Abstract
Purpose :
Experimental autoimmune uveitis (EAU) in rats is a suitable model for the respective intraocular inflammatory disease in humans. We investigated the in vivo effect of the small molecule dihydroorotate dehydrogenase inhibitor PP-001 in spontaneously relapsing-remitting and monophasic/chronic EAU with chorioretinal neovascularization and in vitro on rat and human lymphocytes and human RPE cells.
Methods :
Lewis rats were immunized with S-Antigen peptide PDSAg or interphotoreceptor retinoid-binding protein peptide R14 to induce monophasic or relapsing EAU, respectively. PP-001 was fed daily or injected intraocularly once. Uveitis was graded clinically and histologically, neovascularization was determined by histology. Rat lymph node cells and human peripheral lymphocytes of a healthy donor were stimulated with PHA and coincubated with PP-001. The human RPE cell line ARPE 19 and primary human RPE cells were cocultured with PP-001 or anti-VEGF, cytokines in culture supernatants were measured by bioplex bead assay.
Results :
Daily oral treatment with PP-001 after onset or peak of EAU induced with retinal S-Antigen peptide PDSAg (monophasic uveitis) significantly reduced neovascularization. A significant reduction of the number and intensity of relapses in R14-induced EAU was observed when daily oral PP-001 treatment was initiated or a single intraocular injection performed after resolution of the first attack of uveitis. Proliferation of autoantigen-specific rat T-cell lines and secretion of IFN-γ, IL-17, IL-10, IP-10 and VEGF were efficiently suppressed by PP-001. PP-001 also suppressed proliferation and cytokine secretion of PHA-stimulated human PBL without affecting the viability of the cells. Treating the human retinal pigment epithelial cell line ARPE-19 with PP-001 no suppressive effect on proliferation, viability and VEGF production was observed, in contrast to treatment with anti-VEGF bevacizumab. PP-001 showed no toxic effect on rat eye tissues after intraocular injection.
Conclusions :
Here we present a novel drug for systemic and local treatment of autoimmune uveitis without adverse effects on resident ocular cells. Furthermore, our data show that neovascularization as a sequel in uveitis can be caused by VEGF-producing autoreactive T cells only and not by RPE.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.