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

被引：55

作者：

Bardwell, Philip D. ^{[1
]}

Gu, Jijie ^{[1
]}

McCarthy, Donna ^{[1
]}

Wallace, Craig ^{[2
]}

Bryant, Shaughn ^{[2
]}

Goess, Christian ^{[2
]}

Mathieu, Suzanne ^{[2
]}

Grinnell, Chris ^{[3
]}

Erickson, Jamie ^{[3
]}

Rosenberg, Saul H. ^{[5
]}

Schwartz, Annette J. ^{[3
]}

Hugunin, Margaret ^{[4
]}

Tarcsa, Edit ^{[3
]}

Elmore, Steven W. ^{[5
]}

McRae, Bradford ^{[2
]}

Murtaza, Anwar ^{[2
]}

Wang, Li Chun ^{[2
]}

Ghayur, Tariq ^{[1
]}

机构：

[1] Abott Biores Ctr, Dept Biol, Worcester, MA 01605 USA

[2] Abott Biores Ctr, Dept Pharmacol, Worcester, MA 01605 USA

[3] Abott Biores Ctr, Dept Drug Safety Metab & Pharmacokinect, Worcester, MA 01605 USA

[4] Abott Biores Ctr, Dept Mol & Cellular Biol, Worcester, MA 01605 USA

[5] Abbott Labs, Global Pharmaceut Res & Dev Oncol, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF IMMUNOLOGY | 2009年 / 182卷 / 12期

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; COLLAGEN-INDUCED ARTHRITIS; B-LYMPHOCYTE STIMULATOR; RHEUMATOID-ARTHRITIS; T-CELL; MONOCLONAL-ANTIBODY; APOPTOSIS; EXPRESSION; PROTEINS; DISEASE;

D O I：

10.4049/jimmunol.0802813

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 Journal of Immunology, 2009, 182: 7482-7489.

引用

页码：7482 / 7489

页数：8

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