Tregitope peptides: the active pharmaceutical ingredient of IVIG?

Abstract

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.

Figure 1

Potential IgG (and Tregitope) Mechanisms of Action. From left to right, IVIG has been demonstrated to affect the cells of the innate and adaptive immune system including NK cells, macrophages, B cells, T cells, dendritic cells and other antigen presenting cells.

Figure 2

The broader relevance of Tregitopes is shown from left to right (counter clockwise). Tregitopes may be incorporated into protein drugs and monoclonal antibodies, to suppress antitherapeutic protein immune responses. Removing Tregitopes from autologous antigens would improve the ability of protein engineers to develop effective antibodies for target (autologous) antigens, and engineering Tregitope-depleted antibodies may improve the delivery of vaccine antigens. As described in this paper, Tregitopes may represent a new therapeutic option for autoimmune disease. In addition, Tregitopes could be used to suppress autoimmune diseases in companion animals.