Immunobiology of Transplant Obliterative Disease

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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.