Deleterious Effect of CTLA4-Ig on a Treg-Dependent Transplant Model
Deleterious Effect of CTLA4-Ig on a Treg-Dependent Transplant Model
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DOI：
10.1111/j.1600-6143.2011.03929.x
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发表时间：
2012-04-01
影响因子：
8.8
通讯作者：
Chandraker, A.
中科院分区：
文献类型：
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作者：
Riella, L. V.;Liu, T.;Chandraker, A.
阻断B7:CD28共刺激通路已成为预防同种异体移植排斥反应的一种有前景的治疗方法。然而，来自belatacept III期临床试验的结果表明，与环孢素相比，belatacept的排异率更高，这引起了人们对该药物潜在有害作用的关注。在这项研究中，我们研究了hCTLA4Ig阻断B7:CD28对不同主要组织相容性复合体（MHC）错配移植模型中调节性T细胞（Treg）生成的影响。hCTLA4Ig显著降低了B6 WT动物体内Tregs的数量，这种作用在胸腺诱导的Tregs （Helios+）中最为明显。尽管hCTLA4Ig在完全同种异体错配模型中阻止了排斥反应，但在MHC ii类错配模型中，hCTLA4Ig加速了排斥反应（MST = 26, p < 0.0001），其中同种异体移植的长期存活依赖于Tregs。这种加速的排斥反应与胸腺诱导的treg显著减少有关，并导致次级淋巴器官和同种异体移植物中效应/调节性t细胞比例更高。本研究证实了体内移植模型中B7:CD28通路在Treg稳态中的重要性，并提示hCTLA4Ig治疗在移植依赖Treg的情况下可能是有害的。
Blockade of the B7:CD28 costimulatory pathway has emerged as a promising therapy to prevent allograft rejection. However, results from the belatacept phase III clinical trial demonstrated a higher rejection rate when compared to cyclosporine, raising concern about potential deleterious effects of this agent. In this study, we investigated the consequences of B7:CD28 blockade by hCTLA4Ig on regulator T cell (Treg) generation in different major histocompatibility complex (MHC) mismatch transplant models. Administration of hCTLA4Ig significantly decreased the amount of Tregs in B6 WT animals and this effect was predominant in thymus-induced Tregs (Helios+). Although hCTLA4Ig prevented rejection in a fully allogeneic mismatch model, it accelerated rejection in a MHC class-II mismatch model (MST = 26, p < 0.0001), in which long-term allograft survival is dependent on Tregs. This accelerated rejection was associated with a marked reduction in thymus-induced Tregs and led to a higher effector/regulatory T-cell ratio in secondary lymphoid organs and in the allograft. This study confirms the importance of the B7:CD28 pathway in Treg homeostasis in an in vivo transplant model and suggests that hCTLA4Ig therapy may be deleterious in circumstances where engraftment is dependent on Tregs.