Tregitope applications to tolerance induction in autoimmune diseases. (116.10)

Modulation of T cell responses may contribute to the design of new approaches for the treatment of autoimmune and inflammatory diseases. IVIG is one example of a therapy with this effect, and evidence is accumulating that Tregitopes (De Groot et al. Blood, 2008, 112:3303; natural T regulatory epitopes derived from IgG) provide beneficial immunomodulatory effects that parallel the effects of IVIG. In this presentation, we will provide evidence that Tregitope sequences derived from human IgG can reproduce immunomodulatory effects of IVIG in vitro and in vivo. In vitro, Tregitopes activate CD4+CD25+FoxP3+ natural regulatory T cells (nTreg). In vitro and in vivo, Tregitopes cause Tregs to produce IL-10, and to expand, and iTreg are induced. Induction and functions of nTregs have been examined in model systems such as D011.10 TCR transgenic mice, transplant of BM12 to C57BL/6, AAV-mediated gene transfer and EAE. Together, the data show that effector T cells, Th17, and Th9 cells are modified in the presence of Tregitopes. In OVA-induced allergic airway disease, we observed significant and reproducible expansion of Tregs in conjunction with decreased airway reactivity that was comparable to, if not greater than IVIG. We will provide additional unpublished evidence demonstrating the antigen specificity of tolerance induction using Tregitopes in conjunction with target antigens, and discuss the relevance of Tregitopes to the treatment of human immune-mediated diseases.