Selective Rapid B-Cell Depletion In Vivo by Pharmacologic IKK2 Inhibition.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2481-2481
Author(s):  
Christopher C. Fraser ◽  
Kumiko Nagashima ◽  
Vito Sasseville ◽  
Jim Deeds ◽  
Alice McDonald ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Oral Dose ◽  
B Cell ◽  
Single Oral Dose ◽  
Colony Growth ◽  
B Cell Development ◽  
Cell Depletion ◽  
B Cell Depletion

Abstract Studies using genetically deficient mice have revealed that members of the NF-kB family play key roles in B-cell development. IKK2 which activates NF-kB by targeting degradation of IkB, is also required for B-cell development. We have studied the role of IKK2 in hematopoiesis using a chemical specific inhibitor (ML120B). Mice given daily oral dosing of ML120B for 4 days had severe B-cell depletion in spleen and bone marrow. B-cells at all stages (pro-B, pre-B, immature and mature B) were depleted 10 fold in the bone marrow while granulocyte numbers were largely unaffected. IKK2 inhibition in vivo showed selective sensitivity of B-cell progenitors (4 fold decrease) in the marrow compared to myeloid progenitors which were unaffected at an equivalent dose. Foci of cells with an apoptotic morphology were visible in bone marrow and spleen within 6 hours of a single oral dose. Apoptotic cells detected by labeling fragmented DNA were increased within splenic follicles (6 fold) and bone marrow. Also an increase in B220+ / annexin V+ cells and a decrease in pre-B (B220+/IgM−) cells in the marrow were observed. RNA expression studies in the marrow 6 hours after a single oral dose revealed a decrease in IL-7 and increased GM-CSF expression. Image analysis of B220 in spleens within 18 hours of a single dose of an IKK inhibitor revealed decreased follicle size. In order to evaluate hematopoietic progenitor sensitivity to NF-kB inhibition, dose responses to ML120B, panepoxydone (PPD) and proteasome inhibitor Lactacystin (Lcyst) were evaluated in B-cell and myeloid bone marrow colony assays. Inhibitors PPD and Lcyst were more effective at inhibiting B-cell colony growth than myeloid colony growth. In summary, pharmacologic inhibition of IKK2 results in a rapid induction of apoptosis with preferential depletion of B-cells and retention of myeloid cells and progenitors within the bone marrow.

Autoantibody Production during Chronic Graft-Versus-Host Disease Does Not Associate with Long-Term Persistence of Host B Cells in Humans

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1180-1180
Author(s):  
Simona Piemontese ◽  
Zulma Magnani ◽  
Jacopo Peccatori ◽  
Claudio Bordignon ◽  
Chiara Bonini ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Graft Versus Host Disease ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Autoantibody Production ◽  
Graft Versus Host

Abstract Background. Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic hemopoietic cell transplantation (allo-HCT). The pathogenesis of cGvHD is poorly understood. In cGvHD, the homeostasis of B lymphocytes is perturbed, as demonstrated by the production of autoantibodies. B-cell depletion with monoclonal antibodies (mAb) interferes with autoantibody production and ameliorates signs and symptoms of cGvHD. In mouse models, cGvHD and autoantibodies associate with the long-term persistence of host B cells after allo-HCT (Sylvain Perruche et al., Transplantation 2006). It has been postulated that host B cells may present alloantigens to donor T cells and, in turn, receive help for autoantibody production. This could be crucial to the pathogenesis of cGvHD. Aim. To investigate whether the long-term persistence of host B lymphocytes is associated with cGvHD and autoantibodies in humans. Patients and methods. We recruited 13 consecutive patients with active cGvHD (4 mild, 5 moderate, 4 severe according to NIH classification) with a median time of onset of 6 months (range 3–36) from HLA-identical sibling (9 patients) and HLA-matched unrelated (4) allo-HCT. As controls, we chose 10 patients that underwent HLAidentical sibling (2), HLA-matched unrelated (5) or haploidentical (3) allo-HCT and never experienced cGvHD. In the two groups, we studied: circulating autoantibodies, including anti-nuclear (ANA), anti-DNA, anti-extractable nuclear antigen, anti-beta2 glycoprotein, anti-neutrophil cytoplasm, anti-thyroid, anti-mytocondria antibodies, rheumatoid factor, absolute numbers of T (CD3+, CD4+, CD8+), conventional B (CD19+), B1 (CD5+/CD19+) and NK cells (CD16+/CD56+) in the graft and in the peripheral blood, microchimerism by short-tandem repeats (STR) on B, T and myeloid cells purified by immunomagnetic cell sorting (sensitivity 0,01%). Results. Patients with cGvHD had high-titer circulating ANA (>1:160) more frequently than controls (54% versus 10%, P<0,05). All other autoantibodies were negative. Peripheral T-cell counts were lower in patients with cGvHD than in controls (for CD8+ cells P<0,05). This was not due to a difference in the absolute numbers of T lymphocytes within the graft between the two groups. Peripheral counts of conventional B and B1 cells in patients with cGvHD were similar to controls. Autoantibodies and cGvHD were not associated with the persistence of host B lymphocytes, since the analysis of STR on purified B cells revealed that they were all of donor origin. T and myeloid cells were also of donor origin. Of interest, in univariate analysis, in vivo B-cell depletion with mAb for the prophylaxis against Epstein-Barr virus-related lymphoproliferative disease showed a trend towards a lower risk of cGvHD (P=0,06). Conclusions. This study indicates that autoantibody production during cGvHD does not associate with long-term persistence of host B cells in humans. Moreover, it suggests that the early depletion of donor B lymphocytes in vivo may be effective for GvHD prophylaxis

scholarly journals Chronic GvHD Is Characterized By Impaired B Cell Development in the Bone Marrow

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1883-1883
Author(s):  
Oleg Kolupaev ◽  
Michelle West ◽  
Bruce R. Blazar ◽  
Stephen Tilley ◽  
James Coghill ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Cell Development ◽  
B Cell Development ◽  
B Lymphopoiesis

Abstract Background. Chronic-graft-versus-host disease (cGvHD) continues to be a major complication following allogeneic hematopoietic stem cell transplantation (HSCT). Despite significant progress, mechanisms underlying development of the pathology are yet to be fully understood. Recent studies utilizing mouse models and patient samples have demonstrated a critical role for B cells in GvHD pathogenesis. Bone marrow (BM)-derived B cells can produce auto-reactive antibodies causing tissue fibrosis and multiorgan cGvHD. Impaired B cell homeostasis in the periphery, activation due to abnormally high levels of B cell-activating factor (BAFF), increased survival of auto-reactive B cells and aberrant BCR signaling are shown to be important for disease progression in cGvHD patients. Murine models also highlighted the critical role of germinal center reactions, particularly interactions between T follicular helper (Tfh) cells and B cells for generation of auto-antibodies which are responsible for triggering immune responses and cell-mediated toxicity. A growing body of evidence has emerged highlighting the fact that BM itself is a target organ during acute GvHD (aGvHD) with recent work suggesting a role for donor CD4+ T cells in BM specific aGvHD. Our group has shown that patients with higher numbers of BM B cell precursors were less likely to develop cGvHD after allogeneic HSCT (Fedoriw et al., 2012). These observations indicate clinical relevance of impaired BM B lymphopoiesis for cGvHD development. Methods. In order to investigate the effect of cGvHD on BM B cell development, we used the well-characterized major mismatch B6 into B10.BR model of systemic cGvHD. Recipient mice were treated with cyclophosphamide on day -3 and -2, irradiated with 700 cGy on day -1, and injected with 107 T cell depleted (TCD) BM with or without total splenic T cells (0.5-1x105). Mice were monitored for 30 days, and BM and spleen was harvested and analyzed using flow cytometry. Results. Consistent with patient data, we observed a decrease in the frequency and number of donor-derived uncommitted common lymphoid progenitors (CLP) and B cell progenitors in the BM+ allogeneic T cells group (CLP: 0.17±0.03% vs. 0.06±0.01%, p <0.01; pro B: 2.2 ± 0.5% vs. 0.7 ± 0.3%, p<0.05; pre B: 15.3±1.8% vs. 6.3±2.4%, p<0.05; immature B cells: 5.7±0.7% vs. 2.1±0.7%, p<0.01) (Fig.1). As previously reported for this model, we also found a decrease in the frequency of follicular (FO) B cells (Flynn et al., 2014). We hypothesized that during cGvHD the B cell progenitor BM niche is affected by donor CD4+ T cells leading to impaired B lymphopoiesis. Bone marrow from BM+T cell animals had a significantly higher frequency of CD4+ cells compared to the control group (0.45±0.06% vs. 0.2±0.02%). Depletion of CD4+ T cells using anti-CD4 antibody during the first two weeks after transplant improved pathology scores and prevented weight loss in BM+T cells mice. We also observedpartial recovery of B cell progenitors and Lin-CD45-CD31-CD51+ osteoblasts (OB) in animals treated with anti-CD4 antibodies (pre B 3.5±1.1% vs. 20.4±4.5%, p<0.05; immature B: 1.9±0.9% vs. 3.5±0.3%; OB: 0.8±0.1% vs.1.2±0.2%). A recent study showed that activation and proliferation of conventional T cells in aGvHD model can be prevented by in vivo expansion of regulatory T cells (Tregs) using αDR3 antibody (4C12). We adopted this approach to determine whether Tregs can suppress the cytotoxic effect of donor CD4+ T cells in BM in cGvHD model. Animals that received T cells from 4C12-treated donors had an increase in survival and lower cGvHD pathology scores. These mice also had higher frequency of pro B, pre B, and immature B cells compared to the mice infused with T cells from isotype-treated donors. Conclusions. These studies demonstrate that BM development of B lymphocytes is impaired in a mouse model of systemic cGvHD. Our data suggests that donor-derived CD4+ T cells are involved in the destruction of hematopoietic niches in BM, particularly OB, which support B lymphopoiesis. Moreover, depletion of CD4+ T cells and infusion with in vivo expanded Tregs reduced the severity of cGvHD. Thus, Treg therapy in patients with cGvHD may be important for BM B cell development, and improvement of clinical outcomes. Disclosures No relevant conflicts of interest to declare.

Rituximab Mediated Depletion of B Cells Following Transplant of Human CD20 Transgenic Mouse Bone Marrow Results in Prolonged B Cell Depletion and Augmented Anti-Tumor Immune Response.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2205-2205
Author(s):  
Yu D. Zhang ◽  
Hovav Nechushtan ◽  
Monica Jones ◽  
Andrew Chan ◽  
Seung-uon Shin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Transgenic Mouse ◽  
Treated Group ◽  
Cell Depletion ◽  
Mouse Bone Marrow ◽  
B Cell Depletion ◽  
Post Transplant

Abstract We previously demonstrated rejection of murine tumors due to enhanced anti-tumor cytolytic and Th1 cytokine responses in mice lacking B cells (BCDM) compared to immunocompetent mice. We wished to compare immune and anti-tumor responses in BCDM to mice functionally depleted of B cells using an anti-human CD20 antibody (Rituximab). We evaluated Rituximab effects on the outgrowth of human CD20 transgenic mouse (huCD20 Tg) B cells following the transplant of huCD20Tg CD45.2+ bone marrow (BM) into sublethally irradiated congenic CD45.1+ mice. CD45.1 mice were irradiated with 9.5Gy at day -1, followed by infusion of 3x106 huCD20Tg BM cells on day 0, and by treatment with or without Rituximab at 400ug/mouse given once weekly i.v. for 4 weeks. Without Rituximab treatment, B cell percentages in the peripheral blood (PB) were approximately 46.4%±1.3; spleen, 77.8%±1.5; and peripheral lymph nodes (pLNs), 43%±1.5 at day 47. With Rituximab treatment, CD19+ cells in the PB, spleen and pLNs were 1.8%±0.4, 4.3%±1.3, and 0.8%±0.2 respectively at 47days post transplant. Higher percentages of CD3+ T cells in PB, spleen and pLNs (66.1%±0.5, 51.7%±1.1 and 43.0%±3.8) were noted in the Rituximab treated group compared to controls (19%±0.9, 10.3%±1.0 and 32.3%±1.7 respectively). The percentage of remaining B cells in PB declined progressively from 5.6% at day 13 to 1.8% at day 47 post transplant indicating that Rituximab depletion of huCD20+ transgenic B cells was progressive, durable and very effective. In contrast, CD3+ cells in PB increased from 11.2% (day 13) to 66.1 % (day 47) following Rituximab treatment. Interestingly reconstitution with endogenous murine B cells in huCD20 transplanted mice was minimal. The huCD20 Tg donor-derived T cells in the Rituximab treated group maintained a CD44low naive phenotype. The growth of MC38 tumors implanted 15 days following transplant was significantly slowed in the Rituximab treated group. Increased IFN-γ production and higher expression of the cytolytic marker CD107a by T cells was seen in the Rituximab treated group compared to controls. The combination of myeloablative irradiation, huCD20 transgenic bone marrow transfer and Rituximab depletion, was able to generate mice devoid of CD20+ B cells. Rituximab treated huCD20+ reconstituted B cell depleted mice have substantially higher percentages of T cells than control non-Rituximab treated mice, show sustained depression of B cell numbers and manifest an increased anti-tumor Th1 response. The huCD20 transplant model will be useful in studying effects of post-transplant B cell depletion on immune reconstitution and in the design of future clinical transplant and immunization strategies.

scholarly journals Interactions Between c-kit and Stem Cell Factor Are Not Required for B-Cell Development In Vivo

Blood ◽  
1997 ◽  
Vol 89 (2) ◽  
pp. 518-525 ◽  
Author(s):  
Shunichi Takeda ◽  
Takeyuki Shimizu ◽  
Hans-Reimer Rodewald
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Fetal Liver ◽  
Critical Role ◽  
Cell Development ◽  
B Cell Development ◽  
Wild Type ◽  
Hematopoietic Stem

Abstract The receptor-type tyrosine kinase, c-kit is expressed in hematopoietic stem cells (HSC), myeloid, and lymphoid precursors. In c-kit ligand-deficient mice, absolute numbers of HSC are mildly reduced suggesting that c-kit is not essential for HSC development. However, c-kit− HSC cannot form spleen colonies or reconstitute hematopoietic functions in lethally irradiated recipient mice. Based on in in vitro experiments, a critical role of c-kit in B-cell development was suggested. Here we have investigated the B-cell development of c-kitnull mutant (W/W ) mice in vivo. Furthermore, day 13 fetal liver cells from wild type or W/W mice were transferred into immunodeficient RAG-2−/− mice. Surprisingly, transferred c-kit− cells gave rise to all stages of immature B cells in the bone marrow and subsequently to mature conventional B2, as well as B1, type B cells in the recipients to the same extent as transferred wild type cells. Hence, in contrast to important roles of c-kit in the expansion of HSC and the generation of erythroid and myeloid lineages and T-cell precursors, c-kit− HSC can colonize the recipient bone marrow and differentiate into B cells in the absence of c-kit.

Emergence of Long-Lived Autoreactive Plasma Cells in the Spleen of Primary Warm Auto-Immune Hemolytic Anemia Patients Treated with Rituximab

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 569-569
Author(s):  
Matthieu Mahevas ◽  
Marc Michel ◽  
Benoit Vingert ◽  
Julien Moroch ◽  
David Boutboul ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Blood Cells ◽  
Plasma Cells ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Bone Marrow Plasma ◽  
Previously Treated

Abstract Introduction: We recently proposed that B-cell depletion in immune thrombocytopenia (ITP) promotes the generation of long-lived plasma cells in the spleen, some of them being auto-reactive; but it remained possible that this observation was related to ITP itself rather than to B-cell depletion. Primary warm autoimmune hemolytic anemia (wAIHA) is a rare disease characterized by IgG auto-antibodies directed against antigens at the surface of red blood cells (RBCs) antigens, leading to their accelerated destruction. The use of B-cell depletion in wAIHA leads to 60 % to 70% of overall response at one-year and beyond. Nevertheless, 30-40 % of patients may resist to rituximab and then require a splenectomy. Nothing is known about antibody secreting cells (ASC) in the spleen of wAIHA patients, who have previously been treated or not with rituximab. In this study, we analyzed at the single cell level the splenic ASC from patients with chronic and active wAIHA, previously treated or not with rituximab (RTX), and we compared them with splenic ASC from ITP patients, and with splenic and bone marrow plasma cells from healthy donors (HD). Methods: We took advantage of the different therapeutic outcomes to analyze the splenic B-cell compartment of wAIHA patients, not previously treated with RTX (n=6), or after failure RTX treatment (n=3).Splenic tissues from organ donors and bone marrow from cardiovascular thoracotomy were used as controls. Blood samples from wAIHA (n=19), and (HD) (n=8) enrolled in this study were obtained after giving written informed consent in accordance with the Declaration of Helsinki. Results: We observed by flow cytometry and microscopy that the spleen from wAIHA patients who received less than 3 months of steroid therapy was the site of a B-cell response characterized by the presence of Bcl6+ germinal-center (GC) B-cells. Furthemore, splenic ASC secreted anti-red blood cell IgG in vitro. In line with this observation, we observed in the peripheral blood from patients with a newly diagnosed wAIHA (n=11), that short-lived IgG plasmablasts were increased compared with HD (n=8) (Mean 4.2 ± 0.84 % vs 0.99 ± 0.19% of CD19+ cells, p< 0.01). Moreover, for patients receiving long term steroid therapy (> 6 months) the plasmablast response was suppressed in the peripheral blood (Mean: 0.68 ± 0.2 % of CD19+ cells, n=8) and the splenic GC B-cell reaction was impaired (n=3). We conclude that short-lived IgG ASC result from an over-activity of GC reactions in wAIHA. We then analyzed the spleen of 3 patients who failed to respond to RTX, and observed a residual population of CD19+B-cells (median: 0.9% of lymphoid cells), including non-proliferative memory B-cells and plasma cells (PC). A fraction of these residual PC secreted anti-red blood cells IgG in vitro, thus accounting for the faillure of the B-cell depletion therapy. By using a single cell multiplex quantitative RT-PCR (Fluidigm dynamic arrays), we showed that such RTX-resistant plasma cells display a long-lived transcriptional program, which differs from PC from untreated wAIHA patients or HD, as well as from plasmablasts. Interestingly, the gene expression profile of wAIHA long-lived plasma cells segregated with long-lived PC previously observed in the spleen of ITP patients treated with rituximab. By a principal component analysis, we observed a gradient of maturation from plasmablasts to bone marrow plasma cells in which PC from RTX-treated spleens segregated close to bone marrow PC. We also observed that the cytokine BAFF was increased in the supernatants of spleen cell cultures from wAIHA patients treated with rituximab compared with controls (p< 0.05), suggesting, in keeping with our previous report in ITP, a role for BAFF in the differentiation of short-lived plasma cells into long-lived plasma cells. Conclusion: The presence of splenic long-lived autoreactive PC in wAIHA may explain why some patients cannot achieve a response after RTX. Our results show that, the B-cell depletion induced by rituximab itself, as opposed to the underlying auto-immune condition, promotes a suitable environment for the maturation of auto-immune long-lived plasma cells in the spleen. Targeting specifically some factors such as BAFF right after rituximab injection could be an interesting therapeutic option in the future. Disclosures No relevant conflicts of interest to declare.

scholarly journals B Cell Depletion and Signs of Sepsis Acquired Immunodeficiency in Bone Marrow and Spleen of COVID-19 Deceased

2021 ◽  
Author(s):  
Jana Ihlow ◽  
Edward Michaelis ◽  
Selina Greuel ◽  
Verena Heynol ◽  
Annika Lehmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Acquired Immunodeficiency

scholarly journals Differential Regulation of Mouse B Cell Development by Transforming Growth Factor β1

2002 ◽  
Vol 9 (2) ◽  
pp. 86-95 ◽  
Author(s):  
Denise A. Kaminski ◽  
John J. Letterio ◽  
Peter D. Burrows
Keyword(s):  
B Cells ◽  
Growth Factor ◽  
B Cell ◽  
Transforming Growth Factor ◽  
Plasma Cells ◽  
Population Analysis ◽  
Cell Development ◽  
B Cell Development

Transforming growth factor β (TGFβ) can inhibit thein vitroproliferation, survival and differentiation of B cell progenitors, mature B lymphocytes and plasma cells. Here we demonstrate unexpected, age-dependent reductions in the bone marrow (BM) B cell progenitors and immature B cells in TGFβ1-/-mice. To evaluate TGFβ responsiveness during normal B lineage development, cells were cultured in interleukin 7 (IL7)±TGFβ. Picomolar doses of TGFβ1 reduced pro-B cell recoveries at every timepoint. By contrast, the pre-B cells were initially reduced in number, but subsequently increased compared to IL7 alone, resulting in a 4-fold increase in the growth rate for the pre-B cell population. Analysis of purified BM sub-populations indicated that pro-B cells and the earliest BP1-pre-B cells were sensitive to the inhibitory effects of TGFβ1. However, the large BP1+pre-B cells, although initially reduced, were increased in number at days 5 and 7 of culture. These results indicate that TGFβ1 is important for normal B cell developmentin vivo, and that B cell progenitors are differentially affected by the cytokine according to their stage of differentiation.

scholarly journals Ligand-independent Signaling Functions for the B Lymphocyte Antigen Receptor and Their Role in Positive Selection during B Lymphopoiesis

2001 ◽  
Vol 194 (11) ◽  
pp. 1583-1596 ◽  
Author(s):  
Gregory Bannish ◽  
Ezequiel M. Fuentes-Pananá ◽  
John C. Cambier ◽  
Warren S. Pear ◽  
John G. Monroe
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Antigen Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Lymphopoiesis ◽  
Biologically Relevant ◽  
Developmental Progression

Signal transduction through the B cell antigen receptor (BCR) is determined by a balance of positive and negative regulators. This balance is shifted by aggregation that results from binding to extracellular ligand. Aggregation of the BCR is necessary for eliciting negative selection or activation by BCR-expressing B cells. However, ligand-independent signaling through intermediate and mature forms of the BCR has been postulated to regulate B cell development and peripheral homeostasis. To address the importance of ligand-independent BCR signaling functions and their regulation during B cell development, we have designed a model that allows us to isolate the basal signaling functions of immunoglobulin (Ig)α/Igβ-containing BCR complexes from those that are dependent upon ligand-mediated aggregation. In vivo, we find that basal signaling is sufficient to facilitate pro-B → pre-B cell transition and to generate immature/mature peripheral B cells. The ability to generate basal signals and to drive developmental progression were both dependent on plasma membrane association of Igα/Igβ complexes and intact immunoregulatory tyrosine activation motifs (ITAM), thereby establishing a correlation between these processes. We believe that these studies are the first to directly demonstrate biologically relevant basal signaling through the BCR where the ability to interact with both conventional as well as nonconventional extracellular ligands is eliminated.

scholarly journals In Vivo Tungsten Exposure Alters B-Cell Development and Increases DNA Damage in Murine Bone Marrow

2012 ◽  
Vol 131 (2) ◽  
pp. 434-446 ◽  
Author(s):  
Alexander D. R. Kelly ◽  
Maryse Lemaire ◽  
Yoon Kow Young ◽  
Jules H. Eustache ◽  
Cynthia Guilbert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Murine Bone Marrow

scholarly journals B cell depletion with anti-CD20 mAb exacerbates anti-donor CD4+ T cell responses in highly sensitized transplant recipients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asuka Tanaka ◽  
Kentaro Ide ◽  
Yuka Tanaka ◽  
Masahiro Ohira ◽  
Hiroyuki Tahara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Responses ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Transplant Recipients ◽  
Cell Responses ◽  
Anti Cd20

AbstractPretransplant desensitization with rituximab has been applied to preformed donor-specific anti-human leukocyte antigen antibody (DSA)-positive recipients for elimination of preformed DSA. We investigated the impact of pretransplant desensitization with rituximab on anti-donor T cell responses in DSA-positive transplant recipients. To monitor the patients’ immune status, mixed lymphocyte reaction (MLR) assays were performed before and after desensitization with rituximab. Two weeks after rituximab administration, the stimulation index (SI) of anti-donor CD4+ T cells was significantly higher in the DSA-positive recipients than in the DSA-negative recipients. To investigate the mechanisms of anti-donor hyper responses of CD4+ T cells after B cell depletion, highly sensitized mice models were injected with anti-CD20 mAb to eliminate B cells. Consistent with clinical observations, the SI values of anti-donor CD4+ T cells were significantly increased after anti-CD20 mAb injection in the sensitized mice models. Adding B cells isolated from untreated sensitized mice to MLR significantly inhibited the enhancement of anti-donor CD4+ T cell response. The depletion of the CD5+ B cell subset, which exclusively included IL-10-positive cells, from the additive B cells abrogated such inhibitory effects. These findings demonstrate that IL-10+ CD5+ B cells suppress the excessive response of anti-donor CD4+ T cells responses in sensitized recipients.

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