Vascularized bone grafts are successful in compromised hosts and host beds, such as are present following chemotherapy, immunosuppression or radiation therapy. Because of this, there is likely to be increasing clinical demand for vascularized bone grafts which can only be met by using allogeneic bone. Our previous research has shown that vascularized autografts are superior to nonvascularized bone grafts; the immunogenicity of vascularized allografts affect their incorporation; and immunosuppression enhances the biology of a maximally immunogenic graft. The proposed research plan is an extension of these observations. Major histocompatibility antigen (MHC) matched and mismatched vascularized allografts in dogs receiving cyclosporin for an extended, but finite, period will be studied by mechanical, morphologic and metabolic techniques. The early cellular response to MHC matched and mismatched grafts will be defined and correlated with graft biology to understand the systemic and local immunological rejection process, and to provide a basis for comparison with transplants of parenchymal organs. Specific methods of reducing vascularized allograft immunogenicity, that is gamma and ultraviolet radiation, will be evaluated. The mechanical, morphological and metabolic properties of MHC-mismatched vascularized allografts immunologically modified by these methods will be studied at 3 and 6 months post- transplantation. The methodologies used in our studies have provided significant correlations between tissue antigen compatibility, graft strength and turnover, and bone formation. New additional analytical methodologies will further extend our understanding of bone transplantation biology. Specifically histomorphometric analysis of the cancellous bone and bone marrow, DNA """"""""fingerprinting"""""""" of graft cells to identify their origin, and functional assays of the local and systemic immune response to allografts will provide important data to understand the complex mechanisms of the host response to vascularized bone allografts. These analyses will establish a comprehensive perspective of the critical parameters determining the fate of a vascularized bone allograft. Specific protocols, based on this work, could be developed for useful clinical applications.
