This is an integrated clinical and laboratory program which will examine the determinants of human cell mediated immunity in the context of AIDS. Model studies of Leprosy and Leishmaniasis are evaluating the factors responsible for the emigratory, vascular and maturational responses of human skin to delayed type antigens. Cellular dynamics, structural and functional phenotypes of dermal and epidermal populations are considered. The role of the recombinant lymphokines gamma- IFN and IL-2 in this milieu as well as the resulting monokines IL- 1, TNF, arachidonate metabolites and O2 intermediates are under investigation. The selective binding, emigration and biochemical dialogues between mononuclear cells and endothelial cells (EC), interacting on defined substrates leads to a mutually cooperative state. In contrast, PMN when stimulated with TNF and LT while attached to EC, lead to a massive respiratory burst and target cell damage. The alpha-keto acid pyruvate is an important, secretory scavenger of H2O2, protecting targets from oxidative attack. The role of these reactions in TNF induced hemorrhagic necrosis and lethality is under study. Dendritic cells (DC) are central, accessory cells for primary T cell responses. They are particularly enriched in the joint fluids of patients with rheumatoid arthritis (RA) where they cluster with T cells. These T cells will be cloned and their restriction to disease associated HLA-DR4 antigens studied. The secretory activity of monocytes and DC obtained from joints of patients with RA is being examined. The role of LFA associated adhesion promoting receptors during monocyte, T cells and DC interactions is under study at the biochemical and ultrastructural level (immunogold labeling). The natural ligands of these important receptors include surface LPS of gram negative bacteria. Purification and cloning of a novel lymphokine required for human CTL differentiation is underway. The preparation of specific antibodies will allow sensitive bioassays and blocking experiments. CTL granulogenesis will be followed by quantitating the biosynthesis of perforin 1 and the serine esterase. A new clinical program at the Rockefeller University Hospital will evaluate the basic immunological defects in patients with AIDS. Longitudinal analysis of the functions of mononuclear phagocytes, DC, T cell subsets, Langerhans cells will include surface receptors, endocytosis, intracellular killing, secretory repertoire, accessory function, tissue emigration and DTH reactivity. Experiments will characterize the presence of the viral genome in patients' cells and establish their permissiveness to infection in vitro.
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