Immunobiology of Transplant Obliterative Disease

描述(申请人提供)：同种异体肺移植经常失败 由于阻塞性呼吸道疾病发展较晚，作为一种 慢性免疫移植排斥反应的后果。这样的失败继续发生， 部分原因是我们目前对免疫生物学的理解 呼吸道纤维化的发生是相当有限的。利用小鼠异位气管移植，我们已经确定了直接同种异体反应性CD8 T细胞和自身MHC限制性的CD4T细胞对Minor的反应 移植抗原在OAD的诱导过程中起协同作用。我们现在建议 利用转基因小鼠技术来研究这种病理 CD8和CD4T细胞对同种异体气管移植物的免疫应答使用这个 技术，可以追踪同种异体气管移植物反应性TCR转基因T细胞 淋巴因子和活化分子在这些T细胞中的表达和功能 可以在OAD的发展过程中确定。因此，我们专门针对 为了：1)调查直接和间接之间存在的协作性的性质 I类同种异体反应性CD8和次要抗原反应性CD4T细胞的诱导 对同种异体气道移植后OAD的影响，2)检查 共刺激信号依赖的T细胞淋巴因子和效应分子 同种异体气管移植物中OAD的发展及3)克隆能力的检测 诱导同种异体反应性CD8和CD4T细胞无能抑制 同种异体气管移植后OAD的发生。越远 该转基因小鼠模型系统的开发和验证将为 移植领域使用一种工具，可以更准确地评估 促进慢性同种异体肺移植的T细胞活性 受伤。此外，在这些实验中获得的信息应该有助于 作为开发有效免疫调节剂的重要临床前数据 同种异体抗原特异性移植耐受问题的解决途径。

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.