Psoriasis is a common skin disease characterized by distinctive histological abnormalities, including excessive proliferation of epidermal keratinocytes (KCs), and an influx of immunocompetent cells. The pathophysiological basis for these multicellular abnormalities is unclear. Clearance of lesions following cyclosporin A and anti-CD4 mAb therapy implicate T cells in the pathogenesis of psoriasis. Adhesion molecules have also been postulated to play an important role in coordinating KC:T lymphocyte intercellular associations. A substantial amount of new data was integrated into a coherent cytokine network model for psoriasis, which emphasized the importance of KC:T lymphocyte interactions. Recently, it has been discovered that gamma interferon (IFN-gamma treated KCs can function as immunologically-competent accessory cells inducing resting T cell proliferation by various stimuli, including bacterial-derived superantigens (SA). This immune reaction between cytokine-activated KCs and T cells was primarily dependent on a pair of adhesion molecules (lymphocyte function associated antigen-1; LFA-l, and intercellular adhesion molecule-I; ICAM-1), because pretreating T cells with anti-LFA-1 mAb or KCs with anti-ICAM-1 mAb significantly inhibited the response involving SA. The principle objective of this grant is to further understand the pathogenetic role of specific adhesion molecules in mediating KC-T cell interactions relevant to psoriasis, as well as to extend our findings regarding bacterial-derived SA that contribute to altered KC-T cell reactions. To address these pathophysiological aspects of psoriasis we propose the following: I) identify the appearance of cytokines responsible for the expression of adhesion molecules by inducing psoriatic lesions with repeated tape stripping; 2) use immunostaining to detect adhesion molecules combined with a functional ex vivo adhesion assay to measure T cell binding 3) determine the molecular basis for SA binding to psoriatic KCs, the role of streptococcal-derived SA in T cell activation with fresh and cultured psoriatic KCs, and characterization of the T cell cytokine production profile with emphasis on IL-10. Thus, in Aims l and 2, we can determine how injury of the skin is translated into the production of cytokines that induce adhesion molecules which are important in the recruitment of circulating T cells into the epidermis. Once in the epidermis, Aim 3 is designed to determine the immunological consequences of juxtaposition of cytokine-activated KCs with T cells with particular emphasis on the role of LFA-1/ICAM-1. This line of inquiry addresses an important immunological component of psoriasis involving KC:T cell interactions. It will foster emergence of therapeutic strategies that can be targeted at critically important molecules and cytokines that mediate adhesive interactions in the skin. Such new therapies are needed for this chronic and difficult to treat skin disease.
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