PD-ligand, a Paradoxical Role in Experimental Uveitis Pathogenesis and Therapy

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 DESCRIPTION (provided by applicant): Programmed death-1 (PD-1) is an immune molecule with two known ligands. In the immune system, the primary role for PD-1, after it binds to one of its ligands, is believed to be down-regulation of the immune response during infection, thereby limiting subsequent autoimmunity. Mice that lack PD-1 or PD-L1 are typically more susceptible to specific types of spontaneous or induced autoimmune disease. We have preliminary data to suggest that the opposite effect occurs in a uveitis model, in the PD-ligand double knock out (PD-L DKO) mice we observed a significant decrease in both incidence and severity of disease. Why is this relevant? The term uveitis describes a group of severe inflammatory diseases of the eye that are responsible for significant blindness in working age adults but can affect individuals of any age. Blocking the PD-1/PD-L1 interaction, or accentuating immunity, is one of the hot areas of cancer immunotherapy in 2014. Over the past year, reports of success blocking PD-1 showed increased survival for patients with multiple types of previously untreatable, advanced cancers. The preliminary success in these clinical trials led to one of the anti-PD-1 antibodies receiving a "Breakthrough Therapy" status by the FDA to expedite drug approval and therefore, blocking the PD-1 system could potentially become a new therapeutic approach to uveitis therapy. In this proposal we seek to address three important issues: 1) Establish whether protection from uveitis in the PD-L DKO animals is because of ocular expression or immune expression of PD-L. 2) Define the immunologic mechanisms of protection from uveitis in the PD-L DKO. 3) Study the potential therapeutic benefit for the use of antibodies against PD-ligand during active intraocular inflammation in murine models. The proposed studies are feasible and the laboratory has amassed the PD-L DKO animals, reagents, and expertise to address these areas. Importantly, successful completion of the proposed work could lead to new approaches in uveitis therapy in humans in a bench to bedside clinical translational approach.