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

 描述（由申请人提供）：程序性死亡-1（PD-1）是一种具有两种已知配体的免疫分子。在免疫系统中，PD-1与其配体之一结合后的主要作用被认为是在感染期间下调免疫应答，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特定类型的自发性或诱导性自身免疫性疾病。我们有初步数据表明，在葡萄膜炎模型中发生了相反的作用，在PD-配体双敲除（PD-L DKO）小鼠中，我们观察到疾病的发病率和严重程度均显著降低。为什么这是相关的？术语葡萄膜炎描述了一组严重的炎症性疾病的眼睛是负责显着失明的工作年龄的成年人，但可以影响个人 任何年龄。阻断PD-1/PD-L1相互作用或增强免疫力是2014年癌症免疫治疗的热点领域之一。在过去的一年里，成功阻断PD-1的报告显示，患有多种类型以前无法治疗的晚期癌症的患者的生存率增加。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”地位，以加快药物批准，因此，阻断PD-1系统可能成为葡萄膜炎治疗的新治疗方法。在该提议中，我们寻求解决三个重要问题：1）确定PD-L DKO动物中的葡萄膜炎保护是否是由于PD-L的眼部表达或免疫表达。2)定义PD-L DKO中葡萄膜炎保护的免疫学机制。3)在小鼠模型中研究在活动性眼内炎症期间使用抗PD-配体抗体的潜在治疗益处。拟定的研究是可行的，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问题。重要的是，成功完成所提出的工作可能会导致在实验室到床边临床转化方法中人类葡萄膜炎治疗的新方法。

 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.