AS101 ameliorates experimental autoimmune uveitis by regulating Th1 and Th17 responses and inducing Treg cells

J Autoimmun. 2019 Jun;100:52-61. doi: 10.1016/j.jaut.2019.02.006. Epub 2019 Mar 8.

Abstract

AS101 is an organotellurium compound with multifaceted immunoregulatory properties that is remarkable for its lack of toxicity. We tested the therapeutic effect of AS101 in experimental autoimmune uveitis (EAU), a model for human autoimmune uveitis. Unexpectedly, treatment with AS101 elicited Treg generation in vivo in otherwise unmanipulated mice. Mice immunized for EAU with the retinal antigen IRBP and treated with AS101 developed attenuated disease, as did AS101-treated recipients of retina-specific T cells activated in vitro. In both settings, eye-infiltrating effector T cells were decreased, whereas regulatory T (Treg) cells in the spleen were increased. Mechanistic studies in vitro revealed that AS101 restricted polarization of retina-specific T cells towards Th1 or Th17 lineage by repressing activation of their respective lineage-specific transcription factors and downstream signals. Retina-specific T cells polarized in vitro towards Th1 or Th17 in the presence of AS101 had impaired ability to induce EAU in naïve recipients. Finally, AS101 promoted differentiation of retina-specific T cells to Tregs in vitro independently of TGF-β. We conclude that AS101 modulates autoimmune T cells by inhibiting acquisition and expression of effector function and by promoting Treg generation, and suggest that AS101 could be useful as a therapeutic approach for autoimmune uveitis.

Keywords: AS101; Experimental autoimmune uveitis; Regulatory T cell; Th17 cell.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Disease Models, Animal
  • Ethylenes / pharmacology*
  • Mice
  • Mice, Transgenic
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Th1 Cells / immunology*
  • Th1 Cells / pathology
  • Th17 Cells / immunology*
  • Th17 Cells / pathology
  • Uveitis / drug therapy*
  • Uveitis / genetics
  • Uveitis / immunology
  • Uveitis / pathology

Substances

  • Ethylenes
  • ammonium trichloro(dioxoethylene-O,O'-)tellurate