Publications

Abstract

Objective. TNF-ligand family members BAFF and APRIL can exert powerful effects upon B cell activation and development, Th1-type immune responses and autoimmunity. We examined the effect of blocking BAFF and APRIL upon the development of autoimmune diabetes. Research Design and Methods. Female NOD mice were administered BCMA-Fc from 9-15-weeks-of-age. Diabetes incidence, islet pathology, as well as T and B cell populations were examined. Results. BCMA-Fc treatment reduced the severity of insulitis and prevented diabetes development in NOD mice. BCMA-Fc-treated mice showed reduced follicular, marginal-zone and T2MZ B cells. B cell reduction was accompanied by decreased frequencies of pathogenic CD4+ CD40+ T cells and reduced Th1-type cytokines IL-7, IL-15 and IL-17. Thus T cell activation was blunted with reduced B cells. However, BCMA-Fc treated mice still harboured detectable diabetogenic T cells; suggesting regulatory mechanisms contributed to diabetes prevention. Indeed, BCMA-Fc treated mice accumulated increased CD4+ CD25+ Tregs with age. CD4+ CD25+ cells were essential for maintaining euglycaemia as their depletion abrogated BCMA-Fc-mediated protection. BCMA-Fc did not directly effect Treg homeostasis as; CD4+ CD25+ Foxp3+ T cells did not express TACI or BR3 receptors; and, CD4+ CD25+ Foxp3+ T cell frequencies were equivalent in WT, BAFF(-/-), TACI(-/-), BCMA(-/-) and BR3(-/-) mice. Rather, B cell depletion resulted in CD4+ CD25+ T cell-mediated protection from diabetes; as anti-CD25 mAb treatment precipitated diabetes in both diabetes resistant NOD.muMT(-/-) and BCMA-Fc-treated mice. Conclusions. BAFF/APRIL blockade prevents diabetes. BCMA-Fc reduces B cells, subsequently blunting autoimmune activity and allowing endogenous regulatory mechanisms to preserve a pre-hyperglycaemic state.