Autoimmune diabetes results from inflammatory destruction of the pancreatic beta cells. The final stage hyperglycemia represents the ability of autoreactive T lymphocytes to overcome natural counter- regulatory forces that maintain tissue homeostasis. In this proposal we will study two interesting and potentially important counter-regulatory forces. The first mechanism under investigation is the potential of the infiltrated pancreas to proliferate and regenerate. This process can occur in several animal models and we present evidence that islet cell regeneration can be induced by factors elicited from activated T cells. In this proposal, we plan to determine the extent of duct cell proliferation and islet regeneration following infiltration of islet reactive T cells. We will test the hypothesis that T cells have the ability stimulate the proliferation of ductal cells and their differentiation into islet cells. This will be approached using a transgenic model where the islet antigen is defined and specific subcategories of effector cells can be studied for their ability to induce pancreatic proliferation in vivo. The second counter-regulatory mechanism we propose to study is the ability of localized cytokines to induce immune deviation and prevent inflammation and islet destruction. We present compelling preliminary data to support the notion that this can occur in the NOD mouse. To study this process in a more defined system we will use the targeted transgenic models where the expression of regulatory cytokines in islets can affect the destruction induced by antigen specific CD4 and CD8 T cells. These experiments will allow us to understand the mechanism of this observed immune deviation in vivo and the conditions that T cells can be influenced. These latter experiments will utilize the talents of all of the investigators in this program, and should allow an understanding of the localized regulation of inflammatory cells within islets in vivo. The results from these studies could point to new opportunities for therapeutic intervention.
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