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

PD-配体，在实验性葡萄膜炎发病机制和治疗中的矛盾作用

基本信息

批准号：
9040967
负责人：
Lynn K Gordon
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040967
关键词：
Address Adult Advanced Malignant Neoplasm Affect Age Animals Antibodies Antigens Area Attenuated Autoimmune Diseases Autoimmunity Automobile Driving B7-DC antigen Binding Blindness Bone Marrow Breeding Cells Cessation of life Childhood Chimera organism Clinical Clinical Trials Data Development Disease Down-Regulation Drug Approval Eye diseases Goals Health Human Immune Immune response Immune system Immunity Immunologics Incidence Individual Infection Inflammation Inflammatory Knock-out Knockout Mice Laboratories Lead Ligands Malignant Neoplasms Modeling Mouse Strains Mus PDCD1LG1 gene Pathogenesis Patients Peptides Peripheral Phase Predisposition Public Health Reagent Regulatory T-Lymphocyte Reporting Research Resolution Role Severities Severity of illness Stimulus System T-Lymphocyte Therapeutic Time Tissues Tumor Immunity Uveitis Work base bench to bedside cancer immunotherapy cytokine immune function interstitial retinol-binding protein knockout animal mouse model neoplastic cell novel novel strategies novel therapeutic intervention prevent programs success translational approach tumor

项目摘要

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.

描述（由适用提供）：编程死亡-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与其一种配体之一结合后的主要作用被认为是感染过程中免疫响应的下调，从而限制了随后的自身免疫性。缺乏PD-1或PD-L1的小鼠通常更容易受到特定类型的赞助或诱导自身免疫性疾病的影响。我们有初步的数据表明，在葡萄膜炎模型中，在PD-rigand double敲除（PD-L DKO）小鼠中，我们观察到疾病的事件和严重程度都显着降低。为什么这有意义？葡萄膜炎一词描述了一组严重的眼睛炎症性疾病，导致成年人的工作年龄重大失明，但会影响个体任何年龄。阻止PD-1/PD-L1相互作用或强调免疫学是2014年癌症免疫疗法的热门地区之一。在过去的一年中，成功阻止PD-1的报道显示，PD-1的报告显示出了多种以前无法治疗的高级癌症患者的生存率增加。在这些临床试验中，初步成功导致FDA获得“突破疗法”状态的抗PD-1抗体之一，以加快药物批准，因此，阻止PD-1系统可能会成为一种新的治疗方法，以实现葡萄炎治疗的新治疗方法。在此提案中，我们试图解决三个重要问题：1）确定PD-L DKO动物中葡萄膜炎的保护是否是因为PD-L的眼部表达或免疫学表达。 2）定义PD-L DKO中葡萄膜炎的免疫机制。 3）研究在鼠模型中，在主动眼内感染过程中使用抗体对PD - 配体的抗体的潜在治疗益处。拟议的研究是可行的，实验室使PD-L DKO动物，试剂和专业知识逗乐以解决这些领域。重要的是，拟议的工作的成功完成可能会导致人类在床边临床翻译方法中的葡萄膜炎治疗方法。