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）：闭塞性支气管炎（OB）是肺移植的频繁且经常毁灭性的并发症，通常对治疗难治性。尽管OB的发病机理显然是免疫介导的，但这些机制的细节仍然不确定。我们最近表明，具有OB的移植受者的CD4 T细胞似乎总是以极端的寡克隆增殖和CD28下调为特征，并且这些异常在很大程度上不存在而没有排斥。我们认为，这些异常的T细胞通过对同种异体移植物造成直接伤害，或者通过使用趋化和激活的介体进行精心策划来造成炎症性级联反应，在OB的发展中起着至关重要的作用。该提案的项目将进行肺移植受者队列的串行测定，以确定CD4克隆扩张的发现和CD28下调是否有助于诊断或预测OB。其他研究将表征这些异常细胞并建立其抗原特异性，并描述它们的增殖和细胞溶解功能。我们还使用免疫缺陷小鼠中人类气道的异种移植物开发了一种新型的人类熔融嵌合模型，该模型将在同种异体转移（向气道）人类T细胞后产生免疫作用和功能的体内测定。我们预计，这些研究的重点是对同种异体移植的免疫反应的早期事件，将导致重要的新发现，从而提供对OB的免疫发病发生的见解。此外，这里的发现还可能开放开发创新，诊断和治疗方式的途径，包括预防或治疗OB的早期和更有效的干预措施。