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

 描述(申请人提供)：程序性死亡-1(PD-1)是一种具有两个已知配体的免疫分子。在免疫系统中，PD-1与其配体结合后的主要作用被认为是在感染期间下调免疫反应，从而限制随后的自身免疫。缺乏PD-1或PD-L1的小鼠通常更容易患上特定类型的自发或诱导的自身免疫性疾病。我们有初步数据表明，在葡萄膜炎模型中出现相反的效果，在PD配体双基因敲除(PD-L DKO)小鼠中，我们观察到疾病的发病率和严重程度都显著降低。这有什么关系呢？葡萄膜炎一词描述的是一组严重的眼部炎症性疾病，这些疾病会导致工作年龄成年人的严重失明，但也会影响个体。 任何年龄的人。阻断PD-1/PD-L1相互作用，或增强免疫，是2014年癌症免疫治疗的热点领域之一。在过去的一年里，关于成功阻断PD-1的报告表明，患有多种以前无法治疗的晚期癌症的患者的存活率增加。这些临床试验的初步成功导致其中一种抗PD-1抗体获得FDA的“突破性治疗”状态，以加快药物审批，因此，阻断PD-1系统可能成为葡萄膜炎治疗的一种新的治疗方法。在这项建议中，我们试图解决三个重要问题：1)确定PD-L DKO动物对葡萄膜炎的保护是因为PD-L的眼睛表达还是免疫表达。2)明确PD-L口服液预防葡萄膜炎的免疫学机制。3)研究PD配体抗体在小鼠活动性眼内炎症模型中的潜在治疗作用。拟议的研究是可行的，实验室已经积累了PD-L DKO动物、试剂和专业知识来解决这些领域的问题。重要的是，这项拟议工作的成功完成可能会导致人类葡萄膜炎治疗的新方法，即从长凳到床边的临床转换方法。

 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.