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The Bcl-2 Family Antagonist ABT-737 Significantly Inhibits Multiple Animal Models of Autoimmunity

Philip D. Bardwell^1,2,*, Jijie Gu^1,*, Donna McCarthy^*, Craig Wallace, Shaughn Bryant, Christian Goess, Suzanne Mathieu, Chris Grinnell, Jamie Erickson, Saul H. Rosenberg^¶, Annette J. Schwartz, Margaret Hugunin, Edit Tarcsa, Steven W. Elmore^¶, Bradford McRae, Anwar Murtaza, Li Chun Wang and Tariq Ghayur^2,*

^* Department of Biologics, Department of Pharmacology, Department of Drug Safety, Metabolism and Pharmacokinetics, and Department of Molecular and Cellular Biology, Abbott Bioresearch Center, Worcester, MA 01605; and ^¶ Global Pharmaceutical Research & Development-Oncology, Abbott Laboratories, Abbott Park, IL 60064

The Bcl-2 family of proteins plays a critical role in controlling immune responses by regulating the expansion and contraction of activated lymphocyte clones by apoptosis. ABT-737, which was originally developed for oncology, is a potent inhibitor of Bcl-2, Bcl-x_L, and Bcl-w protein function. There is evidence that Bcl-2–associated dysregulation of lymphocyte apoptosis may contribute to the pathogenesis of autoimmunity and lead to the development of autoimmune diseases. In this study, we report that ABT-737 treatment resulted in potent inhibition of lymphocyte proliferation as measured by in vitro mitogenic or ex vivo Ag-specific stimulation. More importantly, ABT-737 significantly reduced disease severity in tissue-specific and systemic animal models of autoimmunity. Bcl-2 family antagonism by ABT-737 was efficacious in treating animal models of arthritis and lupus. Our results suggest that treatment with a Bcl-2 family antagonist represents a novel and potentially attractive therapeutic approach for the clinical treatment of autoimmunity.

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 P.D.B. and J.G. contributed equally to this work.

² Address correspondence and reprint requests to Dr. Philip D. Bardwell and Dr. Tariq Ghayur, Abbott Bioresearch Center, 100 Research Drive, Worcester, MA 01605. E-mail addresses: philip.bardwell{at}abbott.com and tariq.ghayur{at}abbott.com

³ Abbreviations used in this paper: RA, rheumatoid arthritis; BAFF, B-cell activating factor; CBC, complete blood count; CIA, collagen-induced arthritis; CsA, cyclosporin A; DTH, delayed-type hypersensitivity; KLH, keyhole limpet hemocyanin; LN, lymph node; MAS, mean arthritic score; mBSA, methylated BSA; MMF, mycophenolate mofetil; PU, proteinuria; SLE, systemic lupus erythematosus; Dex, dexamethasone.

⁴ The online version of this article contains supplemental material.