De novo production of K-α1 tubulin-specific antibodies:: Role in chronic lung allograft rejection
De novo production of K-α1 tubulin-specific antibodies:: Role in chronic lung allograft rejection
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DOI：
10.4049/jimmunol.180.7.4487
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发表时间：
2008-04-01
影响因子：
4.4
通讯作者：
Mohanakumar, Thalachallour
中科院分区：
文献类型：
--
作者：
Goers, Trudie A.;Ramachandran, Sabarinathan;Mohanakumar, Thalachallour
肺移植是多种终末期肺部疾病的治疗选择。移植后抗供体HLA和非HLA抗原的抗体的发展与移植器官的急性和慢性排斥反应有关。肺移植后闭塞性细支气管炎综合征（BOS）的发生与抗供者HLA抗体的重新产生相关。然而，只有一部分BOS患者表现出可检测的抗供体HLA抗体。气道上皮被认为是肺移植排斥反应的主要靶点。在这项研究中，我们证明，许多BOS+患者（12 36）开发抗体反应上皮细胞抗原，是从HLA不同。此外，抗上皮细胞Ab的从头产生先于BOS的临床发作。N-末端测序和blastx分析以及用K-α 1微管蛋白特异性Ab阻断鉴定上皮Ag为K-α 1微管蛋白。从头产生的抗K-α 1微管蛋白抗体与气道上皮细胞的结合导致转录因子（TCF 5和c-Myc）表达增加，导致纤维化生长因子表达增加，细胞周期信号传导激活和纤维增生，这是人肺移植后BOS免疫发病机制的中心事件。
Lung transplantation is the treatment option for a variety of end-stage pulmonary diseases. Posttransplant development of Abs against donor HLA and non-HLA Ags have been associated with acute and chronic rejection of transplanted organs. Development of bronchiolitis obliterans syndrome (BOS) following lung transplantation has been correlated with de novo production of anti-donor-HLA Abs. However, only a portion of the patients with BOS demonstrate detectable anti-donor-HLA Abs. Airway epithelium is considered as a major target for lung allograft rejection. In this study we demonstrate that many BOS+ patients (12 of 36) develop Abs reactive to epithelial cell Ag that are distinct from HLA. Furthermore, de novo production of antiepithelial cell Ab precedes clinical onset of BOS. N-terminal sequencing and blastx analysis as well as blocking with K-alpha 1 tubulin-specific Ab identified the epithelial Ag as K-alpha 1 tubulin. Binding of the de novo-produced anti-K-alpha 1 tubulin Abs to the airway epithelial cells resulted in the increased expression of transcription factors (TCF5 and c-Myc), leading to increased expression of fibrogenic growth factors, activation of cell cycle signaling, and fibroproliferation, the central events in immunopathogenesis of BOS following human lung transplantation.