The B Subunit of Escherichia Coli Heat Labile Enterotoxin Prevents Autoimmune Ocular Inflammation, but Promotes Differentiation of Th17 Cells in Established Disease

Abstract

Purpose: : To investigate the efficacy of B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease.Background: Murine experimental autoimmune uveoretinitis (EAU) is an animal model of autoimmune disease of the eye initiated by activation of ocular antigen-specific Th1 and Th17 CD4⁺ T cells, which stimulate resident and infiltrating macrophages, inducing retinal damage. EtxB has been shown to be a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, either by promoting Th2 responses or enhancing regulatory T cell activity.

Methods: : EAU was induced in B10.RIII mice by immunisation with peptide of hIRBP_161-180. Disease severity was measured by clinical and histological assessment and functional responses of macrophages and T cells were assessed both in vivo and in in vitro co-cultures. EtxB was administered intranasally to groups of mice either 3 days before or 3 days after EAU induction.

Results: : Pre-immunisation treatment with EtxB protected mice from the induction of EAU, limiting both the number and the activation status of infiltrating immune cells in the eye. Treatment following EAU induction did not alter disease course, despite suppression of IFN-γ. Although EtxB treatment of in vitro co-cultures of T cells and macrophages increased IL-10 production, EtxB treatment in vivo increased the proportion and numbers of IL-17-producing CD4⁺ cells infiltrating the eye.

Conclusions: : EtxB pre-immunisation protects mice from EAU induction by inhibiting Th1 responses, but the resulting reduction in IFN-γ responses modulated by EtxB does not effect infiltration or structural damage in established EAU. In established inflammation, Th17 responses predominate. These data highlight the critical importance of the dynamics of T cell phenotype and infiltration during EAU when considering immunomodulatory therapy.

Keywords: immunomodulation/immunoregulation • inflammation • uveitis-clinical/animal model