Clonal CD4 T-Cells in Lung Transplant Recipients

肺移植受者中的克隆性 CD4 T 细胞

• 批准号: 7031202
• 负责人: STEVEN R DUNCAN
• 金额: $ 36.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031202
• 关键词: CD28 molecule; NOD mouse; RNase protection assay; SCID mouse; T cell receptor; acute bronchitis; biomarker; clinical research; cytokine; diagnosis design /evaluation; flow cytometry; gene expression; helper T lymphocyte; homologous transplantation; host organism interaction; human subject; immunologic assay /test; immunoregulation; leukocyte activation /transformation; lung transplantation; lymphocyte proliferation; patient oriented research; phenotype; postoperative complications; receptor expression; transplantation immunology

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.

描述（由申请人提供）：闭塞性细支气管炎（OB）是肺移植的一种常见且往往具有破坏性的并发症，通常难以治疗。尽管 OB 的发病机制显然是免疫介导的，但这些机制的细节仍不确定。我们最近发现，患有 OB 的移植受者的 CD4 T 细胞似乎总是具有极端的寡克隆增殖和 CD28 下调的特征，而这些异常在没有排斥的受者中基本上不存在。我们相信这些异常 T 细胞在 OB 的发展中发挥着关键作用，它们要么对同种异体移植物造成直接损伤，要么通过精心设计趋化和激活介质来协调炎症级联反应。该提案的项目将对肺移植受者队列进行系列检测，以确定 CD4 克隆扩增和 CD28 下调的结果是否有助于诊断或预测 OB。其他研究将表征这些不寻常的细胞并确定它们的抗原特异性，并描述它们的增殖和溶细胞功能。我们还利用免疫缺陷小鼠的人类气道异种移植物开发了一种新型人-鼠嵌合模型，该模型将能够在同种异体（至气道）人类T细胞过继转移后体内测定免疫效果和功能。我们预计这些研究重点关注同种异体移植物免疫反应的早期事件，将产生重要的新发现，为 OB 的免疫发病机制提供见解。此外，这里的研究结果还可能为创新、诊断和治疗方式的开发开辟道路，包括更早、更有效的干预措施来预防或治疗 OB。