Autoimmune diseases result from the effect of anti-self T lymphocytes which destroy tissues. In IDDM, the pancreatic beta cells become the target of immunological attack, and their destruction leads to a paucity of insulin and the inability to regulate glucose homeostasis. T cell responses are subject to regulation by cytokines. One group of cytokine molecules is clearly associated with the enhancement of cell mediated immune responses leading to autoimmunity while another group may be associated with protection from disease. A further understanding of the actions of protective molecules may provide important information for the possible role of cytokines in therapy of autoimmune diseases. The investigators have produced a murine model where the localized expression of one protective cytokine, Interleukin-4 (IL-4), prevents inflammation and diabetes in the NOD mouse, a spontaneous model of human autoimmune diabetes. Preliminary characterization indicates that the pancreatic expression of IL-4 in NOD mice induces immunological tolerance to pancreatic islets in vivo, and lymphocytes form this transgenic mouse are not able to induce disease when transferred into a syngeneic recipient. The proposed experiments seek to understand the mechanism of the observed protection from disease by localized expression of IL-4, and test hypotheses which could reveal the mechanism. One likely explanation is polarization of the anti-islet T cell response. Therefore, they will test the hypothesis that polarization of T lymphocytes toward the Th2 phenotype accounts for the observed protection. Another possibility is that IL-4 affects effector cell survival or trafficking. The hypothesis that changes in cell migration and effector cell survival will be tested. Lastly, they will determine whether the protection is mediated by tissue antigen presenting cells, which under the influence of the cytokine, assume altered T cell priming capabilities. The experiments proposed will allow an understanding of the mechanism of the observed protection andy help us to consider the possibility of IL-4 based therapy for IDDM.
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