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Michel Muzi Sun, Ann M. Chan, Ralph D Levinson, Madhuri Wadehra, Lynn K Gordon; Treatment of IRBP-induced Uveitis via PD-1 Blockade is Mediated Through Regulatory T cell Activation. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2538.
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Uveitis consists of a group of intraocular inflammatory diseases thought to be driven by autoreactive T cells that break immune privilege, resulting in autoimmune tissue destruction. Programmed Death-1 (PD-1) is a receptor shown to downregulate autoimmunity. Previous studies in our lab have demonstrated a paradoxical decrease in uveitis susceptibility in mice that lacked PD-1 ligands. Additionally, antibody mediated PD-1 blockade is sufficient to reduce uveitis severity. Here we further investigate the therapeutic potential of PD-1 blockade in the treatment of uveitis and its immune mechanisms, with the hypothesis that protection from uveitis is mediated through blockade of PD-1 inhibition on regulatory T cell activity and number.
Uveitis was induced in C57Bl/6 and B10.RIII mice using the appropriate 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 either anti-PD-1, anti-PD-L1, or isotype control antibody starting day 3 post induction and weekly for two weeks (B10.RIII) or three weeks (C57Bl/6). Splenocytes were isolated ex vivo on day 14 (B10.RIII) or day 21 (C57Bl/6), and cultured with IRBP or anti-CD3, anti-CD28, and IL-2. Cells were stained for the immune markers CD3, CD4, CD25, FoxP3, Helios, F4/80, MHC II, PD-1, PD-L1, CD69, CD103, GITR, IL-10, TGF-b, and Ki67.
Preliminary results showed that following uveitis induction, PD-1 and PD-L1 are upregulated on Tregs, and Tregs are shifted to a less activated Helioslo phenotype. In mice treated with PD-1 blockade, Treg population percentage is significantly increased (14.1% vs 11.0% of CD4+). Additionally there is a shift in phenotype back to the more activated Helioshi Tregs (48.7% vs 36.4%), effectively restoring Treg activity to WT levels.
These results support our hypothesis that PD-1 is inhibitory on Tregs, and treatment with antibody blockade of PD-1 relieves that inhibition, resulting in an increased population of more activated Tregs, which are able to maintain the normally immunosuppressive environment of the eye. Blocking antibodies against PD-1 and PD-L1 are currently FDA approved for cancer immunotherapy. This work suggests PD-1 blockade in uveitis may potentially be beneficial, however further investigation is warranted.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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