Role of Dendritic Cells in Cutaneous Malignancy and AIDS

Belsito, Donald

Abstract

My objective is to test the hypothesis that dendritic cell (DC) abnormalities might (1) be involved in the pathogenesis of multiple cutaneous malignancies in humans and in ultraviolet-B (UVB) induced skin cancers in mice and (2) be at least partially responsible for the immunologic dysfunctions of the Acquired Immunodeficiency Syndrome (AIDS). First, I plan to define the percentage, distribution and phenotypic characteristics of DC (1) in skin of patients with multiple cutaneous malignancies; (2) in the skin and lymph nodes (LN) of mice with UVB-induced cutaneous malignancies and, (3) in the skin, LN and blood of patients with AIDS, with AIDS-related complex (ARC) and with an enhanced risk for developing AIDS. Suitable control groups will be included throughout. 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 techniques. Where appropriate, DC suspensions will be made from skin, LN and blood 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 and from LN and blood of patients with AIDS, ARC and an enhanced risk for AIDS will be evaluated in the MLR. This can be done using T cells isolated from LN of these mice and patients and assaying the ability of these T cells to proliferate (thymidine incorporation) and produce interleukin-2. Finally, I shall exmaine the ability of a variety of lymphokines (interleukin-1, interleukin-2 and interferon-Gamma) to modulate any observed effects in cell surface expression and/or antigen-presentation noted in the functional DC studies. I anticipate 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.