Dermal lymphocytic infiltrates, primarily of the CD4+ CD29+ T cell subsets, are characteristic features of psoriasis and may play an important role in the pathogenesis of the disease. We have investigated the mechanism(s) by which the memory T cells are selectively recruited into the lesion and showed that specialized endothelial cells capable of promoting the preferential adherence of human CD29+ T lymphocytes are present in the post-capillary venules of psoriatic dermis. The adhesion between lymphocytes and endothelial cells is energy- and calcium-dependent and is mediated by a novel tissue-specific lymphocyte receptor, designated as gplOO. The long term goal of the research project is to elucidate in humans the molecular mechanisms regulating lymphocyte adhesion to the specialized dermal endothelium of psoriatic plaques and to delineate the relationship of abnormalities in lymphocyte trafficking to disease processes. The primary objectives of this proposal are to define the molecular nature of the surface adhesion molecules which mediate lymphocyte-psoriatic dermal endothelial cell binding and to investigate the role of cytokines in the stimulation and modulation of the adhesiveness of psoriatic endothelial cells for lymphocytes. We will first test the hypothesis that the gplOO molecules are components of tissue-specific lymphocyte receptors that function to mediate mediate adhesion to psoriatic endothelial cells. This will be achieved by testing the ability of monoclonal anti-gp100 antibody to bind to T cells and block lymphocyte adhesion to psoriatic dermal endothelium and to correlate lymphocyte surface expression of gp100 to the capacity to selectively adhere to the endothelium. Using standard molecular biology approaches, we will then isolate and characterize cDNA clones that encode the lymphocyte receptors in order to analyze the relationship between the molecular structure and the adhesive function. We will perform expression cloning by immunoselection of COS1 cells transfected with the CD8 expression vector containing cDNA inserts prepared from CD29+ T cells. The immunoreactive cDNA will be transfected into immature lymphocytes that lacked the capacity to adhere to psoriatic endothelium and the capacity of the transfected cells to bind to psoriatic endothelium will then be examined.In parallel studies, we will also investigate the mechanisms whereby endothelial adhesiveness for lymphocytes are regulated. We will screen the responsiveness of cultured dermal microvascular endothelial cells from psoriatic plaques to such cytokines as tumor necrosis factor, gamma interferon, interleukin 1 and transforming growth factor beta. This integrated approach should provide a comprehensive understanding of the mechanisms regulating lymphocyte traffic into psoriatic lesions and may also provide insights on lymphocyte trafficking into other inflammatory dermatoses.
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| Cai, J P; Falanga, V; Taylor, J R et al. (1992) Transforming growth factor-beta differentially regulates the adhesiveness of normal and psoriatic dermal microvascular endothelial cells for peripheral blood mononuclear cells. J Invest Dermatol 98:405-9 |
