Lung transplantation is a commonly utilized modality for the treatment of end stage pulmonary diseases. However, the lung is rejected more commonly than other solid organ allografts. Repeated acute rejection episodes result in chronic rejection known as bronchiolitis obliterans, the leading cause of death in lung allograft recipients. Presentation of donor major histocompatibility complex (MHC) antigens by antigen presenting cells, such as macrophages and dendritic cells, to recipient lymphocytes is the stimulus for rejection episodes. Conversely, allograft acceptance may be induced by immunizing the recipient, orally, with donor-derived MHC proteins/peptides or MHC-""""""""like"""""""" proteins prior to transplantation. This phenomenon, known as oral tolerance, has been shown to prevent rejection in allografts other than the lung, but has not been examined in lung allograft rejection. Although donor MHC-antigens are the stimulus and target of the rejection response, we have reported recently that type V collagen (col(V)), which may be MHC-""""""""like,"""""""" is also recognized as an antigen during lung allograft rejection in humans, and the local immune response to lung alloantigens in mice. Also, immunizing mice with col(V) induces immunological tolerance to lung alloantigens. However, the ability of col(V) to induce oral tolerance and prevent the immunology and pathology of lung allograft rejection is unknown. Our laboratory is one of the few that developed the rat model of lung allograft rejection in which F344 rat lungs (RT1lv1) are transplanted orthotopically into WKY (RT1I) recipients. Utilizing this model, the current proposal tests the hypothesis that oral tolerance induction by col(V) prevents the immunology and pathology of lung allograft rejection by examining the following specific aims:
Aim 1 : To determine if oral immunization with col(V) induces oral tolerance to alloantigens and prevents the development of rejection pathology in lung allografts, rats will be fed col(V) followed by an assessment of delayed type hypersensitivity (DTH) responses to donor alloantigens, and onset of acute rejection and bronchiolitis obliterans (BO) in allograft lungs.
Aim 2 : To determine the cell types responsible for oral tolerance induced by col(V), the role of specific lymphocyte subsets and APC's in down regulating the immunology and pathology of lung allograft rejection will be investigated.
Aim 3. To determine the peptides of col(V) that induce oral tolerance to lung allografts, peptides of specific alpha-chains of col(V) will be produced by cyanogen bromide digestion followed by an assessment of these peptides to induce oral tolerance and prevent the immunology and pathology of the rejection response.
Aim 4. To determine the role of soluble mediators in oral tolerance induced by col(V), tolerized lung allograft recipients will be treated with antagonists and neutralizing antibodies to cytokines and other mediators believed to have key roles in oral tolerance followed by an assessment of the immunology and pathology of the rejection response.
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