174 : Induction of antigen-specific regulatory T cells as a therapy for autoimmune diseases

Abstract

Regulatory T (Treg) cells play a fundamental role in suppressing excessive inflammatory responses to pathogens and in maintaining peripheral tolerance to self-antigens. A breakdown in self tolerance or defect in Treg cells can result in uncontrolled effector T cell responses to self antigens and the development of autoimmune disorders. Conversely, approaches that enhance the generation of autoantigen-specific Treg cells have potential for the prevention or treatment of autoimmune disease. The induction of Treg cells is enhanced by anti-inflammatory cytokines, with IL-10 and IL-27 promoting the generation of IL-10 secreting Tr1-type Treg cells and TGF-β with retinoic acid inducing peripheral conversion of naïve T cells into conventional CD4+CD25+Foxp3+ Tregs. Finally, certain immunomodulatory molecules form bacteria or helminth parasites can activate dendritic cells (DCs) to promote induction of Treg cells in vivo. The aim of this study was to examine the capacity of IL-10, TGF-β or IL-27 or pathogen-derived molecules that induce IL-10 and TGF-β and suppress IL-12 from DCs to act as adjuvants to promote the induction of Treg cells against self antigen and thereby prevent or reduce the clinical course of an autoimmune disease in a mouse model. The results to date have shown that TGF-β enhanced survival of CD4+ T cells and suppressed IFN-γ production, but upregulated expression of Foxp3, and this was enhanced by IL-10 and IL-27. In vivo studies demonstrated that a low molecular weight fraction from the helminth parasite, Fasciola hepatica, enhanced the frequency of Foxp3+ Treg cells, whereas supernatant from homogenates of liver fluke enhanced IL-10-seceting T cells. These helminth-derived fractions are currently being tested as adjuvants to induce Treg cells against the self antigen, MOG, and to prevent experimental autoimmune encephalomyelitis.