The Impact of B Lymphocyte Depletion on the Pathogenesis of Autoimmune Diabetes (131.28)

Abstract

NOD B cell development is characterized by a defective homeostatic checkpoint in B cell maturation and selection. Having demonstrated that the progression of autoimmune diabetes requires antigen presentation by B-lymphocytes, we hypothesized that B cell depletion may prevent diabetes progression in NOD mice. Here, we employed two distinct approaches for in vivo B lymphocyte depletion: a cohort of adult hCD20 Tg NOD mice were treated with the B lymphocyte depleting mAb, Rituximab (anti-CD20) anda cohort of adult NOD mice were treated with a neutralizing Hamster anti-mouse mAb specific for the B cell survival factor, BLyS/BAFF. Treatment with both Rituximab (2mg/injection x3doses) and anti-BLyS mAb (100?g/injection x2 doses) led to B cell depletion within 10 days. BLyS/BAFF neutralization, using anti-BLyS, caused a profound depletion of mature/recirculating B cells in these mice and lasted for >30 days. Diabetes occurred within 2 weeks in all Rituximab treated female hCD20 Tg NOD mice (n=4); despite their early backcross generations (i.e., N4-6F1) onto the NOD genetic background. Conversely, adult female NOD/LtJ mice (n=20), B cell depleted using anti-BLyS/BAFF did not progress to diabetes for >30 days following treatment. Collectively, these results indicate that BLyS/BAFF neutralization may be required for the prevention of autoimmune diabetes following B lymphocyte depletion.