Plasmacytoid dendritic cells, IFN-alpha, Th-1 response

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DESCRIPTION (provided by applicant): The proposed studies will address the hypothesis that a recently recognized cell type, the plasmacytoid dendritic cell (pDC), is an important participant in the production of cell-mediated (Th-1) immune responses in humans, pDC have been shown to be the principal producers of interferon (IFN)-alpha in the blood and tissues, and function as part of the innate immune system. It is believed that pDCs encounter microbial antigens in the periphery and migrate to secondary lymphoid organs, where they also influence naive T cells and other mononuclear cells in this microenvironment through the local production of IFN-alpha and other cytokines. This leads to a clonally selected, adaptive immune response characterized by the production of IFN-gamma and other cytokines that characterize the Th-1 response. To test the hypothesis, human subjects with either normal, reduced or undetectable numbers of circulating pDC will be immunized with a vaccine with which they have had no prior experience. Hepatitis A vaccine, an FDA-approved immunogen that is well tolerated and often clinically indicated in humans will be the vaccine of choice. The principal endpoint of the study will be the ability of the subjects' CD4+ T cells to generate IFN-gamma in vitro a month after receiving the immunization, compared to results at baseline. Numbers of CD4+ T cells, naive CD4+CD45RA+CD62L+ T cells, pDC number and function during the period of immunization, delayed-type hypersensitivity and serologic response to the immunogen, and clinical data will be monitored. Study subjects will include: healthy volunteers over a range of ages; patients with HIV infection being treated for severe immunodeficiency with active antiretroviral therapy; patients with HIV infection whose successful antiviral therapy is being stopped; patients with common, variable immunodeficiency; and patients or healthy volunteers undergoing courses of corticosteroids. In all these situations, there is a spectrum of pDC availability, while T cell numbers may be less affected. Our experience indicates that in some people in these categories, profound deficits of pDC number, IFN-alpha generation, or both will be present. Through the use of multivariate statistical analysis, the influence of functional, IFN-producing pDC on Th-1 immune responses will be defined.