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.

PUBLIC HEALTH RELEVANCE: Uveitis, a severe intraocular inflammatory disease, is responsible for a significant percent of blindness in working age individuals and affects patients of all age, from childhood through adulthood. New therapeutic approaches would be an important improvement in public health as they relate to this group of blinding diseases. This project seeks to define the role for PD-ligand in uveitis pathogenesis and opens potential new avenues for therapy, and if successful, the work could lead to clinical trials for patient with uveitis.