Immune Checkpoint Inhibition and humoral immune response in systemic autoimmunity

项目概要/摘要 PD-1是抑制T细胞功能的关键免疫检查点受体。虽然广泛的研究 研究了PD-1如何在癌症环境中调节T细胞效应子功能，PD-1如何调节全身性 自身免疫和体液免疫的定义仍然不明确。临床上，免疫检查点抑制剂，包括 抗PD-1，诱导炎性关节炎免疫相关不良事件（IA-irAE），但潜在的 IA-irAE和经典风湿性疾病的机制和关系尚未探索。重要的是， 不存在允许直接分析临床使用的抗PD-1抗体的自身免疫动物模型， 它们不与小鼠PD-1相互作用。我们利用新型人源化PD-1和PD-L1小鼠模型， 研究临床使用的抗PD-1和抗PD-L1生物制剂调节体液免疫的机制， 在经典胶原诱导的关节炎模型中的免疫应答。此外，通过对 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 揭示了IA-irAE和血清阴性类风湿关节炎之间的显著相似性， 系统性自身免疫的一种我们的中心假设是抗PD-1和抗PD-L1生物制剂 诱导T细胞主导和抗体非依赖性自身免疫毒性，并损害PD-1 信号传导是IA-irAE和血清阴性类风湿性关节炎（RA）的促成因素。为了验证这一 我们将（1）确定临床使用的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调节异常如何影响PD-1的表达。 信号传导有助于人类受试者中的IA-irAE和血清阴性RA。建立在我们的临床和基础 研究专业知识和创新，整合新的小鼠模型，创新的药理学 干预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，与临床改善直接相关 实践和患者的福祉。此外，本研究还将为动物实验提供一种有价值的动物模型 在irAE领域。

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.