This is an application for competitive renewal of Grant AI-18471. The long-term objectives of this proposal are to elucidate mechanisms of tuberculin-specific immunosuppression in human tuberculosis and to examine the basis for the association between HLA-DRw8 and active pulmonary tuberculosis.
The specific aims are: 1) to examine the phenotype, immunoregulatory function and selected mediators of adherent mononuclear cell subpopulations in tuberculosis; 2) to characterize regulation of tuberculin responses by nonadherent lymphocytes in tuberculosis by determining the phenotype and state of activation of suppressor lymphocytes; and 3) to explore the basis for genetically-determined susceptibility to tuberculosis by establishing levels of response to mycobacterial antigens and patterns of immunoregulation in patients with and without the HLA-DRw8 phenotype and their families. The methodology for achieving these goals involves techniques of cellular immunology (characterization of phenotypes and state of activation/differentiation of blood mononuclear cells by reactivity with monoclonal antibodies and indirect immunofluorescence/cytofluorometry, and cell cycle analysis; characterization of suppressor cell function by cell separation and reconstitution protocols, and assay of antigen-induced blastogenesis and production of interleukin-2; development of T cell clones), immunochemistry (immunoabsorbent chromatography using monospecific and monoclonal antibodies to study the role of interleukin-1 in immunosuppression by adherent mononuclear cells) and immunogenetics (association of HLA-types with tuberculosis, family studies, linkage analysis). This is a health- related project.
