HUMAN LYMPHOCYTE ACTIVATION--ROLE OF DENDRITIC CELLS

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Dendritic cells are a trace subpopulation of white blood cells. When antigens are presented on dendritic cells to the immune system, strong immune responses are induced. Methods have been developed to isolate dendritic cells from human blood, inflamed joints and skin. We use dendritic cells to study different aspects of the immune response in transplantation, arthritis, psoriasis, and resistance to tumors and infectious disease (influenza, AIDS). Our aims include: a) Develop monoclonal antibodies and DNA probes to cell surface and intracellular constituents of dendritic cells. b) Outline the range of inflammatory cytokines and cytokine receptors that are made by dendritic cells from blood and from diseased tissues. c) Clone T cells that may mediate autoreactivity in rheumatoid arthritis and psoriasis, and protective immunity in tumors, influenza, and AIDS. d) Study the transmission of a cytopathic infection with the AIDS virus from dendritic cells that have been exposed to the virus (HIV-1) to CD4+ T cells. Compare dendritic cells isolated from blood, skin, and inflammatory sites. Test the effect of different types of immune T cells and anti-HIV antibodies on this transmission. Generate HIV-specific immune T cells of both CD4 and CD8 subsets. Evaluate the effects of immune T cells on HIV-infected monocytes. e) Develop methods for generating large numbers of dendritic cells from immature progenitors, and use these to present antigens from tumors and infectious agents (influenza, HIV-1) to human T cells. f) Evaluate mechanisms whereby dendritic cells present superantigens to T cells, including attempts to identify superantigens that may be carried by dendritic cells in autoimmune disease. g) Evaluate in human allogeneic bone marrow chimeras the ontogeny and kinetics of dendritic cell engraftment, the role of dendritic cells in immune reconstitution, and the identification of dendritic cell progenitors and conditions supporting their growth. h) Use dendritic cells to generate antigen-specific cytolytic T lymphocytes (CTLs) to viral, tumor, and auto antigens.