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In Vivo BLyS/BAFF Neutralization Ameliorates Islet-Directed Autoimmunity in Nonobese Diabetic Mice¹

Ghazal Zekavat^*, Susan Y. Rostami^*, Armen Badkerhanian^*, Ronald F. Parsons^*, Brigitte Koeberlein^*, Ming Yu^*, Christopher D. Ward, Thi-Sau Migone, Liping Yu, George S. Eisenbarth, Michael P. Cancro, Ali Naji^* and Hooman Noorchashm^2,*

^* Department of Surgery and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Human Genome Sciences, Inc., Rockville, MD 20850; and Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80010

B lymphocytes are required for the pathogenesis of autoimmune diabetes in NOD mice. Previous studies established that a lymphopenic transitional (TR) B cell compartment reduces the competitive constraint on the entry of newly emerging TR B cells into the splenic follicle (FO), thereby disrupting a peripheral negative selection checkpoint in NOD mice. Thus, development of clinically feasible immunotherapeutic approaches for restoration of appropriate negative selection is essential for the prevention of anti-islet autoimmunity. In this study we hypothesized that in vivo neutralization of the B lymphocyte stimulator (BLyS/BAFF) may enhance the stringency of TRFO selection by increasing TR B cell competition for follicular entry in NOD mice. This study demonstrated that in vivo BLyS neutralization therapy leads to the depletion of follicular and marginal zone B lymphocytes. Long-term in vivo BLyS neutralization caused an increased TR:FO B cell ratio in the periphery indicating a relative resistance to follicular entry. Moreover, in vivo BLyS neutralization: 1) restored negative selection at the TRFO checkpoint, 2) abrogated serum insulin autoantibodies, 3) reduced the severity of islet inflammation, 4) significantly reduced the incidence of spontaneous diabetes, 5) arrested the terminal stages of islet cell destruction, and 6) disrupted CD4 T cell activation in NOD mice. Overall, this study demonstrates the efficacy of B lymphocyte-directed therapy via in vivo BLyS neutralization for the prevention of autoimmune diabetes.

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 study was supported in part by the Iacocca Foundation and by National Institutes of Health Grants KO8-DK064603 and R03-DK080286 (to H.N.) and Juvenile Diabetes Research Foundation Grant 4-2005-351 to (A.N.).

² Address correspondence and reprint requests to Dr. Hooman Noorchashm, University of Pennsylvania School of Medicine, 36th Street and Hamilton Walk, Philadelphia, PA 19104-6082. E-mail address: hooman.noorchashm{at}uphs.upenn.edu

³ Abbreviations used in this paper: T1D, type 1 diabetes; BLyS, B lymphocyte stimulator; BM, bone marrow; FO, follicular; IAA, insulin autoantibody; MZ, marginal zone; TR, transitional; Treg, T regulatory cell.

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