Clonal CD4 T-Cells in Lung Transplant Recipients

肺移植受者中的克隆性 CD4 T 细胞

基本信息

批准号：
7568904
负责人：
STEVEN R DUNCAN
金额：
$ 35.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7568904
关键词：
Abnormal Cell Adoptive Transfer Allogenic Allografting Animal Model Antigens Attention Autologous Avidity Biological Assay Biological Markers Bronchiolitis CD28 gene CD4 Positive T Lymphocytes Cell Death Cell Therapy Cell Transplants Cell physiology Cells Characteristics Chimera organism Chronic Clinical Clonal Expansion Clonality Complex Complication Control Animal Cross-Sectional Studies Development Diagnosis Diagnostic Disease Down-Regulation Early Diagnosis Epithelial Cells Event Exhibits Flow Cytometry Gene Expression Generations Human Immune Immune System Diseases Immune response Immunobiology Immunodeficient Mouse Implant Inflammatory Injury Intervention Investigation Lead Lung Lung Transplantation Lymphocyte Measures Mediating Mediator of activation protein Modality Modeling Mus NOD/SCID mouse Natural Killer Cells Pathogenesis Pathogenicity Peripheral Blood Mononuclear Cell Phenotype Play Population Preventive Proliferating RNase protection assay Refractory Role Sensitivity and Specificity Specificity T-Lymphocyte Testing Therapeutic Time Transplant Recipients Treatment Protocols Upper arm Xenograft procedure airway remodeling assay development base clinically significant cohort cytokine in vivo innovation insight lung allograft novel prevent protein expression receptor response

项目摘要

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 oligclonal proliferations and CD28 downregulation, and these abormalities are largely absent amoung 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.

闭孔性支气管炎（OB）是一种频繁且经常毁灭性的肺移植并发症，是通常对治疗难治性。尽管OB的发病机理显然是免疫介导的，但这些机制仍然不确定。我们最近表明，具有移植受者的CD4 T细胞 OB似乎总是以极端的寡头增生和CD28下调为特征，并且这些劣势在很大程度上是没有拒绝的接受者。我们相信这些异常t- 细胞通过对同种异体移植造成直接伤害或通过用趋化和激活介体的阐述来策划炎症性级联。这该提案的项目将进行肺移植接受者队列的串行测定，以确定是否是否 CD4克隆扩张和CD28下调的发现可用于诊断或预测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。我们还开发了一种新型的人类熔融嵌合模型在免疫缺陷的小鼠中使用人类气道的异种移植物，这将使体内实现免疫作用。和同种异体转移（气道）人类T细胞后的功能。我们预计将重点这些关于对同种异体移植物免疫反应的早期事件的研究将导致重要的新发现这提供了对OB的免疫发病发生的见解。此外，这里的发现也可能打开开发创新，诊断和治疗方式的途径，包括早期以及更多有效的干预措施以防止或治疗OB。