ACCESSORY MECHANISMS IN HUMAN LYMPHOCYTE ACTIVATION

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The overall aim of this proposal is to investigate the accessory functions involved in human lymphocyte activation, antigen recognition and immunoregulation. The direction of these studies will be focused on three distinct, yet related, aspects of accessory function. First, studies initiated on the immunobiology of Interleukin-1 (IL-1) or leukocytic pyrogen (LP) will be extended by investigating ways to more precisely identify the structure and function of IL-1/LP. The potential clinical relevance of this work is profound in that the immunophysiologic responses to fever are potentially related to these findings. Second, in vitro models of human T cell antigen recognition utilizing T cells from insulin reactors amongst patients with insulin dependent diabetes mellitus (IDDM) will be established. We anticipate the development of these in vitro insulin specific T cell clones or T-T hybridomas from patients with IDDM whose T cells react vigorously to insulin. The T cell clones or T-T hybridomas will be used to precisely and accurately define the contribution of specific antigenic epitope presentation in humans. The clinical relevance of this project is related to the identification of insulin reactors and the serial study of the immunobiology of antigen specific suppressor T cells in humans with IDDM. In addition, this approach could yield important clinially useful information regarding antigen specific tolerance, so that potentially immunotherapy with altered insulin fragments may lead to abrogation of complications (T cell reactivity, antibody formation) while preserving hormone action. Finally, the accessory functions of human endothelial cells (EC) will be studied so that an understanding of potential EC-T cell intereactions in vitro could be achieved. The implications of these studies for patients with vasculitis is self-evident and these in vitro EC-T cell models may provide a means for modulating immune responsses in vasculitis.