The broad objective of this proposal is to learn how T lymphocytes and keratinocytes influence each other's functions in the setting of immune mediated inflammatory conditions of skin. The underlying hypothesis for the project is that T cells and keratinocytes can regulate each other's activities based on the actions of the cytokines each cell type secretes. The bidirectional interplay of T cell and keratinocyte cytokines will be studied using a unique in vivo model employing human skin grafted onto Rag-2 deficient mice which have no functional T or B lymphocytes. Human T cells specific for allo-MHC gene products or defined foreign proteins will be adoptively transferred into skin-grafted mice, and T cell dependent immune responses in the graft will be examined by histopathological, immunohistochemical , and in situ hybridization techniques.
The specific aims are: 1. To determine the role of keratinocyte inflammatory cytokine expression in human lymphocyte mediated immune responses in human to mouse skin xenografts. The pattern and timing of keratinocyte inflammatory cytokine expression will be descriptively analyzed in the setting of T cell mediated inflammatory responses. Cytokines and cytokine antagonists will be administered in an attempt to alter the phenotype of the immune response. 2. To determine the role of keratinocyte cytokines on selective recruitment of T cell subsets to sites of immune mediated skin inflammation. The functional phenotype of skin graft infiltrating T cells, including the T cell cytokine secretory profile, will be examined at different times and correlated with keratinocyte cytokine production. The effects of adding excess exogenous cytokine produced by keratinocytes, or cytokine antagonists, on the surface and functional phenotype of T cell infiltrates will be examined. This Pilot and Feasibility Study will test the usefulness of a new in vivo model to study T lymphocyte mediated inflammatory diseases of the skin. If the model proves successful, it will provide a unique opportunity to safely study therapeutic approaches to immunopathological processes in human skin.
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