Immunobiology of Transplant Obliterative Disease

描述（由申请人提供）：同种异体肺移植经常失败 由于闭塞性气道疾病（OAD）的晚期发展， 慢性免疫移植排斥的后果。这种失败继续发生， 部分原因是我们目前对免疫生物学的理解 气道纤维化的发作是相当有限的。使用异位气管 在小鼠同种异体移植中，我们已经确定直接同种异体反应性CD8+ T细胞以及自身MHC限制性CD4+ T细胞对微小的 移植抗原协同诱导OAD。我们现建议 利用转基因小鼠技术， CD8+和CD4+ T细胞对同种异体气管移植物的反应。使用此 技术，可以追踪气管同种异体移植物反应性TCR转基因T细胞， 以及这些T细胞中淋巴因子和活化分子的表达和功能 可以在OAD的开发过程中确定。因此，我们特别针对 （1）研究存在于直接 I类同种异体反应性CD8+和次要Ag反应性CD4+ T细胞在诱导 气道同种异体移植后OAD的作用，2）检查 共刺激信号依赖性T细胞淋巴因子和效应分子 OAD在气管移植物中的发展，和3）测试克隆的能力， 在同种异体反应性CD8+和CD4+ T细胞中的无反应性诱导，以抑制 同种异体气管移植后OAD的发生。进一步 这种转基因小鼠模型系统的开发和验证将提供 移植领域的工具，更准确地评估 负责促进慢性肺移植的T细胞的活性 损伤此外，在这些实验中获得的信息应有助于 作为开发有效免疫调节剂的重要临床前数据， 解决同种异体抗原特异性移植耐受问题的方法。

DESCRIPTION (provided by applicant): Lung allotransplantation frequently fails due to the late development of Obliterative Airways Disease (OAD) as a consequence of chronic immune graft rejection. Such failures continue to occur, in part, because our current understanding of the immunobiology responsible for the onset of the airway fibrosis is quite limited. Using heterotopic tracheal allotranspiantation in mice, we have determined that directly alloreactive CD8+ T cells as well as self-MHC-restricted CD4+ T cells responding against minor transplantation antigens cooperate in the induction of OAD. We now propose to take advantage of transgenic mouse technology to investigate this pathological CD8+ and CD4+ T cell response against tracheal allografts. Using this technique, tracheal allograft-reactive TCR-transgenic T cells can be tracked and lymphokine and activation molecule expression and function in these T cells can be determined during the development of OAD. Therefore, we specifically aim to: 1) Investigate the nature of the cooperativity that exists between direct class I-alloreactive CD8+ and minor-Ag reactive CD4+ T cells in the induction of OAD following airway allotranspiantation, 2) examine the role of costimulatory signal-depend T cell lymphokines and effector molecules in the development of OAD in tracheal allografts, and 3) test the capacity of clonal anergy induction in alloreactive CD8+ and CD4+ T cells to inhibit the development of OAD following tracheal allograft transplantation. The further development and validation of this transgenic mouse model system will provide the transplantation field with a tool that more accurately assesses the activities of those T cells responsible for promoting chronic lung allograft injury. In addition, the information obtained in these experiments should serve as important preclinical data for the development of effective immunomodulatory approaches to the problem of alloantigen-specific transplantation tolerance.