Mycobacterial and other chronic infections of man may be associated with depressed delayed hypersensitivity. This proposal uses the scientific disciplines of immunology and biochemistry to examine active immunosuppressive mechanisms manifest in patients with recently diagnosed tuberculosis which may contribute to systemic anergy. Particular emphasis is placed on the role of suppressor macrophages and suppressor lymphocytes in specifically limiting T-lymphocyte responses to antigens derived from the causative organism. Blood moncytes and lymphocyte populations and subpopulations are purified and characterized in patients and healthy control subjects. The cellular components producing suppression are defined by evaluating the effects of depletion and reconstitution of specific cell lines on the functional assays of antigen-induced 3H-thymidine incorporation and lymphokine production. Allogeneic cell mixing experiments between tuberculosis patients and HLA-DR matched healthy tuberculin-reactors will permit confirmation of suppressor activity of particular macrophage and lymphocyte subsets. Once supperssor cells have been identified, basic biochemical and functional attributes of such cells potentially related to suppression will be studied. The expression of Ia antigens on the macrophage surface, cytotoxicity for tumor lines and production of putative mediators of suppression will be evaluated. The contribution of plasma factors to antigen-specific and nonspecific immunosuppression will be assessed with particular attention to the role of immune complexes and effects directed through suppressor cells. The long-term objectives of this project are to elucidate mechanisms of immunosuppression in chronic infections of man. Such insights could prove useful in formulating new strategies for prevention and treatment of tuberculosis and mignt have important ramifications for immunoadjuvant therapy of tumors. Since recent studies have questioned the efficacy of BCG immunization and tuberculosis remains a tremendous world-wide health problem, this project is health-related. Moreover, tuberculosis provides an excellent model for the study of antigen-specific immunosuppression which may be relevant to other chronic infections of man, and could predispose to or accelerate progression of disease.
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