Antibodies to MHC class I induce autoimmunity: role in the pathogenesis of chronic rejection.
Antibodies to MHC class I induce autoimmunity: role in the pathogenesis of chronic rejection.
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DOI：
10.4049/jimmunol.182.1.309
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Mohanakumar T
中科院分区：
文献类型：
--
作者：
Fukami N;Ramachandran S;Saini D;Walter M;Chapman W;Patterson GA;Mohanakumar T
据推测，对不匹配供体 HLA 抗原的同种免疫和对自身抗原的自身免疫在移植器官慢性排斥的免疫发病机制中发挥重要作用。然而，尚不清楚同种免疫反应在诱导自身免疫中起什么作用（如果有的话）。为了测试移植后针对不匹配的供体 MHC 产生的抗体是否会诱导自身免疫和慢性排斥反应，我们开发了一种小鼠模型，其中将抗 MHC I 类抗体或对照（C1.18.4/抗角蛋白）通过支气管内施用到天然肺中。接受抗 MHC I 类抗体而非对照抗体的动物在第 15 天时在肺血管和细支气管周围出现明显的细胞浸润，随后出现上皮增生、纤维化和远端气道闭塞，类似于人肺移植后的慢性排斥反应。接受 I 类抗 MHC 的小鼠肺部表现出趋化因子、其受体和生长因子表达增加，并诱导 IL-17 以及针对自身抗原、K-α1 微管蛋白和胶原蛋白 V 的从头抗体。抗IL-17中和IL-17导致自身抗体减少以及抗MHC I类抗体诱导的损伤。因此，我们的结果表明，针对供体 MHC 的抗体可以诱导由 IL-17 介导的自身免疫，而 IL-17 在肺移植后的慢性排斥反应中发挥着关键作用。因此，治疗肺移植后慢性排斥反应应考虑预防自身免疫的方法。
Alloimmunity to mismatched donor HLA-antigens and autoimmunity to self-antigens have been hypothesized to play an important role in immunopathogenesis of chronic rejection of transplanted organs. However, it is not known what role, if any, alloimmune response plays in inducing autoimmunity. To test whether antibody developed post-transplantation to mismatched donor-MHC induces autoimmunity and chronic rejection, we developed a murine model wherein anti-MHC class I antibodies or control (C1.18.4/anti-keratin) were administered intra-bronchially into native lungs. Animals receiving anti-MHC class I, but not control antibodies, developed marked cellular infiltration around vessels and bronchiole of lung by day 15 followed by epithelial hyperplasia, fibrosis and occlusion of the distal airways similar to chronic rejection following human lung transplantation. Lungs of mice receiving anti-MHC class I showed increased expression of chemokines, their receptors and growth factors and induced IL-17 as well as de novo antibodies to self-antigens, K-α1 tubulin and collagenV. IL-17 neutralization by anti-IL-17 resulted in reduction of autoantibody and lesions induced by anti-MHC class I antibodies. Thus, our results indicate that antibodies to donor-MHC can induce autoimmunity, mediated by IL-17, which plays a pivotal role in chronic rejection post-lung transplantation. Therefore, approaches to prevent autoimmunity should be considered for the treatment of chronic rejection post-lung transplantation.
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