MARROW TRANSPLANTATION: IMMUNE DYSFUNCTION IN GVH

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A murine model of graft versus host disease (GVH) due to minor histocompatibility antigens has been developed to investigate the mechanisms of the immunodeficiency syndrome (IDS) which is associated with GVH (GVH-IDS). Donor and recipient strains of mice were selected for serologic identity at the H-2 major histocompatibility complex and for mutual nonreactivity in MLC. Mice with minor antigen GVH develop a profound immunodeficiency characterized by depressed cellular and humoral immunity. We propose to use this model to determine the mechanism(s) of GVH-IDS and to develop therapeutic methods to prevent and/or treat the immunodeficiency of bone marrow transplant recipients. Complementary in vivo and in vitro antigen-specific assays will be used. The first step will be to characterize the immunodeficiency associated with minor antigen GVH in our murine model. Antigens selected for these studies include H-2 alloantigens to measure cell mediated immunity, H-2 antigens and the viral neoantigen bacteriophage OX 174 to measure T-dependent humoral immunity, and TNP-brucella abortus to measure T-independent humoral immunity. Once the IDS has been characterized, we will use in vivo adoptive transfer and mixing experiments to determine whether GVH-IDS is due to the loss of an immunologic function (T help, B cells, etc.) or due to an active suppressor mechanism. In vitro and in vivo assays will be used to identify the specific cell populations which mediate suppression or which, if replaced, will correct the IDS. Based on the results of these studies we will begin to develop methods to prevent or correct the GVH-associated IDS, including thymus transplantation, low dose irradiation, immunosuppressive drugs, in vivo treatment with monoclonal antibodies, and injection of thymic-replacing factors. These experiments will, we hope, significantly contribute to the improved immunologic reconstitution of bone marrow transplant recipients. (TT)