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）发展较晚， 慢性免疫移植排斥反应的后果。此类故障不断发生， 部分原因是我们目前对免疫生物学的理解 气道纤维化的发作相当有限。使用小鼠异位气管同种异体移植，我们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 细胞对轻微的反应做出反应 移植抗原协同诱导 OAD。我们现在建议 利用转基因小鼠技术来研究这种病理学 CD8 和 CD4 T 细胞对气管同种异体移植物的反应。使用这个 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 这些 T 细胞中淋巴因子和激活分子的表达和功能 可以在OAD的开发过程中确定。因此，我们特别致力于 1）调查直接之间存在的合作性的性质 诱导中的 I 类同种异体反应性 CD8 和次要 Ag 反应性 CD4 T 细胞 气道同种移植后 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 气管同种异体移植物中 OAD 的发育，以及 3) 测试克隆能力 同种异体反应性 CD8 和 CD4 T 细胞中的无反应性诱导可抑制 气管同种异体移植后 OAD 的发展。进一步的 该转基因小鼠模型系统的开发和验证将提供 移植领域有一个工具可以更准确地评估 那些负责促进慢性肺同种异体移植的 T 细胞的活动 受伤。此外，这些实验中获得的信息应该用于 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.