The Journal of Immunology, 2007, 178: 131.26.
Copyright © 2007 by The American Association of Immunologists, Inc.
Anti-CD20 Therapy in NOD Model of Type 1 Diabetes
Changyun Hu1,
Daniel Rodriguez1,
Wei Du1,
Anupama. Ahuja2,
F.Susan Wong3,
Mark Shlomchik2 and
Li Wen1
1 Internal Medicine,
2 Immunobiology, Yale University School of Medicine, Mail Box 208020, TAC S130, 330, Cedar Street, New Haven, CT, 06510,
3 Cellular and Molecular Medicine, Bristol University, University Walk, Bristol, BS8 1TD, United Kingdom
Abstract
B cells play an important role in the pathogenesis of T1D although T1D is primarily a T cell mediated autoimmune disease. Apart from producing antibodies, B cells are important APCs and a rich source for production of various cytokines. Nonetheless, the precise roles of B cells in promoting diabetes onset and progression have not been defined. Rituximab targets human CD20 causing rapid and specific B cell depletion. A clinical trial is currently launched in treating T1D patients with Rituximab. However, there has not been a single preclinical study to test this particular therapy in T1D. To evaluate the efficacy of anti-CD20 in treating T1D, we have generated a transgenic NOD mouse expressing human CD20 on their B cells. This allows the use of anti-hCD20 antibody (2H7), which is closely related to Rituximab. Our preliminary data showed that a single cycle of anti-hCD20 treatment (4 injections within 10 days) to temporarily deplete B cells significantly delays and/or reduces the onset of diabetes in hCD20 transgenic NOD mice. This was seen at both the disease initiation and pre-diabetic stages. The same treatment also rendered 36% (5/14) of diabetic mice euglycemic, either transiently or for a long period. Anti-hCD20 treatment appears to induce and/or expand regulatory T cells and enhance TGF-
production. Our results provide extremely valuable in vivo information for the human studies using a similar approach.
