Regulation Of Experimental Autoimmune Uveitis (EAU) Induction In Mice By The Phosphodiesterase Inhibitor Dipyrimidol And Of Active EAU By Bindarit, An Inhibitor Of Monocyte Chemotactic Proteins

Abstract

Purpose: : The induction of experimental autoimmune uveitis (EAU)in mice by immunization with a uveitogenic peptide depends on the activation of Th17 T cells and the retinal infiltration of monocytic cells attracted by MCP-1/CCL2 and MCP-3/CCL7 chemokines. We therefore, investigated whether EAU induced by immunization with an interphotoreceptor binding protein (IRBP) peptide is inhibited by an elevation in intracellular cAMP and whether active EAU onset is prevented by inhibition of the production of MCP-1/CCL2, MCP-3/CCL7.

Methods: : EAU was induced in C57BL10.RIII mice by immunization with IRBP peptide161-180 in Complete Freund’s Adjuvant(CFA)and an injection of pertussis toxin (PTX). The mice were euthanized 13-19 days after immunizing. Mice received the non-selective phosphodiesterase inhibitor dipyrimidol 1 day before immunizing or bindarit, an indazolic derivative able to inhibit of the production of MCP-1 and MCP-3 13 days post-immunization, prior to the expected peak of EAU. The eyes were enucleated, fixed, imbedded in paraffin, sectioned, stained with hematoxylin/eosin (H&E) and the sections examined microscopically to score EAU.

Results: : EAU was reduced or did not appear in mice receiving dipyrimidol before immunization with IRBP peptide. EAU apparent 13-15 days after immunization was inhibited or reduced in mice receiving intraperitoneal or intracameral bindarit 11 days after immunization. Delayed-type hypersensitivity to ovalbumin (OVA)in OVA-immunized mice was not inhibited by bindarit.

Conclusions: : The induction of EAU is inhibited by the non-selective phosphodiesterase inhibitor dipyrimidol. Bindarit inhibits active EAU in immunized mice providing additional evidence that the chemokines MCP-1 and/or MCP-3 are instrumental in the effector phase of EAU.

Keywords: autoimmune disease • immunomodulation/immunoregulation • uveitis-clinical/animal model