Acute graft-versus-host disease and graft rejection remain two of the major complications following bone marrow transplantation. Despite chemoprophylaxis posttransplant for prevention of graft versus host disease, approximately 30% of recipients of HLA identical sibling transplant develop severe acute graft-versus-host disease. Among patients with leukemia, who have received total body irradiation and cyclophosphamide, the incidence of graft rejection following a non-T-cell depleted transplant is less than 1% for recipients with HLA matched marrow and 5% for recipients of HLA mismatched family member marrow. In contrast, graft rejection has been observed following every method of T- cell depletion and the incidence ranges from 10-30% among recipients of HLA identical to as high as 50-75% among recipients of HLA nonidentical marrow. T cell immunity to minor histocompatibility (minor H) antigens is presumed to be responsible for the development of graft rejection and graft-versus-host disease following bone marrow transplantation from an HLA identical sibling. The minor H antigens are thought to be endogenous polymorphic peptides presented by MHC molecules for recognition by T cells. Their role in clinical marrow transplantation has been suggested by the identification of MHC restricted cytotoxic lymphocytes in patients with prior sensitization to blood products or in patients experiencing acute graft-versus-host disease post bone marrow transplantation. The role of minor antigens as targets for graft rejection has not been as clearly delineated. The overall objective for this project is to identify the target antigen(s), i.e. the MHC restricted minor histocompatibility antigens, for marrow graft rejection or acute graft- versus-host disease following an HLA identical sibling transplant. In addition, we propose to utilize MHC restricted cytotoxic T cell lines and clones derived from patients with graft rejection/graft failure or acute graft-versus-host disease to identify, characterize and isolate the peptide(s) constituting minor H antigen(s). It is our hope that identification and isolation of the minor H antigens ultimately will allow for selection of a minor H antigen matched related or unrelated donor among donors who are HLA identical to the patient or permit identification of patients who are at high risk for either graft rejection or acute graft-versus-host disease following as HLA identical transplant. Pretransplant determination of minor H antigen matched or mismatched donor-recipient pairs would permit clinicians to select the most appropriate graft versus host disease or graft rejection prophylaxis approach for patient management.
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