Immune Checkpoint Inhibition and humoral immune response in systemic autoimmunity

全身性自身免疫中的免疫检查点抑制和体液免疫反应

基本信息

批准号：
10468162
负责人：
Hu Zeng
金额：
$ 34.59万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10468162
关键词：
Address Adverse effects Affect Agonist Animal Model Antibodies Autoantibodies Autoimmune Autoimmune Diseases Autoimmunity B-Lymphocytes Basic Science Binding Biological Products Blocking Antibodies Cancer Patient Cell physiology Cells Clinical Clinical Data Clinical Pathology Clinical Research Cohort Analysis Collagen Arthritis Complement Data Deposition Development Disease Extracellular Domain FDA approved Helper-Inducer T-Lymphocyte Homeostasis Human Humoral Immunities Immune Immune checkpoint inhibitor Immune response Immune system Immunoglobulins Immunologics Impairment Inflammation Inflammatory Arthritis Intervention Ligands Link Malignant Neoplasms Mediating Modeling Molecular Mouse Strains Mus PD-L1 blockade Patients Personal Satisfaction Pharmacology Phenotype Production Research Resources Rheumatism Rheumatoid Arthritis Sampling Signal Transduction System Systems Development T cell differentiation T-Lymphocyte Testing Th1 Cells Therapeutic anti-PD-1 anti-PD-1/PD-L1 anti-PD-L1 anti-PD-L1 antibodies anti-PD-L1 therapy anti-PD1 antibodies autoimmune toxicity base cancer therapy checkpoint inhibition checkpoint receptors clinical practice clinically relevant comparative effector T cell experimental study human subject humanized mouse immune checkpoint immune checkpoint blockade immune function immune-related adverse events immunopathology innovation mouse model novel pembrolizumab programmed cell death ligand 1 programmed cell death protein 1 systemic autoimmunity tool

项目摘要

PROJECT SUMMARY/ABSTRACT PD-1 is a key immune checkpoint receptor that dampens T cell function. While extensive studies have investigated how PD-1 modulates T cell effector function in cancer settings, how PD-1 regulates systemic autoimmunity and humoral immunity remains poorly defined. Clinically, immune checkpoint inhibitors, including anti-PD-1, induces inflammatory arthritis immune related adverse events (IA-irAE), but the underlying mechanisms and the relationship between IA-irAE and classic rheumatic diseases are unexplored. Importantly, no autoimmune animal models exist that permit direct analysis of clinically-used anti-PD-1 antibodies because they do not interact with mouse PD-1. We utilize novel humanized PD-1 and PD-L1 mouse models to investigate the mechanisms by which clinically-used anti-PD-1 and anti-PD-L1 biologics modulate humoral immune response in a classic collagen induced arthritis model. Furthermore, through comparative analysis of clinical data and immunological profiles between anti-PD-1 induced IA-irAE and rheumatoid arthritis, we uncover remarkable similarity between IA-irAE and seronegative rheumatoid arthritis, a hitherto little understood form of systemic autoimmunity. Our central hypothesis is that anti-PD-1 and anti-PD-L1 biologics induces T cell-dominating and antibody-independent autoimmune toxicity, and impaired PD-1 signaling is a contributing factor to IA-irAE and seronegative rheumatoid arthritis (RA). To test this hypothesis, we will (1) To determine the immunopathology and molecular mechanisms of clinically-used PD-1 and PD-L1 blockade mediated autoimmune diseases, and (2) To investigate how dysregulation of PD-1 signaling contributes to IA-irAE and seronegative RA in human subjects. Building on our clinical and basic research expertise and innovations that integrate novel mouse models, innovative pharmacological interventions and comparative patient cohort analysis, our research will address fundamental questions in PD- 1 signaling, humoral immunity, and systemic autoimmunity, with direct relevance to the improvement of clinical practice and patients’ wellbeing. Additionally, our study will provide a valuable animal model as a research tool for the field of irAE.

项目摘要/摘要 PD-1是该死T细胞功能的关键免疫检查点接收器。而广泛的研究有研究了PD-1如何调节T细胞效应子在癌症环境中的功能，PD-1如何调节全身性自身免疫性和体液免疫受到的定义仍然很差。在临床上，免疫切解点抑制剂，包括抗PD-1，诱导炎症性关节炎免疫与广告事件（IA-IRAE），但基础机理以及IA-IRAE与经典风湿病之间的关系是意外的。重要的是，没有自身免疫动物模型可以直接分析临床使用的抗PD-1抗体，因为它们不与鼠标PD-1相互作用。我们利用新型的人源化PD-1和PD-L1小鼠模型研究临床使用的抗PD-1和抗PD-L1生物制剂调节体液的机制经典胶原蛋白诱导关节炎模型中的免疫反应。此外，通过比较分析抗PD-1诱导的IA-IRAE和类风湿关节炎之间的临床数据和免疫学特征，我们发现IA-IRAE和血清神经类风湿关节炎之间的显着相似性，一个隐藏的很少了解系统性自身免疫的形式。我们的中心假设是抗PD-1和抗PD-L1生物制剂诱导T细胞为主流和抗体无关的自身免疫性毒性，并损害PD-1 信号传导是导致IA-IRAE和血清神经类风湿关节炎（RA）的一个因素。测试这个假设，我们将（1）确定临床中使用的PD-1的免疫病理学和分子机制和PD-L1阻断介导的自身免疫性疾病，以及（2）研究PD-1的失调如何信号传导有助于人类受试者的IA-IRAE和血清质RA。基于我们的临床和基本研究专业知识和创新，整合了新型鼠标模型，创新的药物干预措施和比较患者队列分析，我们的研究将解决PD-的基本问题 1信号传导，体液免疫（和全身自身免疫），与临床的改善直接相关练习和患者的健康。此外，我们的研究将提供有价值的动物模型作为研究工具对于Irae领域。