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Originally published In Press as doi:10.1167/iovs.08-1848 on May 9, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4008-4017.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-1848
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The B Subunit of Escherichia coli Heat-Labile Enterotoxin Inhibits Th1 but Not Th17 Cell Responses in Established Experimental Autoimmune Uveoretinitis

Ben J. E. Raveney,1 Claire Richards,1 Marie-Laure Aknin,2 David A. Copland,3 Bronwen R. Burton,1 Emma Kerr,3 Lindsay B. Nicholson,1,3 Neil A. Williams,1 and Andrew D. Dick1,3

1From the Department of Cellular and Molecular Medicine, School of Medical Sciences and the 3Unit of Ophthalmology, Department of Clinical Sciences at South Bristol, University of Bristol, Bristol, United Kingdom; and the 2Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.

PURPOSE. To investigate the efficacy of the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. 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 immunization with peptide hIRBP161-180. Disease severity was measured by clinical and histologic assessment, and functional responses of macrophages (M{phi}s) and T cells were assessed, both in vivo and in cocultures in vitro. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EAU induction.

RESULTS. Preimmunization treatment with EtxB protected mice from EAU, limiting both the number and the activation status of retinal infiltrating immune cells. Treatment after EAU induction did not alter the disease course, despite suppression of IFN-{gamma}. Although EtxB treatment of in vitro cocultures of T cells and M{phi}s increased IL-10 production, EtxB treatment in vivo increased the proportion and number of IL-17-producing CD4+ cells infiltrating the eye.

CONCLUSIONS. EtxB preimmunization protects mice from EAU induction by inhibiting Th1 responses, but the resultant reduction in IFN-{gamma} 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.




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