Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis.
Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis.
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DOI：
10.1002/hep.26067
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发表时间：
2013-02
期刊：
影响因子：
13.5
通讯作者：
Gershwin, M. Eric
中科院分区：
文献类型：
--
作者：
Dhirapong, Amy;Yang, Guo-Xiang;Nadler, Steven;Zhang, Weici;Tsuneyama, Koichi;Leung, Patrick;Knechtle, Stuart;Ansari, Aftab A.;Coppel, Ross L.;Liu, Fu-Tong;He, Xiao-Song;Gershwin, M. Eric
总的来说，人类原发性胆汁性肝硬化（PBC）的人类和小鼠模型中的数据表明，活化的T细胞，特别是CD 8 T细胞，在胆汁细胞破坏中起关键作用。在生理条件下，T细胞活化涉及两个关键信号，其涉及MHC和一组共刺激分子，所述共刺激分子包括T细胞上的受体，即细胞毒性T淋巴细胞抗原4（CTLA-4）。根据本文报道的研究，经由CTLA-4的信号传导具有调节共刺激和诱导抑制信号的潜力。在这项研究中，我们利用了我们定义明确的PBC小鼠模型，其中小鼠用偶联BSA的2-辛炔酸免疫，导致产生高滴度的抗线粒体自身抗体和门静脉细胞浸润。为了研究CTLA-4 IG作为免疫抑制剂的潜力，我们在诱导自身免疫性胆管炎之前和之后处理小鼠。首先，我们证明在2-OA-BSA免疫前一天开始CTLA-4 IG治疗，完全抑制胆管炎的表现，包括AMA产生、肝内T细胞浸润和胆管损伤。然而，更重要的是，在先前免疫的小鼠中发生自身免疫性胆管炎后开始的CTLA-4 IG治疗也产生了显著的治疗益处，包括减少肝内T细胞浸润和胆管细胞损伤，尽管AMA水平没有改变。这些数据表明，CTLA-4 IG的优化方案有可能作为PBC患者的研究性治疗工具。
Collectively, the data in both humans and murine models of human primary biliary cirrhosis (PBC) suggest that activated T cells, particularly CD8 T cells, play a critical role in biliary cell destruction. Under physiological conditions, T cell activation involves two critical signals that involve the MHC and a set of co-stimulatory molecules which include a receptor on T cells coined cytotoxic T lymphocyte antigen 4 (CTLA-4). Germane to the studies reported herein, signaling via CTLA-4 has the potential to modulate co-stimulation and induce inhibitory signals. In this study we have taken advantage of our well-defined murine model of PBC in which mice are immunized with 2-octynoic acid coupled to BSA, leading to the production of high titer anti-mitochondrial autoantibodies and portal cellular infiltrates. To investigate the potential of CTLA-4 Ig as an immunotherapeutic agent, we treated mice both before and after induction of autoimmune cholangitis. Firstly, we demonstrate that CTLA-4 Ig treatment begun one day before 2-OA-BSA immunization, completely inhibits the manifestations of cholangitis, including AMA production, intra-hepatic T cell infiltrates and bile duct damage. However, and more critically, treatment with CTLA-4 Ig initiated after the development of autoimmune cholangitis in previously immunized mice, also resulted in significant therapeutic benefit, including reduced intra-hepatic T cell infiltrates and biliary cell damage, although AMA levels were not altered. These data suggest that an optimized regimen with CTLA-4 Ig has the potential to serve as an investigative therapeutic tool in patients with PBC.
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影响因子：
27.4
作者：
Buch MH;Boyle DL;Rosengren S;Saleem B;Reece RJ;Rhodes LA;Radjenovic A;English A;Tang H;Vratsanos G;O'Connor P;Firestein GS;Emery P
通讯作者：
Emery P
DOI：
10.1073/pnas.91.11.5138
发表时间：
1994-05-24
影响因子：
11.1
作者：
GUERDER, S;PICARELLA, DE;FLAVELL, RA
通讯作者：
FLAVELL, RA
影响因子：
15.9
作者：
KNOERZER, DB;KARR, RW;MENGLEGAW, LJ
通讯作者：
MENGLEGAW, LJ
DOI：
10.1073/pnas.0703872104
发表时间：
2007-08-14
影响因子：
11.1
作者：
Good, Kim L.;Tangye, Stuart G.
通讯作者：
Tangye, Stuart G.
影响因子：
64.8
作者：
BRUNET, JF;DENIZOT, F;GOLSTEIN, P
通讯作者：
GOLSTEIN, P