In transplantation, increasing evidence support that B cells can play a major regulatory role in addition to their critical functions in allo-immunity and graft rejection. We have described a regulatory B cells-dependent model of tolerance in fully a MHC-mismatched islet allograft setting in mice using a short course of combined anti-TIM-1 and anti-CD45RB antibody treatment. In this model, tolerance is both regulatory B cell-dependent and regulatory T cell-dependent. We found that adoptively transferred Bregs require the presence of Tregs to establish tolerance, and that adoptive transfer of Bregs increases the number of Tregs. Bregs are antigen-specific, IL-10-dependent, and are capable of transferring tolerance to untreated, transplanted animals. Interaction with Bregs in vivo induces significantly more Foxp3 expression in CD4+CD25- T cells than with naive B cells.

We have interesting preliminary results indicating that regulatory B cells through their production of TGF-β, induce regulatory T cells.Breg-mediated graft prolongation post-adoptive transfer is abrogated by neutralization of TGF-β activity. Also, Graft survival induced by dual antibodies is abrogated by co-injection of anti-TGF-β neutralizing antibody. Although informative, this result does not localize the critical source of TGF- β to Bregs. To definitively assess whether Breg production of TGF- β is essential to Breg tolerance, we generated a novel B cell-specific TGF-β mutant mice by mating CD19-cre mice with floxed-TGF-β mice. In contrast to WT recipients, B cell-specific TGF-β-mutant recipients rapidly reject allogeneic islet grafts. These B cells from TGFβ−mutant animals to do not express significant Levels of IL-10 after in-vitro stimulation.

CITATION INFORMATION: Deirawan H, Kojima L, Washburn L, Markmann J, Kim J. TGFb in Regulatory B Cells-Dependent Tolerance. Am J Transplant. 2016;16 (suppl 3).

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