Bardwell Philip D, Gu Jijie, McCarthy Donna, Wallace Craig, Bryant Shaughn, Goess Christian, Mathieu Suzanne, Grinnell Chris, Erickson Jamie, Rosenberg Saul H, Schwartz Annette J, Hugunin Margaret, Tarcsa Edit, Elmore Steven W, McRae Bradford, Murtaza Anwar, Wang Li Chun, Ghayur Tariq
Department of Biologics, Abbott Bioresearch Center, Worcester, MA 01605, USA.
J Immunol. 2009 Jun 15;182(12):7482-9. doi: 10.4049/jimmunol.0802813.
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.
Bcl-2蛋白家族通过凋亡调节活化淋巴细胞克隆的扩增和收缩，在控制免疫反应中发挥关键作用。最初为肿瘤学开发的ABT-737是Bcl-2、Bcl-x(L)和Bcl-w蛋白功能的有效抑制剂。有证据表明，Bcl-2相关的淋巴细胞凋亡失调可能导致自身免疫性疾病的发病机制，并导致自身免疫性疾病的发展。在本研究中，我们报告ABT-737治疗可有效抑制淋巴细胞增殖，这通过体外促有丝分裂或体内抗原特异性刺激来衡量。更重要的是，ABT-737显著降低了自身免疫性疾病的组织特异性和全身性动物模型中的疾病严重程度。ABT-737对Bcl-2家族的拮抗作用在治疗关节炎和狼疮的动物模型中有效。我们的结果表明，用Bcl-2家族拮抗剂治疗代表了一种用于自身免疫性疾病临床治疗的新颖且潜在有吸引力的治疗方法。
