Clonal CD4 T-Cells in Lung Transplant Recipients

描述（由申请人提供）：闭塞性细支气管炎（OB）是肺移植中一种常见且常常具有破坏性的并发症，通常难以治疗。虽然OB的发病机制显然是免疫介导的，但这些机制的细节仍不清楚。我们最近的研究表明，OB移植受者的CD4 t细胞似乎总是以极端的寡克隆增殖和CD28下调为特征，而这些异常在没有排斥反应的受者中基本不存在。我们认为，这些异常t细胞在OB的发展中发挥着关键作用，要么对同种异体移植物造成直接损伤，要么通过精心设计的趋化和激活介质协调炎症级联反应。本提案的项目将对肺移植受体队列进行系列分析，以确定CD4克隆扩增和CD28下调的发现是否有助于OB的诊断或预测。其他研究将表征这些不寻常的细胞，建立它们的抗原特异性，并描述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气道的异种移植物，可以在过继性转移异体（气道）人类t细胞后进行体内免疫效果和功能的检测。我们预计，这些研究的重点是同种异体移植物免疫反应的早期事件，将导致重要的新发现，为OB的免疫发病机制提供见解。此外，这里的发现也可能为开发创新的诊断和治疗方式开辟道路，包括早期和更有效的干预措施来预防或治疗OB。

DESCRIPTION (provided by applicant): 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 oligoclonal proliferations and CD28 downregulation, and these abnormalities are largely absent among 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.