Transplantation of solid organs currently requires nonspecific immunosuppressive agents to prevent rejection. A number of toxicities are associated with the use of these agents. The induction of DONOR SPECIFIC TRANSPLANTATION TOLERANCE has been suggested as one approach to overcome these limitations. The only experimental circumstances in which stable tolerance occurs are those which result when chimerism is induced using bone marrow transplantation. Tolerance results when fully allogeneic chimeras (A-B) are prepared, but recipients exhibit inferior survival, are immunoIN-competent, and are susceptible to graft versus host disease (GVH). Transplantation of a mixture of syngeneic (host-type) plus allogeneic (donor-type) of bone marrow to produce mixed allogeneic chimeras (A+B-B) also achieves donor-specific transplantation tolerance, but recipients exhibit excellent survival, superior immunocompetence, and are resistant to GVH disease. Donor-specific skin grafts are permanently accepted. Whether similar donor-specific transplantation tolerance can be achieved for primarily vascularized solid organ grafts has not yet been examined. The purpose of the current proposal is to APPLY MIXED CHIMERISM, WITH ALL OF ITS ADVANTAGES, TO INDUCE DONOR-SPECIFIC TRANSPLANTATION TOLERANCE FOR LIVER TRANSPLANTATION (SPECIFIC AIM I), and to identify factors which may influence clinical application of this model. The liver is a complex organ composed of a number of nonparenchymal cells (vascular endothelial cells, bile duct epithelial cells, Kupffer cells, Ito cells, and dendritic cells) which may express tissue-specific antigens not shared by the tolerizing bone marrow cells. Similar antigens have been characterized for skin and reside in the non-MHC (background) genes. Because all solid organ transplants involve background as well as MHC disparities, we will exploit the model of mixed chimerism to IDENTIFY THE ROLE OF TISSUE-SPECIFIC ANTIGENS PRESENT IN TRANSPLANTED LIVER (SPECIFIC AIM II), which may result in graft rejection in spite of tolerance. We will identify which cells, when co-administered with bone marrow, will overcome this lack of tolerance to tissue-specific antigen. Finally, we will use the model for MIXED CHIMERISM TO CHARACTERIZE THE PHENOTYPE AND TURNOVER OF NONPARENCHYMAL HEPATIC CELLS, IN AUTOCHTHONOUS AND TRANSPLANTED LIVER (SPECIFIC AIM III). We are seeking to identify selected factors which may influence clinical application of mixed allogeneic chimerism, and to understand the liver as an immunologic organ.
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