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Negin Ashki, Ann Chan, Yu Qin, Lynn K. Gordon; Paradoxically Decreased Uveitis Susceptibility in PD-L1/L2 Double Knockout Mice . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):850.
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Uveitis is a potentially blinding, immune mediated intraocular inflammatory disease. Programmed death-1 (PD-1), an immune molecule with two known ligands, is believed to down-regulate autoimmunity. Mice that lack PD-1 or its ligands are typically more susceptible to specific types of spontaneous or induced autoimmune disease. We tested the hypothesis that susceptibility to uveitis increases in animals that lack PD-ligands using an animal model of experimental autoimmune uveitis (EAU).
Uveitis was induced in C57Bl/6 (WT) and PD-L1/L2 double knockout (DKO) mice on the C57Bl/6 background using IRBP (1-20) according to published protocols. All experiments were carried out in strict accordance with ARVO guidelines and the Guide for the Care and Use of Laboratory Animals. Animals that did not receive IRBP immunization served as controls for the uveitis studies. A masked clinical assessment by funduscopic examinations of the retinal inflammation was done every day for 3 weeks after the immunization. The severity of the retinal inflammation was graded on a four-point scale. At 3 weeks following immunization, the eyes were enucleated, fixed tissues were stained, and the histological severity was graded by multiple masked observers using a published scale.
Surprisingly, we found significant abrogation of uveitis in the DKO animals. This experiment was repeated with a total number of 20 animals per group. The percent of WT mice that developed uveitis was 70%, whereas only 30% of the DKO developed intraocular inflammation (P<0.05). Histologic activity score by immunohistochemistry was also reduced in the DKO animals as compared to WT (P<0.001).
The decrease in uveitis susceptibility in the DKO mice was an unanticipated result. First, this observation may lead to a new understanding of uveitis pathogenesis. Second, the availability of blocking antibodies for PD-1 and PD-ligands, recently approved for use in cancer immunotherapy allows us to explore the feasibility blocking the PD-1 system as a possible therapeutic target in ocular inflammation
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