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IVIG is frequently used in the ‘pre-conditioning’ regimens for higher risk transplants; its effects are attributed in part to induction of Tregs. We have identified regulatory T cell (Treg) epitopes, now known as Tregitopes, in IgG, the main component of intravenous immunoglobulin therapy (IVIg). Tregitopes provide one explanation for the expansion and activation of Treg cells following IVIg treatment. Tregitopes are peptides that exhibit high affinity binding to multiple human HLA Class II DR; they are conserved across IgG isotypes and mammalian species. In vitro and in vivo, for human PBMC and in animal models, Tregitopes activate Tregs. Studies to delineate the mechanism of action have shown that Tregitopes’ effects are very similar to IVIg in vitro. Here we demonstrate that Tregitopes induce Tregs to produce IL-10, leading to modulation of dendritic cell phenotype (down-regulation of Class II, CD80 and CD86 and up-regulation of ILT3), and describe the effects of Tregitopes in the ABM-TCR-transgenic skin transplantation model. The discovery of Tregitopes in IgG and other autologous proteins may contribute to improved understanding of the mechanism of action of IVIg and lead to the application of these powerful immunomodulators to improve transplantation success and suppress autoimmune disease, in the future.

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