Clonal CD4 T-Cells in Lung Transplant Recipients

描述(由申请人提供)：闭塞性毛细支气管炎(OB)是肺移植的一种常见且往往是破坏性的并发症，通常难以治疗。虽然OB的发病机制明显是由免疫介导的，但这些机制的细节仍不清楚。我们最近发现，患有OB的移植受者的CD4T细胞似乎总是以极端的寡克隆增殖和CD28下调为特征，而在没有排斥反应的受者中，这些异常基本上是不存在的。我们认为，这些异常的T细胞在OB的发展中起着关键作用，它们要么直接损伤同种异体移植物，要么通过精心策划的趋化和激活介质的炎性级联反应。这项建议的项目将对肺移植受者队列进行一系列分析，以确定CD4克隆性扩张和CD28下调的结果是否有助于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，使用人类呼吸道在免疫缺陷小鼠中的异种移植，将能够在体内分析过继转移同种异体(到呼吸道)人类T细胞后的免疫效果和功能。我们预计，这些研究的重点是同种异体移植免疫反应的早期事件，这将导致重要的新发现，为OB的免疫发病机制提供见解。此外，这里的发现还可能为创新、诊断和治疗模式的发展开辟道路，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.