Klinikum der Universität München, AG Immunbiologie, Augenklinik, München, Germany.
4SC Discovery GmbH, Planegg-Martinsried, Germany.
Invest Ophthalmol Vis Sci. 2014 Dec 16;56(2):1147-57. doi: 10.1167/iovs.14-15518.
We investigated the effect of PP-001, a new small molecule inhibitor of dihydro-orotate dehydrogenase in two experimental rat experimental autoimmune uveitis (EAU) models: a spontaneously relapsing-remitting model and a monophasic/chronic disease model that results in late chorioretinal neovascularization. Both of the diseases are induced by immunization with autoantigen peptides.
Prevention was tested using daily oral applications of PP-001 after immunization with the retinal S-antigen peptide PDSAg (for induction of monophasic uveitis and neovascularization) or the interphotoreceptor retinoid-binding protein peptide R14 (for induction of spontaneously relapsing-remitting EAU). Treatment to inhibit relapses and neovascularization was tested using PP-001 daily after the first attack of R14-induced or after onset of PDSAg-induced EAU. Uveitis was graded clinically and histologically. The effect of PP-001 on cytokine secretion and proliferation was evaluated using rat T-cell lines.
Preventive feeding of PP-001 abrogated both types of EAU. Starting treatment after the resolution of the first attack led to a significant reduction of the number and intensity of relapses in R14-induced EAU. PP-001-treatment initiated after onset or after peak of PDSAg-induced EAU significantly reduced neovascularization (as determined by histology). Proliferation of antigen-specific T-cell lines and secretion of IFN-γ, IL-17, IL-10, IP-10, and VEGF were efficiently suppressed by PP-001.
We investigated a new dihydroorotate dehydrogenase inhibitor as treatment for primary and recurrent disease in relapsing-remitting and chronic rat models of experimental autoimmune uveitis. The small molecule compound PP-001 suppressed proliferation and cytokine secretion of autoreactive T cells (i.e., IFN-g, IL-17, and VEGF) and chorioretinal neovascularization in chronic EAU.
我们研究了新型二氢乳清酸脱氢酶小分子抑制剂 PP-001 在两种实验性自身免疫性葡萄膜炎（EAU）大鼠模型中的作用：一种是自发缓解-复发模型，另一种是单相/慢性疾病模型，导致晚期脉络膜新生血管化。这两种疾病都是通过用自身抗原肽免疫诱导的。
用视网膜 S 抗原肽 PDSAg（用于诱导单相葡萄膜炎和新生血管形成）或光感受器间视黄醇结合蛋白肽 R14（用于诱导自发缓解-复发 EAU）免疫后，每日口服 PP-001 进行预防试验。用 PP-001 每日治疗以抑制复发和新生血管形成，在 R14 诱导的首次发作后或 PDSAg 诱导的 EAU 发病后开始。临床和组织学分级葡萄膜炎。用大鼠 T 细胞系评估 PP-001 对细胞因子分泌和增殖的影响。
预防性喂养 PP-001 可消除两种类型的 EAU。在 R14 诱导的 EAU 首次发作缓解后开始治疗可显著减少复发的次数和强度。在 PDSAg 诱导的 EAU 发病或高峰期后开始 PP-001 治疗可显著减少新生血管化（通过组织学确定）。抗原特异性 T 细胞系的增殖和 IFN-γ、IL-17、IL-10、IP-10 和 VEGF 的分泌均被 PP-001 有效抑制。
我们研究了一种新型二氢乳清酸脱氢酶抑制剂，作为治疗复发和缓解性和慢性大鼠实验性自身免疫性葡萄膜炎的原发性和复发性疾病的治疗方法。小分子化合物 PP-001 抑制了慢性 EAU 中自身反应性 T 细胞（即 IFN-γ、IL-17 和 VEGF）的增殖和细胞因子分泌以及脉络膜新生血管化。
