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）是肺移植的常见并发症，通常具有破坏性，通常难以治疗。虽然OB的发病机制是明确的免疫介导的，这些机制的细节仍然不确定。我们最近的研究表明，OB移植受体的CD 4 T细胞似乎总是以极端寡克隆增殖和CD 28下调为特征，而这些异常在无排斥反应的受体中基本上不存在。我们认为这些异常的T细胞在OB的发展中起着关键作用，它们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性和激活介质来协调炎症级联反应。本提案的项目将对肺移植受者队列进行系列检测，以确定CD 4克隆扩增和CD 28下调的结果是否可用于诊断或预测OB。其他研究将描述这些不寻常的细胞，并建立其抗原特异性，并描绘其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，其使用免疫缺陷小鼠中的人气道异种移植物，这将使得能够在同种异体（至气道）人T细胞过继转移后进行免疫效应和功能的体内测定。我们预计这些研究的重点是对同种异体移植物的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，这些发现也可能为开发创新的诊断和治疗方式开辟道路，包括更早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.