC. The mass of one of the LC was consistent with a lambda 6a LC which is also the most common cDNA (IGLV-6-57) found in the BMPC. Amino acid sequences derived from the tryptic digestion of the amyloid deposits matched the predicted sequence of the cDNA. The calculated weight of the peptide produced by the cDNA (23,304 Da ) was within margin of error of the mass of the lambda 6a LC (23,306 Da). The mass of the second LC (23,092 Da) was consistent with a λ4/λ5 LCs. A search of the amino acid and cDNA sequences failed to identify any similarity. The density ratio of the oligomeric LC to monomeric LC in the UEx was 0.47 which was similar to the intensity ratio by MS of the lambda 6a LC (23,306 Da) to the 23,092 Da LC in the blood (0.43). Discussion: Urinary EXs identified oligomeric LC in a patient with progressive renal disease despite achieving a CR. The mass one of the λ LC matched the predicted peptide product of the cDNA obtained from BMPC. The amino acid sequence predicted by the cDNA matched the trypsin digested sequences from the amyloid deposits. This strongly suggests the oligomeric LC represents the amyloidogenic λ6a LC detected in the blood which was being produced by the BMPC clone which is being deposited as amyloid in the kidney. The origin of the second λ LC is unknown but is likely a new monoclonal gammopathy of undetermined significance that developed after the initial bone marrow biopsy. The blood and urine samples were obtained 3 years after the BMPC. The development of a new monoclonal gammopathy in patients with plasma cell dyscrasia is not uncommon. Unfortunately, bone marrow biopsy collected at the time of the urine and blood sample had insufficient number of plasma cells (CR) for analysis. Conclusion: UEx can identify amyloidogenic LC even when current standard methods could not. The persistent presence of the amyloidogenic LC helps explain why patients can progress despite being in CR. The presence of a second λ LC which was not part of the amyloid deposit also has clinical implication. It may explain why some patients do well despite having a persistent monoclonal protein. If these results are confirmed, UEx may have a powerful role in the determination of organ and hematologic response in patients with AL amyloidosis. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding; Celgene: Research Funding.
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Xiang, Elaine, Hillary Prescott, Jacob Laubach, Paul Richardson, Kaitlen Reyes, Irene M. Ghobrial, and Houry Leblebjian. "Evaluation of Re-Intensification of Daratumumab to Weekly or Biweekly Dosing Schedule." Blood 132, Supplement 1 (November 29, 2018): 2024. http://dx.doi.org/10.1182/blood-2018-99-111191.
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Abstract Introduction: Multiple Myeloma (MM) is a hematologic cancer caused by malignant plasma cells. Daratumumab is an immunoglobin G1 kappa human monoclonal antibody that targets CD38 antigen which is a cell surface glycoprotein highly expressed on myeloma cells. Daratumumab is FDA approved as monotherapy and in combination with dexamethasone and lenalidomide, bortezomib or pomalidomide in relapsed/refractory MM. Daratumumab is typically dosed: 16mg/kg weekly (Weeks 1-8), then 16mg/kg biweekly (Weeks 9-24), then 16mg/kg monthly (Weeks 25 and beyond until disease progression). At Dana-Farber Cancer Institute (DFCI), some patients receiving a daratumumab-containing regimen were "re-intensified" upon progression of disease. "Re-intensification" could include (1) re-escalation to weekly dosing from biweekly or monthly dosing or (2) re-escalation to biweekly dosing from monthly dosing or (3) continuation of biweekly or monthly dosing. However, there is a lack of evidence to support the safety and efficacy of daratumumab dose "re-intensification" (Dara-RI) during treatment. We aimed to assess the efficacy and safety of Dara-RI, with or without the addition of other myeloma-agents, in 13 patients with disease progression while on a daratumumab-containing regimen. Method/Results: This is an institutional review board approved, descriptive, retrospective medical chart review of 13 adult patients with MM who received Dara-RI at DFCI from November 2015 to October 2017. The median age was 68 years (range, 53-88). Most patients (8) had IgG Kappa MM (62%) followed by 2 patients (15%) with Lambda Light Chain, 2 patients (15%) with IgA Kappa, and 1 patient (8%) with IgG Lambda. Of the 13 patients, 1 patient continued weekly dosing, 4 patients continued biweekly dosing; 5 patients re-intensified from monthly to biweekly dosing; 1 patient re-intensified from biweekly to weekly; and 2 patients re-intensified from monthly to weekly. Patients were re-intensified at a median of 14 months after starting a daratumumab-containing regimen (range, 4-26). Of the 13 patients, there were 5 patients who had another drug adjustment at the time of Dara-RI. Of note, there were 3 patients who were on a non-FDA approved daratumumab-containing regimen at the time of Dara-RI. At the time of our final analysis, there were 7 patients (54%) who remained on a daratumumab-based regimen. Of these 7 patients, 6 patients continued Dara-RI and 1 patient transitioned from biweekly to monthly daratumumab due to stable disease. Notably, 3 patients had another drug adjustment at the time of Dara-RI. The median length of Dara-RI is 8 months and ongoing (range, 4-12). There were 5 patients (38%) who discontinued their daratumumab-based regimen after Dara-RI. Of these 5 patients, 2 patients had another drug adjustment at the time of Dara-RI. All 5 patients had at least stable disease or partial response to Dara-RI, with exception of one individual who had progressive disease. In addition, all 5 patients who discontinued Dara-RI was within 4 months of starting Dara-RI. Uniquely, one patient had panobinostat added to their Dara-RI regimen after 1 month of re-intensification, but continued with Dara-RI. No patients experienced a dose delay due to adverse effects or were hospitalized after initiation of Dara-RI. Only one patient was prescribed antibiotics for treatment of a cold sore. There were no new hypersensitivity, cardiovascular, hematologic, gastrointestinal, or central nervous system toxicities noted after initiation of Dara-RI. Conclusion: Limitations of this study include other myeloma drug-related adjustments at the time of Dara-RI and the heterogeneous population as well as the retrospective nature of the study. In our experience with 13 patients, Dara-RI appears to be a safe and tolerable alternative regimen for patients who have disease progression on a daratumumab-containing regimen. Disclosures Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Ghobrial:BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy.
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Nguyen, Stephanie, Laetitia Souchet, Abla Achour, Stéphane Vigouroux, Patrice Chevallier, Sabine Furst, Anne Sirvent, et al. "Impact of NK Cell Reconstitution and Recipient HLA-C Typing on Clinical Outcome after Reduced Intensity Cord Blood Transplant: Results of a Prospective Phase II Multicentric Trial on Behalf of Societe Francaise De Greffe De Moelle Osseuse Et Therapie Cellulaire (SFGM-TC) and Eurocord." Blood 126, no. 23 (December 3, 2015): 4393. http://dx.doi.org/10.1182/blood.v126.23.4393.4393.
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Abstract Background: Unrelated cord blood transplantation (UCBT) after reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly and unfit patients without an HLA identical donor. KIR ligand incompatibility between donor and recipient might favor Natural Killer (NK) cell alloreactivity after UCBT in AML patients (Wilhemze et al, 2009), although contradictory results were reported (Brunstein et al, 2009). We previously reported the results of the biological NK cell reconstitution after RIC-UCBT in a French prospective phase II multicentric trial (Rio et al, 2015). We showed that NK cells generated from RIC-UCBT exhibited features of transient immaturity and stable activation, correlating with a high ability to produce IFN-γ and a quick restoration of the ability both to produce TNF-α and degranulate (Souchet et al, ASH 2013). The aim of the present study is to analyze the impact of KIR ligand incompatibilities and NK cell reconstitution on OS, DFS and TRM after RIC-UCBT in a prospective trial. Materials and methods: Seventy-six patients with a de novo or secondary AML in complete remission were enrolled in 23 centers from Oct. 2007 to Sept. 2009. Peripheral blood samples were collected during the first year following UCBT in order to realize an extensive prospective phenotypic and functional study of NK cells. DNA samples were also collected in recipient and cords blood to perform KIROTYPE and HLA-C allelic typing. NK biological data were available at M1 for 54 patients. The inhibitory Killer-Immunoglobin Receptors (KIR) KIR2DL1, and KIR2DL2/3 bind KIR ligand C2 and C1 respectively, resulting in inhibition of NK-cell mediated lysis. Recipients and UCB were classified into C1 or C2 family depending on their HLA-C typing (C1-C1, C1-C2 or C2-C2). Results: Among the 54 patients, 35 events occurred (relapse or TRM). Median EFS and OS were 13.2 and 18.3 months, respectively. Recipients C2-C2 had a significant worse EFS and OS than C1-C1 or C1-C2 (median EFS C2-C2=3.8 month vs 15.1 month for C1-x; p=0.002); median OS C2-C2 3.8 months vs 29.9 months for C1-x; HR=6.12, IC95% [2.069; 18.113], p=0.001). High intracellular staining of CD107a, reflecting the capacity of NK degranulation with HLA negative K562 target, correlated with better OS. CD107a expression was divided in 2 groups at median (=51%). Median OS of CD107 (0-50%) was 12.8 months vs 20.9 months for CD107a (51-66); p=0.029. Relapse risk was highly increased in recipients C2-C2 (HR=5.04 (IC 95% [1.23; 20.56], p=0.02). Low expression of CD16 (HR=0.97, IC95% [0.937; 0.999], p=0.043), high expression of HLA-DR (HR=1.08, IC95% [1.031; 1.123], p=8e-04) on NK cells, and recipients C2-C2 (HR=9.44, IC95% [1.311; 67.882], p=0.026) significantly increased the risk of TRM. The inhibitory KIR2DL1 receptor binds to C2 ligands. Of interest, KIR2DL1 was significantly decreased on C2-C2 recipients NK cells at M1, as compared to C1-x recipients NK cells. On the contrary, KIR2DL2/3 and KIR3DL1 restored promptly, suggesting a sequential expression of KIRs. As interaction between inhibitory KIRs and their ligands are essential for NK cells to become functional ("licensing" process), we can hypothesize that the weaker expression of KIR2DL1 on C2-C2 NK cells alters the licensing process, rendering the NK cells hypo-responsiveness. Conclusion: Recipient C2-C2 is correlated with a worse outcome (EFS, OS, relapse, TRM) after RIC-UCBT in a prospective trial for AML patients. Weak capacity of degranulation and low expression of CD16 are associated with worse OS and increased TRM, respectively. These features can reflect an alteration of the NK licensing process and might have impact on clinical outcome after UCBT. Disclosures No relevant conflicts of interest to declare.
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Chaganti, Sridhar, Andrew I. Bell, Noelia Begue Pastor, Anne E. Milner, Mark Drayson, John Gordon, and Alan B. Rickinson. "Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes." Blood 106, no. 13 (December 15, 2005): 4249–52. http://dx.doi.org/10.1182/blood-2005-06-2327.
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Immunoglobulin genotyping of Epstein-Barr virus (EBV)-positive posttransplantation lymphoproliferative disease has suggested that such lesions often arise from atypical post-germinal center B cells, in some cases carrying functionally inactivated immunoglobulin genes. To investigate whether EBV can rescue cells that are failed products of the somatic hypermutation process occurring in germinal centers (GCs), we isolated GC cells from tonsillar cell suspensions and exposed them to EBV in vitro. Screening more than 100 EBV-transformed cell lines of GC origin identified 6 lines lacking surface immunoglobulin, a phenotype never seen among lines derived from circulating naive or memory B cells. Furthermore, 3 of the 6 surface immunoglobulin-negative GC lines carried inactivating mutations in the immunoglobulin H (IgH) variable gene sequence. The ability of EBV to rescue aberrant products of the germinal center reaction in vitro strengthens the probability that a parallel activity contributes to EBV's lymphomagenic potential in vivo.
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Chen, Liguang, George Widhopf, Lang Huynh, Laura Rassenti, Kanti R. Rai, Arthur Weiss, and Thomas J. Kipps. "Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia." Blood 100, no. 13 (December 15, 2002): 4609–14. http://dx.doi.org/10.1182/blood-2002-06-1683.
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We examined isolated leukemia B cells of patients with chronic lymphocytic leukemia (CLL) for expression of zeta-associated protein 70 (ZAP-70). CLL B cells that have nonmutated immunoglobulin variable region genes (V genes) expressed levels of ZAP-70 protein that were comparable to those expressed by normal blood T cells. In contrast, CLL B cells that had mutated immunoglobulin variable V genes, or that had low-level expression of CD38, generally did not express detectable amounts of ZAP-70 protein. Leukemia cells from identical twins with CLL were found discordant for expression of ZAP-70, suggesting that B-cell expression of ZAP-70 is not genetically predetermined. Ligation of the B-cell receptor (BCR) complex on CLL cells that expressed ZAP-70 induced significantly greater tyrosine phosphorylation of cytosolic proteins, including p72Syk, than did similar stimulation of CLL cells that did not express ZAP-70. Also, exceptional cases of CLL cells that expressed mutated immunoglobulin V genes and ZAP-70 also experienced higher levels tyrosine phosphorylation of such cytosolic proteins following BCR ligation. Following BCR ligation, ZAP-70 underwent tyrosine phosphorylation and became associated with surface immunoglobulin and CD79b, arguing for the involvement of ZAP-70 in BCR signaling. These data indicate that expression of ZAP-70 is associated with enhanced signal transduction via the BCR complex, which may contribute to the more aggressive clinical course associated with CLL cells that express nonmutated immunoglobulin receptors.
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Forconi, Francesco, Kathleen N. Potter, Isla Wheatley, Nikos Darzentas, Elisa Sozzi, Kostas Stamatopoulos, C. Ian Mockridge, Graham Packham, and Freda K. Stevenson. "The normal IGHV1-69–derived B-cell repertoire contains stereotypic patterns characteristic of unmutated CLL." Blood 115, no. 1 (January 7, 2010): 71–77. http://dx.doi.org/10.1182/blood-2009-06-225813.
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Abstract The cell of origin of chronic lymphocytic leukemia (CLL) has long been sought, and immunoglobulin gene analysis provides new clues. In the unmutated subset (U-CLL), there is increased usage of the 51p1-related alleles of the immunoglobulin heavy chain variable 1-69 gene, often combined with selected genes and with immunoglobulin heavy chain diversity IGHJ6. Stereotypic characteristics of the HCDR3 result and suggest antigen selection of the leukemic clones. We have now analyzed 51p1/IGHJ6 combinations in normal blood B cells from 3 healthy persons for parallel sequence patterns. A high proportion (33.3% of sequences) revealed stereotypic patterns, with several (15.0%) being similar to those described in U-CLL. Previously unreported CLL-associated stereotypes were detected in 4.8%. Stereotypes (13.6%) not detected in CLL also were found. The HCDR2-IGHJ6 sequences were essentially unmutated. Junctional amino acids in normal B cells were heterogeneous, as in cases of stereotyped CLL. Phenotypically, normal B cells expressing 51p1-derived immunoglobulin M were naive. This snapshot of the naive B-cell repertoire reveals subsets of B cells closely related to those characteristic of CLL. Conserved patterns in the 51p1-encoded immunoglobulin M of normal B cells suggest a restricted sequence repertoire shaped by evolution to recognize common pathogens. Proliferative pressure on these cells is the likely route to U-CLL.
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Volkheimer, Alicia D., J. Brice Weinberg, Bethany E. Beasley, John F. Whitesides, Jon P. Gockerman, Joseph O. Moore, Garnett Kelsoe, Barbara K. Goodman, and Marc C. Levesque. "Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification." Blood 109, no. 4 (November 2, 2006): 1559–67. http://dx.doi.org/10.1182/blood-2006-05-020644.
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Abstract Somatic mutations of immunoglobulin genes characterize mature memory B cells, and intraclonal B-cell diversification is typically associated with expansion of B-cell clones with greater affinity for antigen (antigen drive). Evidence for a role of antigen in progression of intraclonal chronic lymphocytic leukemia (CLL) cell diversification in patients with mutated immunoglobulin genes has not been previously presented. We performed a single-cell analysis of immunoglobulin heavy and light chains in 6 patients with somatically mutated CLL-cell immunoglobulin genes and identified 2 patients with multiple related (oligoclonal) subgroups of CLL cells. We constructed genealogic trees of these oligoclonal CLL-cell subgroups and assessed the effects of immunoglobulin somatic mutations on the ratios of replacement and silent amino acid changes in the framework and antigen-binding regions (CDRs) of the immunoglobulin heavy and light chains from each oligoclonal CLL-cell population. In one subject, the amino acid changes were consistent with an antigen-driven progression of clonally related CLL-cell populations. In the other subject, intraclonal diversification was associated with immunoglobulin amino acid changes that would have likely lessened antigen affinity. Taken together, these studies support the hypothesis that in some CLL cases intraclonal diversification is dependent on antigen interactions with immunoglobulin receptors.
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Ellyard, Julia I., Danielle T. Avery, Tri Giang Phan, Nathan J. Hare, Philip D. Hodgkin, and Stuart G. Tangye. "Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow." Blood 103, no. 10 (May 15, 2004): 3805–12. http://dx.doi.org/10.1182/blood-2003-09-3109.
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Abstract Plasma cells (PCs) represent the final stage of B-cell differentiation and are devoted to the production of immunoglobulin (Ig). Perturbations to their development can result in human disorders characterized by PC expansion and hypergammaglobulinemia. Ig-secreting cells (ISCs) have been identified in secondary lymphoid tissues and bone marrow (BM). Most ISCs in lymphoid tissue are short-lived; in contrast, ISCs that migrate to the BM become long-lived PCs and continue to secrete immunoglobulin for extended periods. However, a small population of long-lived PCs has been identified in rodent spleen, suggesting that PCs may persist in secondary lymphoid tissue and that the spleen, as well as the BM, plays an important role in maintaining long-term humoral immunity. For these reasons, we examined ISCs in human spleen and identified a population that appears analogous to long-lived rodent splenic PCs. Human splenic ISCs shared morphologic, cellular, molecular, and functional characteristics with long-lived PCs in BM, demonstrating their commitment to the PC lineage. Furthermore, the detection of highly mutated immunoglobulin V region genes in splenic ISCs suggested they are likely to be antigen-selected and to secrete high-affinity immunoglobulin. Thus, our results suggest that splenic ISCs have an important role in humoral immunity and may represent the affected cell type in some B-cell dyscrasias.
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Ostad, Masih, Margareta Andersson, Astrid Gruber, and Anne Sundblad. "Expansion of immunoglobulin autoreactive T-helper cells in multiple myeloma." Blood 111, no. 5 (March 1, 2008): 2725–32. http://dx.doi.org/10.1182/blood-2006-11-056242.
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Activation and expansion of T helper (Th) cells followed by regulation of activation are essential to the generation of immune responses while limiting concomitant autoreactivity. In order to characterize T cells reactive towards myeloma-derived monoclonal immunoglobulin (mIg), an autologous coculture assay for single-cell analysis of mIg-responding cells was developed. When cultured with dendritic cells loaded with mIg, CD4+ Th cells from patients with progressing multiple myeloma (MM) showed a proliferative MHC class II–dependent response. CD8+ T-cell reactivity and Th1 activation were consistently low or absent, and Th2 and regulatory cytokines were expressed. The presence of such non-Th1 CD4+ T cells in peripheral blood was independent of treatment status, while the frequencies of responding cells varied between patients and reached the same order of magnitude as those measured for tetanus toxoid–specific Th memory cells. Furthermore, investigations of T-cell subpopulations indicated a possible regulatory role on the mIg responsiveness mediated by suppressive CD25highFOXP3+CD4+ T cells. It is proposed from the present results that a predominant in vivo activation of non-Th1 mIg-reactive CD4+ T cells constitute an Ig-dependent autoregulatory mechanism in human MM, with possible tumor growth supporting or permissive effects.
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Borte, Stephan, Qiang Pan-Hammarström, Chonghai Liu, Ulrich Sack, Michael Borte, Ulf Wagner, Dagmar Graf, and Lennart Hammarström. "Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency." Blood 114, no. 19 (November 5, 2009): 4089–98. http://dx.doi.org/10.1182/blood-2009-02-207423.
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Abstract Interleukin-21 (IL-21) is an important promoter for differentiation of human B cells into immunoglobulin (Ig)–secreting cells. The objective of this study was to evaluate an IL-21–based approach to induce immunoglobulin production in B cells from patients with common variable immunodeficiency (CVID) or selective IgA deficiency (IgAD). We show that a combination of IL-21, IL-4, and anti-CD40 stimulation induces class-switch recombination to IgG and IgA and differentiation of Ig-secreting cells, consisting of both surface IgG+ (sIgG+) and sIgA+ B cells and CD138+ plasma cells, in patients with CVID or IgAD. Stimulation with IL-21 was far more effective than stimulation with IL-4 or IL-10. Moreover, spontaneous apoptosis of CD19+ B cells from patients with CVID or IgAD was prevented by a combination of IL-21, IL-4, and anti-CD40 stimulation. Analysis of IL-21 and IL-21 receptor (IL-21R) mRNA expression upon anti-CD3 stimulation of T cells, however, showed no evidence for defective IL-21 expression in CVID patients and sequencing of the coding regions of the IL21 gene did not reveal any mutations, suggesting a regulatory defect. Thus, our work provides an initial basis for a potential therapeutic role of IL-21 to reconstitute immunoglobulin production in CVID and IgAD.
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Mancao, Christoph, Markus Altmann, Berit Jungnickel, and Wolfgang Hammerschmidt. "Rescue of “crippled” germinal center B cells from apoptosis by Epstein-Barr virus." Blood 106, no. 13 (December 15, 2005): 4339–44. http://dx.doi.org/10.1182/blood-2005-06-2341.
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Epstein-Barr virus (EBV) is associated with B-cell lymphomas such as Hodgkin lymphoma, Burkitt lymphoma, and post-transplantation lymphoma, which originate from clonal germinal center (GC) B cells. During the process of somatic hypermutation, GC B cells can acquire deleterious or nonsense mutations in the heavy and light immunoglobulin genes. Such mutations abrogate the cell surface expression of the B-cell receptor (BCR), which results in the elimination of these nonfunctional B cells by immediate apoptosis. EBV encodes several latent genes, among them latent membrane protein 1 (LMP1) and LMP2A, which are regularly expressed in EBV-positive Hodgkin lymphoma and posttransplantation lymphomas. Since LMP1 and LMP2A mimic the function of 2 key receptors on B cells, CD40 and BCR, respectively, we wanted to learn whether EBV infection can rescue proapoptotic GC B cells with crippling mutations in the heavy chain immunoglobulin locus from apoptosis. We show here that BCR-negative GC B cells readily enter the cell cycle upon infection with EBV in vitro and yield clonal lymphoblastoid cell lines that are incapable of expressing a functional BCR because the rearranged and formerly functional heavy chain immunoglobulin alleles carry deleterious mutations. Our findings imply an important role for EBV in the process of lymphomagenesis in certain cases of Hodgkin lymphoma and posttransplantation lymphomas.
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Kolar, Grant R., Takafumi Yokota, Maria Isabel D. Rossi, Swapan K. Nath, and J. Donald Capra. "Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire." Blood 104, no. 9 (November 1, 2004): 2981–87. http://dx.doi.org/10.1182/blood-2003-11-3961.
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Abstract Several characteristics of the immunoglobulin (Ig) repertoire in fetuses and adults set them apart from each other. Functionally, this translates into differences in the affinity and effectiveness of the humoral immune response between adults and the very young. At least 2 possibilities could explain these differences: (1) fetal and adult lymphocyte progenitors differ significantly in their potential to form a diverse repertoire, and (2) factors extrinsic to the immunoglobulin locus are more influential to the character of the repertoire. To address this we used nonobese diabetic-severe combined immunodeficient-β2 microglobulin knockout (NOD/SCID/β2m-/-) mice reconstituted with human B-cell progenitors to compare the immunoglobulin repertoire potential of human fetal, cord blood, and adult sources. We found nearly identical VH and JH gene segment use and only modest differences in the third complementarity determining region of the immunoglobulin heavy chain (HCDR3). We conclude that the repertoire potential is remarkably similar regardless of the age of the individual from which progenitors are derived. Age-related differences in the immunoglobulin repertoire and variance of B-cell responses to immunization appear to arise from selection rather than from changes in recombination of the immunoglobulin locus itself. From the standpoint of the Ig repertoire, an immune system reconstituted from fetal or neonatal stem cells would likely be as diverse as one generated from adult bone marrow.
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Wang, Ying, Jiang Cao, Yan Zhiling, Jianlin Qiao, Deipeng Li, Zhenyu Li, and Kailin Xu. "Kinetics of Immune Reconstitution after CD19 CAR-T Cell Therapy in ALL Patients." Blood 134, Supplement_1 (November 13, 2019): 1301. http://dx.doi.org/10.1182/blood-2019-127808.
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Background: Chimeric antigen receptor (CAR)-T cell therapy has achieved significant efficacy in relapsed or refractory(R/R) hematologic malignancies. CD19 CAR-T cells, which kill B lymphoblasts, but also target normal B lymphocytes, resulting in dysplasia of B cells and suppression of humoral immunity. There were no detailed reports on the profile of immune reconstitution in patients after CD19 CAR-T cell treatment. Our study focused on the kinetics of lymphocyte subsets and immunoglobulin reconstruction in 21 patients with acute lymphoblastic leukemia (ALL) after CD19 CAR-T cell therapy. Methods: Patients with R/R ALL received CD19 CAR-T cell therapy who obtaining complete response at 1 month after CAR-T cell infusion from April 1, 2016 to Feb 28, 2019 were enrolled (Clinical Trials: NCT02782351). Blood was collected before lymphodepletion therapy and at intervals after CAR-T cell infusion for analysis of complete blood counts, lymphocyte subsets, immunoglobulin, and the amplification of CAR T cells. Results: We found that the reconstitution of different immune cell subsets occurred at different rates after CD19 CAR-T cell infusion: CD8+ cells were the first to recover, followed by CD16+CD56+ cells and CD3+ cells, and finally CD4+ cells. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell dysplasia occurred in all patients and CD19+ cells returned to normal 79 days after CAR-T cell infusion, which may be related to CAR-T cell depletion. IgG and IgM recovered on day 184 and 242 after CAR-T treatment, respectively. IgA recovered slowly and sustained longer at a low level compared with IgG and IgM, and did not return to normal 1 year after CAR-T cell treatment. A total of 9 infections occurred in 6 (28.57%) patients, including 6 cases with grade 2 infection and 3 cases with grade 3 infection. No patients died of severe infection. In patients with late relapse, IgG, IgA, and IgM were generally normal before CAR-T cell therapy, and were higher than those with early relapse, suggesting that patients with normal immunoglobulin levels before treatment may have longer remission time. Conclusion: Our results showed the kinetics of lymphocyte subsets and immunoglobulin reconstruction in R/R ALL patients after CD19 CAR-T cell therapy. The recovery of CD8+ cells was fast, whereas the recovery of the CD4+ cell was delayed. All patients developed B cell dysplasia, and it took about 3 months to recover. IgG recovered firstly, followed by IgM and IgA, the later would not recover at least 1 year. Disclosures No relevant conflicts of interest to declare.
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Li, Guangjin, Mingcan Yu, Cornelia M. Weyand, and Jörg J. Goronzy. "Epigenetic regulation of killer immunoglobulin–like receptor expression in T cells." Blood 114, no. 16 (October 15, 2009): 3422–30. http://dx.doi.org/10.1182/blood-2009-01-200170.
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Abstract With increasing age, T cells gain expression of killer immunoglobulin–like receptors (KIRs) that transmit negative signals and dampen the immune response. KIR expression is induced in CD4 and CD8 T cells by CpG DNA demethylation suggesting epigenetic control. To define the mechanisms that underlie the age-associated preferential KIR expression in CD8 T cells, we examined KIR2DL3 promoter methylation patterns. With age, CD8 T cells developed a patchy and stochastic promoter demethylation even in cells that did not express the KIR2DL3-encoded CD158b protein; complete demethylation of the minimal KIR2DL3 promoter was characteristic for CD158b-expressing cells. In contrast, the promoter in CD4 T cells was fully methylated irrespective of age. The selectivity for CD8 T cells correlated with lower DNMT1 recruitment to the KIR2DL3 promoter which further diminished with age. In contrast, binding of the polycomb protein EZH2 known to be involved in DNMT1 recruitment was not different. Our data suggest that CD8 T cells endure increasing displacement of DNMT1 from the KIR promoter with age, possibly because of an active histone signature. The ensuing partial demethylation lowers the threshold for transcriptional activation and renders CD8 T cells more susceptible to express KIR, thereby contributing to the immune defect in the elderly.
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Caligiuri, Michael A. "Human natural killer cells." Blood 112, no. 3 (August 1, 2008): 461–69. http://dx.doi.org/10.1182/blood-2007-09-077438.
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Abstract Natural killer (NK) cells were discovered more than 30 years ago. NK cells are large granular lymphocytes that belong to the innate immune system because unlike T or B lymphocytes of the adaptive or antigen-specific immune system, NK cells do not rearrange T-cell receptor or immunoglobulin genes from their germline configuration. During the past 2 decades there has been a substantial gain in our understanding of what and how NK-cells “see,” lending important insights into their functions and purpose in normal immune surveillance. The most recent discoveries in NK-cell receptor biology have fueled translational research that has led to remarkable results in treating human malignancy.
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Jones, Richard J., Christopher D. Gocke, Yvette L. Kasamon, Carole B. Miller, Brandy Perkins, James P. Barber, Milada S. Vala, et al. "Circulating clonotypic B cells in classic Hodgkin lymphoma." Blood 113, no. 23 (June 4, 2009): 5920–26. http://dx.doi.org/10.1182/blood-2008-11-189688.
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Abstract Although Hodgkin and Reed-Sternberg (HRS) cells are B lymphoid cells, they are unlike any normal cells of that lineage. Moreover, the limited proliferative potential of HRS cells belies the clinical aggressiveness of Hodgkin lymphoma (HL). More than 20 years ago, the L428 HL cell line was reported to contain a small population of phenotypic B cells that appeared responsible for the continued generation of HRS cells. This observation, however, has never been corroborated, and such clonotypic B cells have never been documented in HL patients. We found that both the L428 and KM-H2 HL cell lines contained rare B-cell subpopulations responsible for the generation and maintenance of the predominant HRS cell population. The B cells within the HL cell lines expressed immunoglobulin light chain, the memory B-cell antigen CD27, and the stem cell marker aldehyde dehydrogenase (ALDH). Clonal CD27+ALDHhigh B cells, sharing immunoglobulin gene rearrangements with lymph node HRS cells, were also detected in the blood of most newly diagnosed HL patients regardless of stage. Although the clinical significance of circulating clonotypic B cells in HL remains unclear, these data suggest they may be the initiating cells for HL.
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Kambayashi, Taku, Jan D. Baranski, Rebecca G. Baker, Tao Zou, Eric J. Allenspach, Jonathan E. Shoag, Peter L. Jones, and Gary A. Koretzky. "Indirect involvement of allergen-captured mast cells in antigen presentation." Blood 111, no. 3 (February 1, 2008): 1489–96. http://dx.doi.org/10.1182/blood-2007-07-102111.
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Abstract It is generally thought that mast cells influence T-cell activation nonspecifically through the release of inflammatory mediators. In this report, we provide evidence that mast cells may also affect antigen-specific T-cell responses by internalizing immunoglobulin E–bound antigens for presentation to antigen-specific T cells. Surprisingly, T-cell activation did not require that mast cells express major histocompatibility complex class II, indicating that mast cells were not involved in the direct presentation of the internalized antigens. Rather, the antigen captured by mast cells is presented by other major histocompatibility complex class II+ antigen-presenting cells. To explore how this may occur, we investigated the fate of mast cells stimulated by antigen and found that FcϵRI crosslinking enhances mast cell apoptosis. Cell death by antigen-captured mast cells was required for efficient presentation because protection of mast cell death significantly decreased T-cell activation. These results suggest that mast cells may be involved in antigen presentation by acting as an antigen reservoir after antigen capture through specific immunoglobulin E molecules bound to their FcϵRI. This mechanism may contribute to how mast cells impact the development of T-cell responses.
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KONDO, NAOMI, HIROATSU AGATA, GENG PAI LI, SHUNJI TOMATSU, NOBUYUKI SHIMOZAWA, YASUYUKI SUZUKI, YOSHIHIRO NAKASHIMA, et al. "Correlations Between Serum Immunoglobulin Concentrations and Immunoglobulin Secreting Cells in Healthy Peripheral Blood." Pediatric Asthma, Allergy & Immunology 7, no. 4 (January 1993): 239–42. http://dx.doi.org/10.1089/pai.1993.7.239.
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Hubbard, Nicholas, David Hagin, Karen Sommer, Yumei Song, Iram Khan, Courtnee Clough, Hans D. Ochs, David J. Rawlings, Andrew M. Scharenberg, and Troy R. Torgerson. "Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome." Blood 127, no. 21 (May 26, 2016): 2513–22. http://dx.doi.org/10.1182/blood-2015-11-683235.
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Key PointsThe CD40LG locus can be specifically targeted and repaired in primary human T cells by insertion of a spliced CD40LG complementary DNA. Gene editing restores regulated CD40L expression in X-HIGM T cells, reconstituting B-cell immunoglobulin class switching.
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Grzywacz, Bartosz, Nandini Kataria, Niketa Kataria, Bruce R. Blazar, Jeffrey S. Miller, and Michael R. Verneris. "Natural killer–cell differentiation by myeloid progenitors." Blood 117, no. 13 (March 31, 2011): 3548–58. http://dx.doi.org/10.1182/blood-2010-04-281394.
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Abstract Because lymphoid progenitors can give rise to natural killer (NK) cells, NK ontogeny has been considered to be exclusively lymphoid. Here, we show that rare human CD34+ hematopoietic progenitors develop into NK cells in vitro in the presence of cytokines (interleukin-7, interleukin-15, stem cell factor, and fms-like tyrosine kinase-3 ligand). Adding hydrocortisone and stromal cells greatly increases the frequency of progenitor cells that give rise to NK cells through the recruitment of myeloid precursors, including common myeloid progenitors and granulocytic-monocytic precursors to the NK-cell lineage. WNT signaling was involved in this effect. Cells at more advanced stages of myeloid differentiation (with increasing expression of CD13 and macrophage colony-stimulating factor receptor [M-CSFR]) could also differentiate into NK cells in the presence of cytokines, stroma, and hydrocortisone. NK cells derived from myeloid precursors (CD56−CD117+M-CSFR+) showed more expression of killer immunoglobulin-like receptors, a fraction of killer immunoglobulin–like receptor-positive–expressing cells that lacked NKG2A, a higher cytotoxicity compared with CD56−CD117+M-CSFR− precursor-derived NK cells and thus resemble the CD56dim subset of NK cells. Collectively, these studies show that NK cells can be derived from the myeloid lineage.
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Jimbo, Koji, Takaaki Konuma, Takahiro Ito, Yaeko Nakajima-Takagi, Atsushi Iwama, and Arinobu Tojo. "Immunoglobulin Superfamily Member 8 Is Indispensable for Myeloid Leukemia Via Wnt/β-Catenin Signaling Pathway." Blood 136, Supplement 1 (November 5, 2020): 23–24. http://dx.doi.org/10.1182/blood-2020-136045.
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Immunoglobulin superfamily member 8 (IGSF8, also known as EWI-2, PGRL, and CD316), is a cell surface protein containing 4 immunoglobulin domains. IGSF8 directly binds to the tetraspanin molecules, CD9 and CD81, and modulates cell adhesion, migration, and growth. Previous studies demonstrated that IGSF8 was associated with prognosis and metastasis in several solid tumors. However, the role of IGSF8 in normal hematopoiesis and myeloid leukemia is still unclear. First, we examined the expression levels of Igsf8 in various hematopoietic fraction of wild-type murine bone marrow cells, and found that Igsf8 is expressed in all hematopoietic lineages. To investigate hematopoietic functions of Igsf8, we generated hematopoietic cells specific Igsf8 deleted mice (Igsf8fl/fl; Vav-Cre) and tamoxifen induced Igsf8 deleted mice (Igsf8fl/fl; Rosa26-CreERT). Igsf8fl/fl, Vav-Cre (denoted as Igsf8-/-) mice represented normal maturation. Deletion of Igsf8 did not significantly affect adult hematopoiesis in peripheral blood and bone marrow. Igsf8-/- long-term hematopoietic stem cells (LT-HSCs: CD34- Flk2- c-Kit+ Sca-1+ Lineage- cells) reduced colony forming ability in vitro, and serial competitive transplantation assay showed comparable donor chimerism by 3 months, but led to decrease Igsf8-/- donor chimerism at 4 months and those after second transplantation in vivo. These results suggest that Igsf8 does not affect the adult hematopoiesis, but it can affect their proliferative and reconstitutive capacity of HSCs. To investigate the effects of Igsf8 on myeloid leukemia, we generated MLL-AF9 and NRASG12V-driven acute myelogenous leukemia (AML), or BCR-ABL and NUP98-HOXA9-driven blast crisis of chronic myelogenous leukemia (CML-BC) mice models. Igsf8-/- led to a dramatic reduction in the number of leukemic colonies formed in vitro (Figure 1A). Igsf8-/- leukemia mice showed significantly longer survival in vivo (Figure 1B). This effect was also observed by eliminating Igsf8 expression after leukemia establishment using conditionally deletion. Igsf8-/- AML cells showed decreased S phase fraction. Igsf8-/- leukemia stem cells (LSCs: c-Kit+ Lineage- cells) triggered an increment of the apoptosis, which contribute to significantly lower proportion of LSCs in spleen of Igsf8-/- leukemic mice. Given that Igsf8-/- did not affect homing ability of leukemia cells, these results indicate that Igsf8 is required for propagation of myeloid leukemia and maintenance of LSC. To understand the Igsf8-mediated regulation of myeloid leukemia, we conducted RNA sequencing analysis of LT-HSCs, and LSCs of AML and CML-BC. Gene set enrichment analysis exhibited increase apoptosis related genes and decrease Wnt/β-catenin related genes in Igsf8-/- leukemic cells, but not in LT-HSCs (Figure 1C). Increment of pro-apoptosis genes, and decrement of anti-apoptosis genes and Wnt/β-catenin target genes in Igsf8-/- AML stem cells were validated in quantitative polymerase chain reaction analysis. Further, expression levels of β-catenin protein in Igsf8-/- leukemic cells were significantly lower compared to Igsf8+/+ leukemic cells, but not in normal hematopoietic stem and progenitor cells (Figure 1D). These results suggest that Igsf8 might be critical for myeloid leukemia maintenance via Wnt/β-catenin signaling pathway. Then, we investigated the effects of IGSF8 on human myeloid leukemia. We confirmed IGSF8 expression in several human myeloid leukemia cell line and primary patient-derived leukemia cells. Knockdown of IGSF8 by small hairpin RNA in myeloid leukemia cell lines (THP-1, MV4-11, SKM-1, and K562) and primary patient-derived AML cells exhibited reduced numbers of colony forming cells in vitro. Knockdown of IGSF8 also caused decrease expression of β-CATENIN in AML cell lines. These results indicate that IGSF8 is also required for propagation of human myeloid leukemia cells. Taken together, our present study reveals that Igsf8 is indispensable for myeloid leukemia, but not adult hematopoiesis, suggesting that IGSF8 inhibition should be considered for targeting myeloid leukemia. Disclosures Jimbo: Japan Society for the Promotion of Science: Research Funding. Konuma:SGH Foundation: Research Funding; The Japanese Society of Hematology: Research Funding; Institute for Frontier Life and Medical Sciences, Kyoto University: Research Funding. Ito:Institute for Frontier Life and Medical Sciences, Kyoto University: Research Funding.
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Morvan, Caroline Le, Eric Pinaud, Catherine Decourt, Armelle Cuvillier, and Michel Cogné. "The immunoglobulin heavy-chain locus hs3b and hs4 3′ enhancers are dispensable for VDJ assembly and somatic hypermutation." Blood 102, no. 4 (August 15, 2003): 1421–27. http://dx.doi.org/10.1182/blood-2002-12-3827.
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Abstract The more distal enhancers of the immunoglobulin heavy-chain 3′ regulatory region, hs3b and hs4, were recently demonstrated as master control elements of germline transcription and class switch recombination to most immunoglobulin constant genes. In addition, they were shown to enhance the accumulation of somatic mutations on linked transgenes. Since somatic hypermutation and class switch recombination are tightly linked processes, their common dependency on the endogenous locus 3′ enhancers could be an attractive hypothesis. VDJ structure and somatic hypermutation were analyzed in B cells from mice carrying either a heterozygous or a homozygous deletion of these enhancers. We find that hs3b and hs4 are dispensable both for VDJ assembly and for the occurrence of mutations at a physiologic frequency in the endogenous locus. In addition, we show that cells functionally expressing the immunoglobulin M (IgM) class B-cell receptor encoded by an hs3b/hs4-deficient locus were fully able to enter germinal centers, undergo affinity maturation, and yield specific antibody responses in homozygous mutant mice, where IgG1 antibodies compensated for the defect in other IgG isotypes. By contrast, analysis of Peyer patches from heterozygous animals showed that peanut agglutinin (PNAhigh) B cells functionally expressing the hs3b/hs4-deficient allele were dramatically outclassed by B cells expressing the wild-type locus and normally switching to IgA. This study thus also highlights the role of germinal centers in the competition between B cells for affinity maturation and suggests that membrane IgA may promote recruitment in an activated B-cell compartment, or proliferation of activated B cells, more efficiently than IgM in Peyer patches.
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Kilmon, Michelle A., Nikki J. Wagner, Alaina L. Garland, Li Lin, Katja Aviszus, Lawrence J. Wysocki, and Barbara J. Vilen. "Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6." Blood 110, no. 5 (September 1, 2007): 1595–602. http://dx.doi.org/10.1182/blood-2006-12-061648.
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Abstract Activation of the innate immune system promotes polyclonal antibody secretion to eliminate invading pathogens. Inherent in this process is the potential to activate autoreactive B cells and induce autoimmunity. We showed previously that TLR-stimulated dendritic cells and macrophages regulate B cell tolerance to Smith antigen, in part through the secretion of interleukin-6 (IL-6). In this manuscript, we show that neutralization of IL-6 fails to abrogate macrophage-mediated repression and identify soluble CD40 ligand (CD40L) as a second repressive factor secreted by macrophages. CD40L selectively repressed Ig secretion by chronically antigen-experienced (anergic) immunoglobulin transgenic and nontransgenic B cells but not by transiently stimulated B cells. The importance of macrophages in maintaining B cell tolerance was apparent in lupus-prone MRL/lpr mice. Compared with C57BL/6 mice, macrophages from MRL/lpr mice were significantly less efficient at repressing immunoglobulin secretion coincident with diminished IL-6 and CD40 ligand production. These data indicate that macrophages regulate autoreactive B cells by secreting repressive factors that prohibit terminal differentiation of B cells. The regulation of autoreactive B cells by macrophages is diminished in lupus-prone mice suggesting a role in autoimmunity.
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Bayry, Jagadeesh, Sébastien Lacroix-Desmazes, Cedric Carbonneil, Namita Misra, Vladimira Donkova, Anastas Pashov, Alain Chevailler, et al. "Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin." Blood 101, no. 2 (January 15, 2003): 758–65. http://dx.doi.org/10.1182/blood-2002-05-1447.
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Normal immunoglobulin G for therapeutic use (intravenous immunoglobulin [IVIg]) is used in an increasing number of immune-mediated conditions, including acute and chronic/relapsing autoimmune diseases, transplantation, and systemic inflammatory disorders. Several mutually nonexclusive mechanisms of action account for the immunoregulatory effects of IVIg. Although IVIg inhibits T-cell proliferation and T-cell cytokine production, it is unclear whether these effects are directly dependent on the effects of IVIg on T cells or they are dependent through the inhibition of antigen-presenting cell activity. Here, we examined the effects of IVIg on differentiation, maturation, and function of dendritic cells (DCs). We show that IVIg inhibits the differentiation and maturation of DCs in vitro and abrogates the capacity of mature DC to secrete interleukin-12 (IL-12) on activation while enhancing IL-10 production. IVIg-induced down-regulation of costimulatory molecules associated with modulation of cytokine secretion resulted in the inhibition of autoreactive and alloreactive T-cell activation and proliferation. Modulation of DC maturation and function by IVIg is of potential relevance to its immunomodulatory effects in controlling specific immune responses in autoimmune diseases, transplantation, and other immune-mediated conditions.
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Strati, Paolo, Michael J. Keating, William G. Wierda, Xavier C. Badoux, Steliana Calin, James M. Reuben, Susan O’Brien, et al. "Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia." Blood 122, no. 5 (August 1, 2013): 734–37. http://dx.doi.org/10.1182/blood-2013-04-495341.
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Auner, Holger W., Christine Beham-Schmid, Niall Dillon, and Pierangela Sabbattini. "The life span of short-lived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress." Blood 116, no. 18 (November 4, 2010): 3445–55. http://dx.doi.org/10.1182/blood-2009-10-250423.
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Abstract Apoptosis of short-lived plasma cells after a few days of intense immunoglobulin secretion is critical for maintaining a controlled humoral immune response. The mechanisms that regulate this process are poorly understood. Here we report that the key apoptotic caspases, caspase-3 and caspase-9, become resistant to activation by apoptotic stimuli when B cells differentiate into short-lived plasma cells. As a consequence, apoptosis of most short-lived plasma cells in vitro and in vivo is effector caspase-independent. We also show that a triaspartic acid repeat that normally prevents activation of caspase-3 becomes stabilized in short-lived plasma cells and myeloma cell lines. The block on caspase activation occurs before the accumulation of intracellular immunoglobulins and a progressive rise in secretory stress in the endoplasmic reticulum (ER). Plasma cells show increased susceptibility to ER stress–induced apoptosis and activate the ER-associated caspase-12, which is required specifically for nuclear apoptotic events. In nonlymphoid cells that cannot activate effector caspases, programmed cell death is delayed in response to ER stress. These observations suggest that the block on activation of key apoptotic caspases has evolved in short-lived plasma cells to prolong survival under conditions of ER stress resulting from high-level immunoglobulin secretion.
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Das, Riku, Swetha Ganapathy, Megan Settle, and Edward F. Plow. "Plasminogen promotes macrophage phagocytosis in mice." Blood 124, no. 5 (July 31, 2014): 679–88. http://dx.doi.org/10.1182/blood-2014-01-549659.
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Key Points Plasminogen influences uptake of apoptotic bodies and immunoglobulin-coated red cells by macrophages in mice. Plasminogen regulates expression of genes involved in macrophage phagocytosis in vivo.
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Dobbs, A. Kerry, Amma Bosompem, Elaine Coustan-Smith, Gayle Tyerman, Frank T. Saulsbury, and Mary Ellen Conley. "Agammaglobulinemia associated with BCR− B cells and enhanced expression of CD19." Blood 118, no. 7 (August 18, 2011): 1828–37. http://dx.doi.org/10.1182/blood-2011-01-330472.
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AbstractExpression of a BCR is critical for B-cell development and survival. We have identified 4 patients with agammaglobulinemia and markedly reduced but detectable B cells in the peripheral circulation. These B cells have an unusual phenotype characterized by increased expression of CD19 but no BCR. The cells are positive for CD20, CD22, and CD38, but not for Annexin 5 or activation markers, including CD69, CD83, or CD86. EBV lines derived from these B cells lack functionally rearranged immunoglobulin heavy-chain transcripts, as shown by PCR–rapid amplification of cDNA ends (PCR-RACE). Analysis of BM from 2 of the patients showed a severe reduction in the number of pro-B cells as well as pre-B cells. Functionally rearranged heavy-chain transcripts were identified, indicating that machinery to rearrange immunoglobulin genes was intact. Flow cytometry of B-lineage cells suggested accelerated acquisition of maturation markers in early B-cell precursors and increased phosphorylation of signal transduction molecules. Further, expression of TdT, a molecule that is normally down-regulated by a functional pre-BCR complex, was decreased. We hypothesize that the accelerated maturation, increased expression of CD19, and lack of a BCR were due to the constitutive activation of the BCR signal transduction pathway in these patients.
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Foley, Bree, Sarah Cooley, Michael R. Verneris, Michelle Pitt, Julie Curtsinger, Xianghua Luo, Sandra Lopez-Vergès, Lewis L. Lanier, Daniel Weisdorf, and Jeffrey S. Miller. "Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function." Blood 119, no. 11 (March 15, 2012): 2665–74. http://dx.doi.org/10.1182/blood-2011-10-386995.
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AbstractDuring mouse cytomegalovirus (CMV) infection, a population of Ly49H+ natural killer (NK) cells expands and is responsible for disease clearance through the induction of a “memory NK-cell response.” Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C+ NK cells expanded and were potent producers of IFNγ. NKG2C+ NK cells predominately expressed killer cell immunoglobulin–like receptor, and self-killer cell immunoglobulin–like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56dim NK cells. Strikingly, increased frequencies of NKG2C+ NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C+ NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.
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Ushmorov, Alexey, Olga Ritz, Michael Hummel, Frank Leithäuser, Peter Möller, Harald Stein, and Thomas Wirth. "Epigenetic silencing of the immunoglobulin heavy-chain gene in classical Hodgkin lymphoma-derived cell lines contributes to the loss of immunoglobulin expression." Blood 104, no. 10 (November 15, 2004): 3326–34. http://dx.doi.org/10.1182/blood-2003-04-1197.
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Abstract Immunoglobulin production is impaired in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) in spite of functional clonal rearrangements. The presence of “crippling” mutations in coding and regulatory regions, as well as down-regulation of B-cell-specific transcription factors, has been suggested as a potential reason for the lack of immunoglobulin (Ig) chain gene transcription. We have investigated the impact of epigenetic silencing in suppressing Ig heavy (H)-chain expression. Chromatin immunoprecipitation (ChIP) was used to analyze transcription factor binding to octamer motifs present in the IgH regulatory regions. Transcription factors were bound to these motifs in control cell lines, however, they were absent in the cHL-derived cell lines KMH2, L1236, and L428. Ectopic expression of octamer-binding transcription factor (Oct2) and/or B-cell Oct binding protein/Oct-binding factor (BOB.1/OBF.1) did not result in any measurable binding to these sites. Increased histone 3 Lysine 9 (H3-K9) methylation was observed in the promoter region of the IgH locus in L428 and L1236 cells. This is a typical feature of heterochromatic, transcriptionally silent regions. Treatment of cHL-derived cell lines with the DNA demethylating agent 5-aza-2′-deoxycytidine (5-aza-dC) partially reactivated IgH transcription and affected chromatin modifications. Our results suggest an important role of epigenetic silencing in the inhibition of IgH transcription in HRS cells. (Blood. 2004;104:3326-3334)
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Fauriat, Cyril, Martin A. Ivarsson, Hans-Gustaf Ljunggren, Karl-Johan Malmberg, and Jakob Michaëlsson. "Education of human natural killer cells by activating killer cell immunoglobulin-like receptors." Blood 115, no. 6 (February 11, 2010): 1166–74. http://dx.doi.org/10.1182/blood-2009-09-245746.
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Abstract Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self–major histocompatibility complex (MHC) class I molecules provides an educational signal that generates functional natural killer (NK) cells. However, the effects of activating KIRs specific for self-MHC class I on NK-cell education remain elusive. Here, we provide evidence that the activating receptor KIR2DS1 tunes down the responsiveness of freshly isolated human NK cells to target cell stimulation in donors homozygous for human leukocyte antigen (HLA)–C2, the ligand of KIR2DS1. The tuning was apparent in KIR2DS1+ NK cells lacking expression of inhibitory KIRs and CD94/NKG2A, as well as in KIR2DS1+ NK cells coexpressing the inhibitory MHC class I–specific receptors CD94/NKG2A and KIR2DL3, but not KIR2DL1. However, the tuning of responsiveness was restricted to target cell recognition because KIR2DS1+ NK cells responded well to stimulation with exogenous cytokines. Our results provide the first example of human NK-cell education by an activating KIR and suggest that the education of NK cells via activating KIRs is a mechanism to secure tolerance that complements education via inhibitory KIRs.
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Metcalfe, Dean D. "Mast cells and mastocytosis." Blood 112, no. 4 (August 15, 2008): 946–56. http://dx.doi.org/10.1182/blood-2007-11-078097.
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Abstract Mast cells have been recognized for well over 100 years. With time, human mast cells have been documented to originate from CD34+ cells, and have been implicated in host responses in both innate and acquired immunity. In clinical immunology, they are recognized for their central role in IgE-mediated degranulation and allergic inflammation by virtue of their expression of the high-affinity receptor for IgE and release of potent proinflammatory mediators. In hematology, the clinical disease of mastocytosis is characterized by a pathologic increase of mast cells in tissues, often associated with mutations in KIT, the receptor for stem cell factor. More recently, and with increased understanding of how human mast cells are activated through receptors including the high-affinity receptor for IgE and KIT, specific tyrosine kinase inhibitors have been identified with the potential to interrupt signaling pathways and thus limit the proliferation of mast cells as well as their activation through immunoglobulin receptors.
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Rivera-Munoz, Paola, Pauline Soulas-Sprauel, Gwenaël Le Guyader, Vincent Abramowski, Sylvia Bruneau, Alain Fischer, Frédéric Pâques, and Jean-Pierre de Villartay. "Reduced immunoglobulin class switch recombination in the absence of Artemis." Blood 114, no. 17 (October 22, 2009): 3601–9. http://dx.doi.org/10.1182/blood-2008-11-188383.
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Abstract Nonhomologous end-joining DNA repair factors, including Artemis, are all required for the repair of DNA double-strand breaks, which occur during the assembly of the variable antigen recognition domain of B-cell receptors and T-cell receptors through the V(D)J recombination. Mature B cells further shape their immunoglobulin repertoire on antigen recognition notably through the class switch recombination (CSR) process. To analyze the role of Artemis during CSR, we developed a mature B-cell–specific Artemis conditional knockout mouse to bypass the absence of B cells caused by its early deficit. Although CSR is not overwhelmingly affected in these mice, class switching to certain isotypes is clearly reduced both in vitro on B-cell activation and in vivo after keyhole limpet hemocyanin immunization. The reduced CSR in Artemis-deficient B cells is accompanied by the increase in DNA microhomology usage at CSR junctions, the imprint of an alternative DNA end-joining pathway. Likewise, significant increase in DNA microhomology usage is the signature of CSR junctions obtained from human RS-SCID patients harboring hypomorphic Artemis mutations. Altogether, this indicates that Artemis participates in the repair of a subset of DNA breaks generated during CSR.