Clonal CD4 T-Cells in Lung Transplant Recipients

闭塞性毛细支气管炎(OB)是肺移植术后常见且往往具有破坏性的并发症。 通常对治疗不起作用。尽管OB的发病机制显然是由免疫介导的，但细节 这些机制仍然不确定。我们最近发现移植受者的CD4T细胞 OB似乎总是以极端寡克隆性增殖和CD28下调为特征，并且 这些流产在没有排斥的接受者中基本上是不存在的。我们相信这些不正常的T- 细胞通过对同种异体移植物造成直接损伤或通过 通过精心设计的趋化和激活介质来协调炎症级联反应。这个 该提案的项目将对肺移植受者队列进行一系列测试，以确定 CD_4克隆性扩张和CD_(28)表达下调有助于OB的诊断或预测。 其他研究将确定这些不寻常的细胞的特征，确定它们的抗原特异性，并描绘出 它们的增殖和细胞溶解功能。我们还开发了一种新的人-鼠嵌合模型 在免疫缺陷小鼠中使用人类呼吸道异种移植，将能够在体内测试免疫效果 并在将同种异体T细胞过继转移到(呼吸道)人类T细胞后发挥作用。我们预计将重点关注 这些关于同种异体移植免疫反应早期事件的研究将产生重要的新发现。 这为了解OB的免疫发病机制提供了深入的见解。此外，这里的发现也可能会打开 开发创新、诊断和治疗方式的途径，包括更早和更多 预防或治疗OB的有效干预措施。

Obliterative bronchiolitis (OB) is a frequent and often devastating complication of lung transplantation that is usually refractory to treatments. Although the pathogenesis of OB is clearly immune-mediated, details of these mechanisms remain uncertain. We have recently shown that CD4 T-cells of transplant recipients with OB seem to be invariably characterized by extreme oligclonal proliferations and CD28 downregulation, and these abormalities are largely absent amoung recipients without rejection. We believe these abnormal T- cells play a critical role in development of OB by either causing direct injuries to the allograft, or by orchestrating an inflammatory cascade with elaborations of chemotactic and activating mediators. The projects of this proposal will conduct serial assays of a lung transplant recipient cohort, to establish whether findings of CD4 clonal expansions and CD28 downregulation are useful for diagnosis or prediction of OB. Other studies will characterize these unusual cells and establish their antigen specificities, and delineate their proliferative and cytolytic functions. We have also developed a novel human-murine chimeric model using xenografts of human airways in immunodeficient mice that will enable in vivo assays of immune effects and functions after adoptive transfer of allogeneic (to the airway) human T-cells. We anticipate the focus of these studies on the early events of the immune responses to allografts will result in important new findings that provide insights into the immunopathogenesis of OB. Furthermore, findings here may also open avenues for development of innovative, diagnostic and therapeutic modalities, including earlier and more efficacious interventions to prevent or treat OB.