The aim of this grant is to test the hypothesis that dendritic cell (DC) abnormalities might (1) be involved in the pathogenesis of ultraviolet-B (UVB) induced skin cancers and (2) be at least partially responsible for the immunologic dysfunctions of the Acquired Immunodeficiency Syndrome (AIDS). I will continue to further define the percentage, distribution and phenotypic characteristics of DC (1) in the skin and lymph modes (LN) of mice and UVB-induced cutaneous malignancies and (2) in the skin and LN of patients with AIDS, with AIDS-related complex (ARC) and with an enhanced risk for developing AIDS. Suitable control groups will be included throughtout. Epidermal sheets and cryostat tissue sections of skin and LN will be prepared and stained for a variety of DC surface antigens, including Ia (HLA- DR), using immunoperoxidase and immunofluorescent techniques. In addition, in situ mRNA hybridization will be used to detect the possibility that DC serve as a reservoir for HIV-1. Where appropriate, DC suspensions will be made from skin and LN and analyzed on a FACS 420 cytofluorograph; cytocentrifuge smears will also be prepared and stained as above. The functional status of the DC suspensions from LN and skin of tumor-bearing mice will be evaluated in the MLR. This can be done using T cells isolated from LN of these mice and from the blood of patients and assaying the ability of these T cells to proliferate (thymidine incorporation) and produce interleukin-2. The function of in vitro HIV-1-infected DC will also be assessed in the autologous MLR using T cells isolated from the peripheral blood of patients. Finally, the ability of a variety of lymphokines (interleukin-2, interferon-delta, tumor necrosis factor) to modulate any observed defects in cell surface expression and/or antigen-presentation noted in the functional DC studies will be examined. It is anticipated that these studies will lead to an increased understanding of the biology of DC, especially the inter- relationships among the various DC populations, in normal humans and mice. In addition, these experiments should provide an appreciation of the changes in the percentage, distribution, phenotype and functional properties of DC in patients with cutaneous malignancies, with AIDS, with ARC and with an enhanced risk for AIDS. Finally, data on the potential usefulness of a variety of lymphokines in the treatment of these disorders will be generated.
