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* Department of Laboratory Medicine, Yale University, New Haven, CT 06510;
Biogen Idec, San Diego, CA 92122; and
Department of Pathology, Yale University, New Haven, CT 06510
In mice, genetic deletion of B cells strongly suppresses systemic autoimmunity, providing a rationale for depleting B cells to treat autoimmunity. In fact, B cell depletion with rituximab is approved for rhematoid arthritis patients, and clinical trials are underway for systemic lupus erythematosus. Yet, basic questions concerning mechanism, pathologic effect, and extent of B cell depletion cannot be easily studied in humans. To better understand how B cell depletion affects autoimmunity, we have generated a transgenic mouse expressing human CD20 on B cells in an autoimmune-prone MRL/MpJ-Faslpr (MRL/lpr) background. Using high doses of a murine anti-human CD20 mAb, we were able to achieve significant depletion of B cells, which in turn markedly ameliorated clinical and histologic disease as well as antinuclear Ab and serum autoantibody levels. However, we also found that B cells were quite refractory to depletion in autoimmune-prone strains compared with nonautoimmune-prone strains. This was true with multiple anti-CD20 Abs, including a new anti-mouse CD20 Ab, and in several different autoimmune-prone strains. Thus, whereas successful B cell depletion is a promising therapy for lupus, at least some patients might be resistant to the therapy as a byproduct of the autoimmune condition itself.
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 R01-AR44077. A.A. was supported by a Brown-Coxe fellowship and an Arthritis Foundation postdoctoral fellowship.
2 Address correspondence and reprint requests to Dr. Mark J. Shlomchik, Yale University School of Medicine, PO Box 208035, New Haven, CT 06520-8035. E-mail address: mark.shlomchik{at}yale.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; AFC, Ab- forming cell; ADCC, Ab-dependent cellular cytotoxicity; ANA, anti-nuclear Ab; BAC, bacterial artificial chromosome; DC, dendritic cell; FO, follicular; GN, glomerulonephritis; hCD20, human CD20; IN, interstitial nephritis; LN, lymph node; mCD20, murine CD20; mLN, mesenteric LN; MZ, marginal zone; NP, (4-hydroxy-3-nitrophenyl)acetyl; NZB/W, New Zealand Black x New Zealand White F1; PerC, peritoneal cavity; RA, rheumatoid arthritis; RF, rheumatoid factor; SLT, secondary lymphoid tissue; Sm, Smith Ag; Tg, transgene.
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