Tregitopes regulate the tolerogenic immune response and decrease the foetal death rate in abortion-prone mouse matings

Abstract

The imbalance in immune tolerance may cause the variety of reproductive failures. An intravenous immunoglobulin infusion (IVIg) therapy is used to improve the live birth rate in women suffering from recurrent pregnancy loss, recurrent spontaneous abortions and recurrent implantation failures. However, the results of IVIg studies are still inconclusive as IVIg infusion in women suffering from pregnancy loss is sometimes ineffective. One of the mechanisms of action of this treatment is inhibition of B cells differentiation and expansion of Tregs and secretion of interleukin 10. It was proposed that immunomodulatory effects of IVIg may be attributed to tregitopes - self-IgG-derived epitopes present in the structure of immunoglobulins. Similarly to IVIg, tregitopes cause the expansion of Tregs and secretion of antigen-specific effector cytokine response. Here, we studied whether the administration of mouse tregitope 167 and/or 289 can prevent abortions in mouse abortion-prone mouse matings. We revealed that tregitopes reduce the foetal death rate. This may be driven by observed higher pool of peripheral Tregs, increased production of IL-10 by Tregs and Bregs and/or maintaining the tolerogenic phenotype of antigen-presenting cells. We believe that our findings may indicate a potential alternative to IVIg for therapeutic intervention in case of pregnancy failures.

CD91 Derived Treg Epitope Modulates Regulatory T Lymphocyte Response, Regulates Expression of Costimulatory Molecules on Antigen-Presenting Cells, and Rescues Pregnancy in Mouse Pregnancy Loss Model

“…Additionally, treatment with SGS increased the number of implantation sites, which suggested that SGS can potentially rescue pregnancy in abortion-prone mice. Previously, we had demonstrated that known tregitopes decreased the occurrence of abortion in abortion-prone mice [ 16 ]. SGS may rescue pregnancy in abortion-prone mice by promoting the expansion of Tregs and regulating the levels of serum cytokines.…”

“…The blood samples collected from the pregnant mice were centrifuged at 10,000× g and 4 • C for 10 min, and the serum samples were stored at −80 • C. The concentrations of TGFβ1, IFN-γ, IL-2, IL-4, and IL-10 were evaluated elevated using the murine Ready-SET-Go! Kit (eBioscience, USA) as previously described [16]. First, the wells of the microplates were incubated with anti-TGFβ1, anti-IFN-γ, anti-IL-2, anti-IL-4, and anti-IL-10 antibodies overnight at 4 • C. Next, the plates were blocked for 1 h at room temperature (RT).…”

“…Previous studies have demonstrated that the adoptive transfer of regulatory B and/or T cells can reverse the high abortion rate in abortion-prone mice if the cells are administered immediately after fertilization [ 12 , 15 ]. Recently, we demonstrated that the early administration of T regulatory cell epitopes (tregitopes), which are short peptides found in the light and heavy chains of human and mouse immunoglobulins (IgGs), decreased the incidence of abortion in abortion-prone mice [ 16 ]. These tregitopes may bind to the major histocompatibility complex (MHC II)-binding groove, and this complex is presented to Tregs, which results in the activation and proliferation of Tregs.…”

Tregitopes Improve Asthma by Promoting Highly Suppressive and Antigen-Specific Tregs

“…Since their identification in 2008 by De Groot and Martin, a wide range of mouse studies have explored the antiinflammatory properties of IgG Tregitopes in a range of preclinical models. Potential applications that have been evaluated include Tregitope treatment for Type I diabetes (8), cockroach induced-allergy (9), experimental colitis (10) and pregnancy loss (11). Several studies have demonstrated Tregitope's ability to induce tolerance by activating and expanding Treg in vitro and in vivo.…”

“…Several studies have demonstrated Tregitope's ability to induce tolerance by activating and expanding Treg in vitro and in vivo. Furthermore, many studies show a local and systemic increase in transcription and translation of immunosuppressive cytokines such as TGFb and IL-10 upon treatment with IgG Tregitopes (9,11).…”