Lung allograft is believed to be initiated between donor lung macrophages and dendritic cells leading to presentation of major histocompatibility complex (MHC) antigens that stimulate host lymphocytes. Direct or indirect allo-recognition of donor MHC antigens or proteins homologous to MHC antigens (MHC-""""""""like"""""""") is believed to perpetuate the rejection process. Conversely, indirect allo-recognition of MHC or MHC-""""""""like"""""""" peptides in the pre-transplant period may prevent rejection activity. Although donor MHC antigens are usually the target of allo-immune responses. alpha-chains of type V and XI collagen, that may be homologous to MHC proteins, are also recognized as antigens during lung allograft rejection. Therefore, pre-transplant immunization with peptides of type V or VI collagen may modulate the rejection response. We have developed a murine model in which the instillation of allogeneic (C57BL/6,H-2,1-a/b) bronchoalveolar lavage cells (96% macrophages, 1-2% dendritic cells) into the lungs of recipient mice (BALB/c, H-2/d, 1-a/d) reproduce the histology and cellular and humoral immunology of acute lung allograft rejection observed in humans, as well as, immune responses to type V and XI collagen. Utilizing this unique model the current proposal tests the hypothesis that allogeneic lung macrophages and dendritic cells mediate lung allograft rejection, and examines the molecular mechanisms responsible for the rejection process by examining the following specific aims:
Aim 1. To determine the interactions between donor lung macrophages and dendritic cells and the microenvironment of the lung that lead to up-regulated allo-immune responses in the allograft, soluble signals produced locally in response to the instillation of allogenic macrophages and dendritic cells in recipient lungs will be examined for their role in facilitating rejection. 2. To determine the role of direct and indirect allo- recognition in the pathogenesis of lung allograft rejection, the requirement for functional donor accessory cells or recipient accessory cells in graft destruction will be tested.
Aim 3. To determine the role of MHC alloantigens, and CD4+ and CD8+ lymphocytes in the rejection process, lung accessory cells which do not express MHC II or MHC I or both antigens will be instilled into the lungs of recipient mice followed by an assessment of the cellular and humoral immune changes and histology in recipient lungs.
Aim 4. To determine if indirect allo- recognition of peptides that may be homologous to MHC antigens prior to transplantation down regulates the rejection response, BALB/c mice will be immunized with peptides of type V and XI collagen prior to instilling C57BL/6 bronchoalveolar lavage cells into BALB/c mice followed by an assessment of the histology, and immunology of acute rejection. The goal of these studies is to discern the immune mechanisms of lung allograft rejection at a molecular level so targets may be identified for therapeutic intervention to prolong the survival of lung allograft recipients.
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