B cells display an abnormal distribution and an impaired suppressive function in patients with chronic antibody–mediated rejection

Nouël, Alexandre; Ségalen, I.; Jamin, Christophe; Doucet, Laurent; Caillard, Sophie; Renaudineau, Yves; Pers, Jacques‐Olivier; Meur, Yann Le; Hillion, Sophie

doi:10.1038/ki.2013.457

Cited by 62 publications

(46 citation statements)

References 26 publications

(31 reference statements)

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“…B cells with regulatory properties are of increasing interest in kidney transplantation, in particular clinical outcomes and phenotypes associated with transitional B cells characterized by surface CD19þCD24hiCD38hi expression (5)(6)(7)(8)(9)(10). This study shows that increased frequencies of these transitional B cells are associated with protection from episodes of BPAR in unselected low/medium immune risk transplant recipients followed longitudinally from the time of transplantation.…”

Section: Discussionmentioning

confidence: 75%

“…In kidney transplantation, the importance of CD19þCD24hiCD38hi cells is highlighted by patients who are ''tolerant'' to their graft, who display increased frequencies of these cells (5)(6)(7)(8), although proof as to their direct role in this phenomenon is lacking. Following these landmark studies, 2 subsequent casecontrol, cross-sectional investigations (9,10) revealed associations between reduced CD19þCD24hiCD38hi frequencies and transplant rejection, albeit mainly in the context of antibody-mediated rejection (ABMR) many years following transplantation.…”

Section: Introductionmentioning

confidence: 99%

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Transitional B Lymphocytes Are Associated With Protection From Kidney Allograft Rejection: A Prospective Study

Shabir

Girdlestone

Briggs

et al. 2015

American Journal of Transplantation

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Recent cross‐sectional studies suggest an important role for transitional B lymphocytes (CD19 + CD24hiCD38hi) in promoting transplant tolerance, and protecting from late antibody‐mediated rejection (ABMR). However, prospective studies are lacking. This study enrolled 73 de novo transplant recipients, and collected serial clinical, immunological and biochemical information over 48 ± 6 months. Cell phenotyping was conducted immediately prior to transplantation, and then on five occasions during the first year posttransplantation. When modeled as a time‐dependent covariate, transitional B cell frequencies (but not total B cells or “regulatory” T cells) were associated with protection from acute rejection (any Banff grade; HR: 0.60; 95% CI: 0.37–0.95; p = 0.03). No association between transitional B cell proportions and either de novo donor‐specific or nondonor‐specific antibody (dnDSA; dnNDSA) formation was evident, although preserved transitional B cell proportions were associated with reduced rejection rates in those patients developing dnDSA. Three episodes of ABMR occurred, all in the context of nonadherence, and all associated with in vitro anti‐HLA T cell responses in an ELISPOT assay (p = 0.008 versus antibody‐positive patients not experiencing ABMR). This prospective study supports the potential relevance of transitional (“regulatory”) B cells as a biomarker and therapeutic intervention in transplantation, and highlights relationships between humoral immunity, cellular immunity and nonadherence.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Transitional B Lymphocytes Are Associated With Protection From Kidney Allograft Rejection: A Prospective Study

Shabir

Girdlestone

Briggs

et al. 2015

American Journal of Transplantation

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“…Therefore, the conclusions made are based on indirect evidence of regulation, on depleting specific lymphocyte subsets, rather than a direct demonstration of suppressive activity from purified, and then in vitro assessed cell subpopulations. We presented our flow cytometric analysis of these samples in our earlier article last year, and found no associations between the proportions of B-cell subsets, including transitional or naïve cells and ELISPOT patterns or outcome, 7 although we acknowledge that others working in this field have shown associations between rejection and particular B-cell subsets, including transitional B cells 32, 37, 38. In addition, the associations reported in this article need to be validated in different cohorts of patients, ideally with work to assess the reproducibility of the assays within patients and to more carefully document how patterns change over time.…”

Section: Discussionmentioning

confidence: 93%

Graft dysfunction in chronic antibody-mediated rejection correlates with B-cell–dependent indirect antidonor alloresponses and autocrine regulation of interferon-γ production by Th1 cells

Shiu

McLaughlin

Rebollo‐Mesa

et al. 2017

Kidney International

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Chronic antibody-mediated rejection, a common cause of renal transplant failure, has a variable clinical phenotype. Understanding why some with chronic antibody-mediated rejection progress slowly may help develop more effective therapies. B lymphocytes act as antigen-presenting cells for in vitro indirect antidonor interferon-γ production in chronic antibody-mediated rejection, but many patients retain the ability to regulate these responses. Here we test whether particular patterns of T and B cell antidonor response associate with the variability of graft dysfunction in chronic antibody-mediated rejection. Our results confirm that dynamic changes in indirect antidonor CD4+ T-cell responses correlate with changes in estimated glomerular filtration rates, independent of other factors. Graft dysfunction progressed rapidly in patients who developed unregulated B-cell–driven interferon-γ production. However, conversion to a regulated or nonreactive pattern, which could be achieved by optimization of immunosuppression, associated with stabilization of graft function. Functional regulation by B cells appeared to activate an interleukin-10 autocrine pathway in CD4+ T cells that, in turn, impacted on antigen-specific responses. Thus, our data significantly enhance the understanding of graft dysfunction associated with chronic antibody-mediated rejection and provide the foundation for strategies to prolong renal allograft survival, based on regulation of interferon-γ production.

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“…48 The same observations have been reported in other models. 49 Interestingly, it has been reported that B cells from patients with chronic antibodymediated rejection have a defect in suppressive properties, 50 in contrast with B cells from STAs, which inhibit T cell proliferation and induce Treg generation through a TGF-b-and IDOdependent pathway (personal communication, Nouël et al Ann Rheum Dis abstract A8.32, 2014). In our situation, blocking TGF-b has no effect on the suppressive function of B cells, suggesting that TGF-b is not involved in B cell regulation either.…”

Section: Discussionmentioning

confidence: 99%

Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties

Chesneau¹,

Michel²,

Dugast³

et al. 2015

Journal of the American Society of Nephrology

137

125

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Whereas a B cell-transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells have in this tolerance has not been reported. In this study, we analyzed the role of B cells from operationally tolerant patients, healthy volunteers, and kidney transplant recipients with stable graft function on T cell suppression. Proliferation, apoptosis, and type I proinflammatory cytokine production by effector CD4 + CD25 2 T cells were measured after anti-CD3/anti-CD28 stimulation with or without autologous B cells. We report that B cells inhibit CD4 + CD25 2 effector T cell response in a dosedependent manner. This effect required B cells to interact with T-cell targets and was achieved through a granzyme B (GzmB)-dependent pathway. Tolerant recipients harbored a higher number of B cells expressing GzmB and displaying a plasma cell phenotype. Finally, GzmB + B-cell number was dependent on IL-21 production, and B cells from tolerant recipients but not from other patients positively regulated both the number of IL-21 + T cells and IL-21 production, suggesting a feedback loop in tolerant recipients that increases excessive B cell activation and allows regulation to take place. These data provide insights into the characterization of B cell-mediated immunoregulation in clinical tolerance and show a potential regulatory effect of B cells on effector T cells in blood from patients with operationally tolerant kidney grafts.

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B cells display an abnormal distribution and an impaired suppressive function in patients with chronic antibody–mediated rejection

Cited by 62 publications

References 26 publications

Transitional B Lymphocytes Are Associated With Protection From Kidney Allograft Rejection: A Prospective Study

Transitional B Lymphocytes Are Associated With Protection From Kidney Allograft Rejection: A Prospective Study

Graft dysfunction in chronic antibody-mediated rejection correlates with B-cell–dependent indirect antidonor alloresponses and autocrine regulation of interferon-γ production by Th1 cells

Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties

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