The B subunit of Escherichia coli heat-labile enterotoxin inhibits Th1 but not Th17 cell responses in established autoimmune uveoretinitis

¹ Department of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
² Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
³ University of Bristol - Bristol Eye Hospital, Division of Ophthalmology, Bristol, United Kingdom
⁴ University of Bristol - Bristol Eye Hospital, Division of Ophthalmology, Bristol, United Kingdom; Department of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom

^* To whom correspondence should be addressed. E-mail: ben{at}raveney.co.uk.

	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 posterior uveitis initiated by retinal-antigen-specific Th1 and Th17 CD4⁺ T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, 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 (M) and T cells were assessed both in vivo and in in vitro co-cultures. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EAU induction. Results: Pre-immunisation treatment with EtxB protected mice from EAU, limiting both the number and the activation status of retinal infiltrating immune cells. Treatment following EAU induction did not alter disease course, despite suppression of IFN-. Although EtxB treatment of in vitro co-cultures of T cells and M increased IL-10 production, EtxB treatment in vivo increased the proportion and numbers of IL-17-producing CD4⁺ cells infiltrating the eye. Conclusion: EtxB pre-immunisation protects mice from EAU induction by inhibiting Th1 responses, but the resulting reduction in IFN- responses by EtxB does not effect infiltration or structural damage in established EAU, where Th17 responses predominate. These data highlight the critical importance of the dynamics of T cell phenotype and infiltration during EAU when considering immunomodulatory therapy.

Key Words: experimental autoimmune uveoretinitis, cell proliferation, macrophages, prostaglandins, immunotherapy