Authors:
Eliana Mariño, Jeanette Villanueva, Stacey Walters, David Liuwantara, Fabienne Mackay and Shane T. Grey
Summary:
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.μMT−/− 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.
Source:
Diabetes; (03/31/09)