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Intravenous Transfusion of BCR-Activated B Cells Protects NOD Mice from Type 1 Diabetes in an IL-10-Dependent Manner¹

Shabbir Hussain^* and Terry L. Delovitch^2,*,

^* Laboratory of Autoimmune Diabetes, Robarts Research Institute, and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5K8, Canada

Although B cells play a pathogenic role in the initiation of type 1 diabetes (T1D) in NOD mice, it is not known whether activated B cells can maintain tolerance and transfer protection from T1D. In this study, we demonstrate that i.v. transfusion of BCR-stimulated NOD spleen B cells into NOD mice starting at 5–6 wk of age both delays onset and reduces the incidence of T1D, whereas treatment initiated at 9 wk of age only delays onset of T1D. This BCR-activated B cell-induced protection from T1D requires IL-10 production by B cells, as transfusion of activated B cells from NOD.IL-10^–/– mice does not confer protection from T1D. Consistent with this result, severe insulitis was observed in the islets of NOD recipients of transfused NOD.IL-10^–/– BCR-stimulated B cells but not in the islets of NOD recipients of transfused BCR-stimulated NOD B cells. The therapeutic effect of transfused activated NOD B cells correlates closely with the observed decreased islet inflammation, reduced IFN- production and increased production of IL-4 and IL-10 by splenocytes and CD4⁺ T cells from NOD recipients of BCR-stimulated NOD B cells relative to splenocytes and CD4⁺ T cells from PBS-treated control NOD mice. Our data demonstrate that transfused BCR-stimulated B cells can maintain long-term tolerance and protect NOD mice from T1D by an IL-10-dependent mechanism, and raise the possibility that i.v. transfusion of autologous IL-10-producing BCR-activated B cells may be used therapeutically to protect human subjects at risk for T1D.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant MOP64386 from the Canadian Institute of Health Research, and a grant from the Ontario Research and Development Challenge Fund. S.H. was the recipient of a postdoctoral fellowship from the Canadian Diabetes Association in honor of the late Flora I. Nichol. T.L.D. was the Sheldon H. Weinstein Scientist in Diabetes at the Robarts Research Institute and University of Western Ontario during the course of these studies.

² Address correspondence and reprint requests to Dr. Terry L. Delovitch, Laboratory of Autoimmune Diabetes, Robarts Research Institute, 100 Perth Drive, London, Ontario N6A 5K8, Canada. E-mail address: del{at}robarts.ca

³ Abbreviations used in this paper: T1D, type 1 diabetes; DC, dendritic cell; BGL, blood glucose level; Treg, regulatory T cell; Tr1, T regulatory type 1; EAE, experimental autoimmune encephalomyelitis; FasL, Fas ligand.