Acute and chronic graft versus host reaction (GVHR) are the primary cause of morbidity and mortality after allogeneic and semi-syngeneic bone marrow transplantation in humans. We are studying the genes which influence both of these syndromes in a mouse model. Acute GVHR is seen in unirradiated (B6 X D2)F1 recipients of about 60 million parental spleen cells from B6 but not D2 mice. Using standard genetic approaches, we have identified a single dominant non-H-2 gene from B6 mice which promotes acute bone marrow suppression in the recipient. We are currently attempting to identify genetic linkage using recombinant inbred (RI) mice. This gene is fully expressed by B6 but only partially expressed by B10 donor mice and behaves as a dominant gene in (B6 X B10)F1 donors. Autoimmune phenomena are observed during chronic GVHR induced in (B6 X D2)F1 recipients of D2 parental cells. We have identified a single recessive non-H-2 gene in D2 mice which promotes the production of autoantibody by the recipient with specificity for endogenous xenotropic envelope antigens. Progeny testing of (B6 X D2)F1 X D2 mice has confirmed this hypothesis and linkage studies will soon be carried out in RI mice.