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Negin Ashki, Ann M Chan, Ralph D Levinson, Yu-Ling Chang, Lynn K Gordon; PD-1 Receptor Blockade Decreases IRBP-induced Uveitis in Mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):534.
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Uveitis is a potentially blinding, immune mediated, intraocular inflammatory disease. Although programmed death-1 (PD-1) binding to its two ligands is believed to down-regulate autoimmunity, we previously observed that blockade of PD-Ligand 1 prevents uveitis in a mouse model of experimental autoimmune uveitis (EAU). To further investigate these findings, we tested the hypothesis that PD-1 blockade using an antibody against PD-1 receptor would decrease EAU.
Uveitis was induced in C57Bl/6 mice using an IRBP peptide 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. Mice were treated with 5mg/kg of anti-PD-1 antibody (BioXCell) or a control IgG (EAU+IgG) once a week for three weeks. Analysis of uveitis severity was done through a masked examination of the fundus and the animals were subject to euthanasia and histologic evaluation at 3 weeks after peptide immunization; both on a four-point scale.
Clinical scores were significantly decreased (P<0.0001) in animals that received early treatment with anti-PD-1 antibody compared to either EAU or EAU+IgG groups. In concordance with the clinical examination, histological evaluation of the mice at the peak of inflammation (day 21) revealed that 100% of control EAU and EAU+IgG mice developed uveitis with an average histological score of 1.19 and 0.83, respectively. Only 25% of EAU+PD-1 antibody treated animals developed uveitis with average histological score of 0.094; p<0.0001). No spontaneous clinical or histological evidence for uveitis was seen in any of the control wild type mice
The decrease in uveitis susceptibility following treatment with anti-PD-1 antibody confirmed our previous findings; suggesting that it is the blockade of PD-1, PD-ligand interaction, and not an alternative PD-ligand pathway that is protective for uveitis development in EAU. This observation may lead to a new understanding of the role of the PD-1 system in inflammation pathogenesis. The availability of blocking antibodies for PD-1 and PD-ligands, recently approved for use in cancer immunotherapy, presents the potential for clinical use of these agents in uveitis prevention. Additional studies are required to determine if blockade of this system would improve inflammation in ongoing uveitis.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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