The presence of oligoclonal or monoclonal T cell expansion is implicated in the pathogenesis of a variety of autoimmune and neoplastic diseases. In autoimmune and neoplastic diseases. In autoimmune diseases the autoreactive T cells may be directly responsible for tissue damage or they have be indirectly responsible by providing help to autoreactive B cells to secrete autoantibodies involved in tissue damage and/or dysfunction. The ability to down modulate specific autoimmune responses or to eliminate a specific neoplastic T cell clone, therefore, would be an important advance in the therapy of these chronic illnesses. We have determined the cellular and molecular interactions involved in the regulation of the human autoreactive T and B cell responses to DNA topoisomerase I (topo I), a major autoantigen in systematic sclerosis. Our studies indicate that the Recent data concerning the functional capacity of dendritic cells (DCs) to regulate immune responses indicate that mature DC are potent antigen- presenting cells (APC) by virtue of their high constitutive expression of co-stimulatory molecules, although certain DC subsets T cell hyporesponsiveness or tolerance. In the proposed studies we will examine two approaches to the regulation of autoreactive T cells specific for topo I: first, we plan to use dendritic cells as potent antigen presenting cells to induce to TCR-specific (anti-clonotypic) regulatory T cells directed toward the autoreactive topo I-specific T cells; second, we plan to use functionally immature (i.e. tolerogenic) DCs and genetically modified DCs to directly delete (through apoptosis) or energize autoreactive T cells. These studies will investigate approaches for elimination and/or energy of the autoreactive T cells in vitro and will serve as the basis for the development of novel targeted immunosuppressive therapy for SSc, other autoimmune diseases, and malignant T cell disorders.
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