The long term goals of this research are to understand the pathogenesis of cutaneous T cell lymphoma (CTCL) so that more effective therapy can be designed. CTCL is the most prevalent form of lymphoma today and its reported incidence is increasing. It is generally accepted that the epidermal microenvironment in CTCL is responsible for the accumulation of T cells within the epidermis. However EM and light microscopic studies from this laboratory have shown that a subset of epidermal dendritic cells bear markers for both CD1 (T6) and CD2 (T11) and for CD1, CD2, CD3, CD4, CD5 and CD7 antigens, respectively. Murine epidermis harbors a subset of dendritic T cells defined by the gamma/delta T cell receptor identical to that seen on immature thymocytes. Thymocytes normally mature into T cells in the thymic microenvironment. The hypothesis of this research states that in CTCL the epidermis becomes thymogenic, thereby inducing the differentiation and maturation of analogous immature dendritic cells into T cells in situ. The dysfunctional production of epidermal cytokines, many of which have been shown to have hematopoietic and lymphopoietic properties may be responsible for producing the thyrogenic environment. The heterogeneous population of dermal T cells in early CTCL could be a composite of migrating cells from the microvasculature and emigrating cells from the epidermis. The research strategies are as follows. The density and distribution of dendritic cells will be quantitated by morphologic means using immunolabelling for cell surface markers at the light and EM level as well as by FACS analysis of epidermal cell suspensions. The phenotypes of dendritic cells will be assessed in situ and in epidermal cell suspensions by immunolabelling simultaneously for 2 and 3 cell markers with colloidal gold probes. A panel of monoclonal and polyclonal antibodies will be used to identify the phenotypic subsets. The distribution and phenotypes of the epidermal and dermal T cell populations will be assessed in situ and in epidermal cell suspensions by immunolabelling with antibodies against the T cell receptor and T cell specific markers. Assays for activity of the different cytokines in CTCL skin, combined with localization of these molecules by immunolabelling and in situ hybridization with recombinant cytokines, will be correlated with the parameters of the dendritic and T cell populations. Based upon these profiles of cytokine activity and their related cell markers, in vitro conditions mimicking the in vivo conditions will be designed for cocultivation experiments with bone marrow stem cells and normal epidermal dendritic cells to determine whether T cell phenotypes can be induced in these cells. CTCL skin during activity, remission and relapse will be compared with skin from normals, pre-CTCL disorders and a variety of other inflammatory dermatoses.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Yale University
Schools of Medicine
New Haven
United States
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