We propose to extend preliminary observations on the role of minor non- DLA histocompatibility antigens in transfusion-induced sensitization and subsequent marrow graft rejection in a preclinical dog model. As reviewed in projects 4 and 5, transfusion-induced sensitization and graft rejection have been major complications in marrow transplantation for severe aplastic anemia, problems which have only partly been resolved by more intensive immunosuppressive conditioning programs. We have observed that sensitization to blood products from DLA-identical littermate marrow donors can be prevented by gamma irradiation of the blood products, thereby avoiding subsequent marrow graft rejection. We propose studies aimed at extending these observations to transfusions from unrelated donors, disparate not only for non-DLA but also for DLA histocompatibility antigens. Furthermore, we propose to carry out repeated transfusions from phenotypically DLA-identical unrelated donors before marrow transplantation from donors. This will enable us to evaluate whether there are additional as yet unrecognized transplantation antigens in linkage with DLA. We also would like to determine whether treatment by gamma irradiation induces true tolerance or merely results in lack of sensitization. The mechanism by which gamma irradiation achieves the avoidance of sensitization, e.g. interference with viability of the antigen-presenting cell, or with antigen processing or presentation, and the cell type affected by gamma irradiation, will also be studied. Results from these preclinical studies are likely to lead to recommendations for clinical transfusion practices which ultimately will make the treatment of patients with severe aplastic anemia by marrow transplantation more safe. Avoidance of transfusion-induced sensitization would enable clinicians to develop less intensive conditioning regimens with a resultant decrease in short- and long-term toxicities.
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