Saturday, March 2, 2013

anti-CD20 and anti-CD3 by Hu and Wen at Yale

Combination treatment with anti-CD20 and oral anti-CD3 prevents and reverses autoimmune diabetes

Abstract: Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease, although B cells also play an important role in T1D development. Both T cell- and B cell-directed immunotherapies have shown efficacy in the prevention and reversal of T1D. However, whether the combined strategy of targeting both T and B cells could further improve the therapeutic efficacy remains to be explored. Herein we show that the combined treatment with intravenous anti-human CD20 (hCD20) and oral anti-CD3 significantly delayed diabetes development in pre-diabetic hCD20 transgenic NOD mice. More importantly, the combined treatment reversed diabetes in more than 60% of mice newly diagnosed with diabetes. Further mechanistic studies demonstrated that the addition of oral anti-CD3 to the B cell depletion therapy synergistically enhanced the suppressive function of Treg. Interestingly, the oral anti-CD3 treatment induced a fraction of IL-10-producing CD4 T cells in the small intestine through IL-10 and IL-27-producing dendritic cells. Thus, our findings demonstrated that combining anti-CD20 and oral anti-CD3 is superior to anti-CD20 monotherapy for restoring normoglycemia in diabetic NOD mice, providing important preclinical evidence for the optimization of B cell-directed therapy for type 1 diabetes.