Five years ago, we reported the identification and characterization of several regulatory T-cell epitopes (now called Tregitopes) that were discovered in the heavy and light chains of IgG (De Groot et al. Blood, 2008). When added ex vivo to human PBMCs, these Tregitopes activated regulatory T cells (Tregs), increased expression of the transcription factor FoxP3, and induced IL-10 expression in CD4+ T cells. We have now shown that coadministration of the Tregitopes in vivo, in a number of different murine models of autoimmune disease, can suppress immune responses to antigen in an antigen-specific manner, and that this response is mediated by Tregs. In addition we have shown that, although these are generally promiscuous epitopes, the activity of individual Tregitope peptides is restricted by HLA. In this brief report, we provide an overview of the effects of Tregitopes in vivo, discuss potential applications, and suggest that Tregitopes may represent one of the “active pharmaceutical ingredients” of IVIg. Tregitope applications may include any of the autoimmune diseases that are currently treated almost exclusively with intravenous immunoglobulin G (IVIG), such as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and Multifocal Motor Neuropathy (MMN), as well as gene therapy and allergy where Tregitopes may provide a means of inducing antigen-specific tolerance. 1. Introduction In recent work [1], we identified an important trigger for the expansion and activation of regulatory T cells (Tregs), which are T cell epitopes contained in the framework sequences of immunoglobulin G (IgG). Further studies suggested that these peptides were natural T regulatory cell epitopes (Tregitopes) that may explain, at least in part, the tolerance-inducing effects of polyclonal immunoglobulin when delivered as a therapy (intravenous immunoglobulin or IVIG). The defining characteristics of Tregitopes were that they (i) stimulated CD4+, CD25hi, and FoxP3+ T cells; (ii) suppressed effector T-cell responses to other antigens in suppressor assays; and (iii) were associated with T cell IL-10 production in vivo and in vitro [1]. Subsequently, Tregitope peptides have been shown to replicate the effects of IVIG in mouse models of Multiple Sclerosis (EAE), allergy, and asthma, confirming our primary observations [2–4]. Consistent with their intrinsic immunosuppressive property, Tregitope peptides administered in complete or incomplete Freund’s Adjuvant (CFA or IFA) suppress immune responses to coadministered antigens, but are not immunogenic per se [5]. While
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