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B Lymphocyte Depletion by CD20 Monoclonal Antibody Prevents Diabetes in Nonobese Diabetic Mice despite Isotype-Specific Differences in FcR Effector Functions¹

Yan Xiu^2,*, Carmen P. Wong^2,, Jean-David Bouaziz^*, Yasuhito Hamaguchi^*, Yaming Wang, Shannon M. Pop, Roland M. Tisch^3, and Thomas F. Tedder^3,4,*

^* Department of Immunology, Duke University Medical Center, Durham, NC 27710; and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599

NOD mice deficient for B lymphocytes from birth fail to develop autoimmune or type 1 diabetes. To assess whether B cell depletion influences type 1 diabetes in mice with an intact immune system, NOD female mice representing early and late preclinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term CD20 mAb treatment in 5-wk-old NOD female mice reduced B cell numbers by 95%, decreased subsequent insulitis, and prevented diabetes in >60% of littermates. In addition, CD20 mAb treatment of 15-wk-old NOD female mice significantly delayed, but did not prevent, diabetes onset. Protection from diabetes did not result from altered T cell numbers or subset distributions, or regulatory/suppressor T cell generation. Rather, impaired CD4⁺ and CD8⁺ T cell activation in the lymph nodes of B cell-depleted NOD mice may delay diabetes onset. B cell depletion was achieved despite reduced sensitivity of NOD mice to CD20 mAbs compared with C57BL/6 mice. Decreased B cell depletion resulted from deficient FcRI binding of IgG2a/c CD20 mAbs and 60% reduced spleen monocyte numbers, which in combination reduced Ab-dependent cellular cytotoxicity. With high-dose CD20 mAb treatment (250 µg) in NOD mice, FcRIII and FcRIV compensated for inadequate FcRI function and mediated B cell depletion. Thereby, NOD mice provide a model for human FcR polymorphisms that reduce therapeutic mAb efficacy in vivo. Moreover, this study defines a new, clinically relevant approach whereby B cell depletion early in the course of disease development may prevent diabetes or delay progression of disease.

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 National Institutes of Health Grants CA105001, CA96547, and AI56363 (T.F.T.), and AI058014 (R.M.T.). C.P.W. was supported by a Fellowship from the Juvenile Diabetes Research Foundation.

² Y.X. and C.P.W. contributed equally to these studies and share first authorship.

³ R.M.T. and T.F.T. contributed equally to these studies and share senior authorship.

⁴ Address correspondence and reprint requests to Dr. Thomas F. Tedder, Department of Immunology, Duke University Medical Center, Box 3010, Room 353 Jones Building, Research Drive, Durham, NC 27710. E-mail address: thomas.tedder{at}duke.edu

⁵ Abbreviations used in this paper: T1D, type 1 diabetes; ADCC, Ab-dependent cellular cytotoxicity; [Ca²⁺]_i, intracellular calcium level.

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