scholarly journals SAT0029 B cell depletion affects CD8 T cells in anca-associated vasculitis

2017 ◽  
Author(s):  
A Néel ◽  
M Bucchia ◽  
M Néel ◽  
M Rimbert ◽  
C Agard ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Anca Associated Vasculitis

scholarly journals CD20 B Cell Depleting Therapy Is Associated with up-Regulation of CD8+CD25highFoxp3+ T Regulatory Cells in a Murine Model of Immune Thrombocytopenia (ITP)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2785-2785
Author(s):  
Li Guo ◽  
Rukhsana Aslam ◽  
Yajing Zhao ◽  
Edwin R. Speck ◽  
Heyu Ni ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Scid Mice ◽  
Cell Depletion ◽  
B Cell Depletion

Abstract Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and/or impaired megakaryocyte production, mediated by autoreactive B cells and T cells. B cell depletion therapy by rituximab, a monoclonal human anti-CD20 antibody, has been shown effective in both anti-platelet antibody positive (B cell mediated) and negative (T cell mediated) ITP patients. Those patients responsive to rituximab therapy showed normalized CD4+ and CD8+ T cell responses (Stasi et al. Blood. 2007), however, the mechanism of T cell regulation by B cell depletion is not clear. One possibility is through normalization of CD4+ T helper cells or up-regulation of CD4+ regulatory T cells (Tregs) (Stasi et al. Blood. 2008). Another possibility is by suppression of activated conventional CD8+ T cells or the up-regulation of CD8+ Tregs. We examined the changes of both CD4+ and CD8+ T cells and Tregs (CD25highFoxp3+) after B cell depletion in vivo in our ITP mouse model. Briefly, BALB/c GPIIIa (CD61) KO mice were either given PBS (ND) or mouse monoclonal anti-CD20 antibody (B-dep, Biogen) at day -1 and day 13 (250ug/mouse, ip). Residual CD19+ B cells in peripheral blood were less than 0.1% within 24hours in the latter group. All mice were immunized by transfusions of wildtype (WT) platelets at day 0, 7, 14, and 21 (1×108/mouse, iv). At day 28, we examined the percentages of T cell subsets in the spleens of the immunized mice. B cell-depleted immune CD61 KO mice showed significantly higher percentages of both CD3+CD8+ T cells and CD8+CD25highFoxp3+ T cells (Table 1). There was no significant difference in the CD3+CD4+ and CD4+CD25highFoxp3+ T cell populations. Both ND and B-dep immune CD61 KO splenocytes showed increased cytotoxicity activity against CD61+ PU5-1.8 target cells in vitro compared with naïve CD61 KO splenocytes, indicating the activation of CD8+ T cells. To test their in vivo effect on ITP development, splenocytes were engrafted from immune mice into irradiated and AsialoGM-1 treated severe combined immunodeficient (SCID) mice at a dose of 2.5×104/mouse and the mice were monitored for weekly platelet counts. ND and in vitro B cell depleted splenocytes from immune KO mice induced persistent ITP during 3 weeks observation whereas splenocytes from B-dep immune mice did not. To further confirm the role of B cell depletion on CD8+ T cell responses, CD8+ T cells from either ND or B-dep immune CD61 KO splenocytes were purified and transferred into SCID mice at 3×104/mouse. CD4+ T cells from ND immune CD61 KO splenocytes were added at 3×104/mouse to all the SCID mice to support the CD8+ T cell survival in vivo. SCID mice received CD8+ T cells from B-dep group showed higher platelet count at Day 14. Overall, our results indicate a protective role of CD8+CD25highFoxp3+ T cells against the development of cell mediated ITP that is enhanced by B cell depleting therapy in vivo. Table 1. CD61 KO MouseSpleens CD3+CD8+(%) CD8+CD25highFoxp3+ (%) Naïve Control 9.12±0.37 0.12±0.08 Immune, ND 6.78±2.37 0.0925±0.03 Immune, B-dep 14.15±5.1 0.2367±0.11 P value (ND vs B-dep) 0.0007 0.0064 Disclosures No relevant conflicts of interest to declare.

OR.63. B Cell Depletion in Multiple Sclerosis Results in Diminished Th1 and ThIL-17 Responses by CD4 and CD8 T Cells

2008 ◽  
Vol 127 ◽  
pp. S26
Author(s):  
Lama Fawaz ◽  
Boli Fan ◽  
Aja Rieger ◽  
Ichiro Nakashima ◽  
Farzaneh Jalili ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cell Depletion ◽  
B Cell Depletion

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.

scholarly journals Short-Term Immunopathological Changes Associated with Pulse Steroids/IVIG/Rituximab Therapy in Late Kidney Allograft Antibody Mediated Rejection

Kidney360 ◽  
2020 ◽  
Vol 1 (5) ◽  
pp. 389-398
Author(s):  
Kenna R. Degner ◽  
Nancy A. Wilson ◽  
Shannon R. Reese ◽  
Sandesh Parajuli ◽  
Fahad Aziz ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Hla Class I ◽  
B Cell Depletion ◽  
Short Term ◽  
Antibody Mediated Rejection ◽  
Pulse Steroids

BackgroundB cell depletion is a common treatment of antibody-mediated rejection (ABMR). We sought to determine the specific immunopathologic effects of this therapeutic approach in kidney transplantation.MethodsThis was a prospective observational study of recipients of kidney transplants diagnosed with late ABMR (>3 months after transplant). Patients received treatment with pulse steroids, IVIG, and rituximab. Donor-specific HLA antibodies (DSA), kidney allograft pathology, renal function, immune cell phenotypes, and 47 circulating cytokines were assessed at baseline and at 3 months.ResultsWe enrolled 23 patients in this study between April 2015 and March 2019. The majority of patients were male (74%) and white (78%) with an average age of 45.6±13.8 years. ABMR was diagnosed at 6.8±5.9 years (4 months to 25 years) post-transplant. Treatment was associated with a significant decline in circulating HLA class I (P=0.003) and class II DSA (P=0.002) and peritubular capillaritis (ptc; P=0.04) compared to baseline. Serum creatinine, BUN, eGFR, and proteinuria (UPC) remained stable. Circulating B cells were depleted to barely detectable levels (P≤0.001), whereas BAFF (P=0.0001), APRIL (P<0.001), and IL-10 (P=0.02) levels increased significantly post-treatment. Notably, there was a significant rise in circulating CD4+ (P=0.02) and CD8+ T cells (P=0.003). We also noted a significant correlation between circulating cytotoxic CD8+ T cells and BAFF (P=0.05), regulatory T cells and IL-10 (P=0.002), and regulatory T cells and HLA class I DSA (P=0.005).ConclusionsShort-term pulse steroids/IVIG/rituximab therapy was associated with inhibition of ABMR (DSA and ptc), stabilization of kidney function, and increased regulatory B cell and T cell survival cytokines. Additional studies are needed to understand the implications of B cell depletion on the crosstalk between T cells and B cells, and humoral components that regulate ABMR.

scholarly journals In vivo generation of human CD 19‐ CAR T cells results in B‐cell depletion and signs of cytokine release syndrome

2018 ◽  
Vol 10 (11) ◽  
Author(s):  
Anett Pfeiffer ◽  
Frederic B Thalheimer ◽  
Sylvia Hartmann ◽  
Annika M Frank ◽  
Ruben R Bender ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

scholarly journals Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus

2019 ◽  
Vol 11 (482) ◽  
pp. eaav1648 ◽  
Author(s):  
Rita Kansal ◽  
Noah Richardson ◽  
Indira Neeli ◽  
Saleem Khawaja ◽  
Damian Chamberlain ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Murine Lupus ◽  
Car T Cells ◽  
Car T

The failure of anti-CD20 antibody (Rituximab) as therapy for lupus may be attributed to the transient and incomplete B cell depletion achieved in clinical trials. Here, using an alternative approach, we report that complete and sustained CD19+ B cell depletion is a highly effective therapy in lupus models. CD8+ T cells expressing CD19-targeted chimeric antigen receptors (CARs) persistently depleted CD19+ B cells, eliminated autoantibody production, reversed disease manifestations in target organs, and extended life spans well beyond normal in the (NZB × NZW) F1 and MRLfas/fas mouse models of lupus. CAR T cells were active for 1 year in vivo and were enriched in the CD44+CD62L+ T cell subset. Adoptively transferred splenic T cells from CAR T cell–treated mice depleted CD19+ B cells and reduced disease in naive autoimmune mice, indicating that disease control was cell-mediated. Sustained B cell depletion with CD19-targeted CAR T cell immunotherapy is a stable and effective strategy to treat murine lupus, and its effectiveness should be explored in clinical trials for lupus.

Potent B-Cell Depletion by IMGN529, a CD37-Targeting Antibody-Maytansinoid Conjugate for the Treatment of B-Cell Malignancies,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3726-3726
Author(s):  
Jutta Deckert ◽  
Sharon Chicklas ◽  
Yong Yi ◽  
Min Li ◽  
Jan Pinkas ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Whole Blood ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
B Cell Malignancies

Abstract Abstract 3726 CD37 is a B-cell surface antigen which is widely expressed on malignant B cells in non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). In normal tissues CD37 expression is limited to blood cells and lymphoid tissues. This restricted expression profile makes CD37 an attractive therapeutic target for antibodies and antibody-drug conjugates. We developed a novel anti-CD37 antibody, K7153A, which provides a unique combination of functional properties: it demonstrated strong pro-apoptotic and direct cell killing activity against NHL cell lines and could mediate effector activity such as CDC and ADCC. The antibody-maytansinoid conjugate, IMGN529, was produced by conjugation of K7153A with the potent maytansinoid, DM1, via the non-cleavable linker, SMCC. The direct cytotoxic potency of the K7153A antibody was superior to that of the CD20-directed rituximab and was further enhanced with maytansinoid conjugation in IMGN529. In vivo, IMGN529 demonstrated better anti-tumor activity than the K7153A antibody in established subcutaneous follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and CLL xenograft models in SCID mice. A single administration of IMGN529 showed similar or improved efficacy compared to anti-CD20 antibodies or standard chemotherapy where tested. Immunohistochemical (IHC) staining of formalin fixed paraffin-embedded (FFPE) NHL tissue sections was performed to evaluate CD37 expression. CD37 exhibited a similar prevalence to CD20 in subtypes of NHL such as FL, DLBCL, Burkitt's lymphoma (BL) and mantle cell lymphoma (MCL). B-cell depletion is an important measure of efficacy for targeted therapies, such as CD20-directed antibodies, in B-cell malignancies. CD37 expression in blood cells from healthy human donors was measured by quantitative flow cytometry in comparison to CD20. The greatest CD37 expression was found in B cells at approximately 77,000 antibodies bound per cell (ABC), which was similar to CD20 expression in B cells at 95,000 ABC. In other blood cell types CD37 staining was seen at low levels, about 2,000 – 5,000 ABC, in monocytes, NK cells and T cells. In vitro depletion experiments were performed with purified peripheral blood mononuclear cells (PBMCs) and with whole blood, both derived from several healthy donors. Cells were incubated for 1 hr with 10 μg/mL of either K7153A, IMGN529, CD37-targeting TRU-016, rituximab or the anti-CD52 antibody alemtuzumab, with cell depletion determined relative to counting beads by flow cytometry. The K7153A antibody and the IMGN529 conjugate efficiently and specifically depleted B-cells in a dose-dependent manner in the context of purified PBMCs and whole blood. With purified PBMCs, both K7153A and IMGN529 caused 50–60% depletion of B cells, with little to no depletion of T cells or monocytes. IMGN529 was more potent than rituximab, which led to 30–40% B-cell depletion, or TRU-016, which caused 20–30% B-cell depletion. IMGN529 also was more specific than alemtuzumab, which depleted T-cells and monocytes as well as B cells. With whole blood samples, both K7153A and IMGN529 resulted in 30–40% B-cell depletion with no effect on T cells, NK cells or monocytes. IMGN529 was again more potent than rituximab or TRU-016, which caused approximately 10% B-cell depletion, and was more specific than alemtuzumab, which depleted the majority of T cells in addition to 40% of B cells. IMGN529 embodies a unique B-cell targeted agent as it combines the intrinsic pro-apoptotic, CDC and ADCC activities of its anti-CD37 antibody component with the potent cytotoxic mechanism provided by the targeted delivery of its maytansinoid payload. It is highly active in vitro and in vivo against B-cell lymphoma and CLL cell lines. In addition, it mediates specific B-cell depletion in vitro that is greater than B-cell depletion by CD20-directed rituximab. Together, these findings indicate that IMGN529 is a promising therapeutic candidate for the treatment of B-cell malignancies. Disclosures: Deckert: ImmunoGen, Inc.: Employment. Chicklas:ImmunoGen, Inc.: Employment. Yi:ImmunoGen, Inc.: Employment. Li:ImmunoGen, Inc.: Employment. Pinkas:ImmunoGen, Inc.: Employment. Chittenden:ImmunoGen, Inc.: Employment. Lutz:ImmunoGen, Inc.: Employment. Park:ImmunoGen, Inc.: Employment.

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