Role of IL-10 in the Regulation of Autoimmune Disease

Yale University, New Haven CT

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Abstract

It has become clear that immune regulation is a major mechanism which prevents the development of autoimmunity. Indeed, human individuals that are genetically identical to autoimmune patients rarely develop diseases that afflict their siblings. Immune regulation can be defined by regulatory or suppressor T cells and the regulatory cytokines TGF-b and IL-10. The relationship between these important cytokines and the cells that regulate the immune response is not clear. Moreover, the mechanisms whereby these cytokines act on other cell types, through well characterized in vitro, have not been connected mechanistically to the regulation of two autoimmune diseases, EAE and IBD. We will first generate a novel reporter mouse that will use the eGFP marker to visualize IL-1O production during the autoimmune response. Specifically, in IL-10 knock-in mouse will be generated wherein an IRES-eGFP cistron is placed downstream of the IL-10 gene. This will be part of the same IL-10 transcription unit and most cells expressing IL-10 will express eGFP. Mice carrying this reporter knock-in will be used to show when and where IL-10 is expressed and what the consequence of immune regulation are on IL-10 gene expression during the development and resolution of EAE and IBD. To elucidate the cell types that are the target of IL-10 mediated inhibition of immune responses we will employ transgenic mice in which a dominant negative IL-10 receptor is directed to either T cells or various antigen presenting cells/inflammatory cells. Thus, the CD4 promoter will be used to direct the synthesis of the dnIL-10R1. T cells from these transgenic mice are non-responsive to IL-10 and therefore autoaggressive T cells cannot be inhibited by IL-10. Similarly, if IL-10 acts to induce regulatory T cells this will not be possible in mice that carry this transgene. We will investigate both possibilities for the function of IL-10 in a similar vein, we will generate transgenic mice in which the dnIL-10R1 is expressed on dendritic cells, macrophages and B cells by using different promoters to direct the synthesis of the transgene. Using these mice, we will elucidate which antigen presenting cells or inflammatory cells are the target of IL-10 mediated signaling during the development and resolution of the two diseases, EAE and IBD. In collaboration with Dr. Janeway, we will also use our approaches to elucidate the role of IL-1O in the protection provided by the therapeutic vaccine being studied in the role of IL-10 in that system. We believe that these approaches should substantially advance our understanding of the role of IL-10 in immunoregulation and autoimmune disease.