IN VITRO STUDIES OF T-CELL UNRESPONSIVENESS

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DESCRIPTION (adapted from investigator's abstract and/or aims): The major portion of the study is based on the applicant's previous work demonstrating that coincubation of Ia+ murine keratinocytes with syngeneic T cell clones results in prolonged antigen specific T cell tolerance. Although the mechanism by which "aberrant" accessory cells produce T cell anergy is not completely understood, it apparently is due to their inability to provide an as yet uncharacterized second signal. Production of clonal anergy by presentation of antigen on "aberrant" accessory cells appears to be operative in mice in-vivo as well. Thus, if such a method of T cell unresponsiveness induction could be produced in humans, it would have important ramifications for the treatment of T cell mediated hypersensitivity diseases such as allergic contact dermatitis. While human T cell tolerance has been produced in humans before, there have been no studies to determine whether clonal anergy can be produced in human T cells. This is important since there are several mechanisms (suppressor T cell, clonal deletion, clonal anergy) by which T cells can be made unresponsive. The three specific aims propose to study the immunobiology of human T cell clonal anergy, to examine the phenotypic and functional changes in T cells associated with its induction, and to determine whether anergic T cells have abnormalities in their activation pathways. Establishment of such an in-vivo model of T cell unresponsiveness should provide the theoretical basis for attempts to induce unresponsiveness in-vivo in patients with allergic diseases.