Immune Checkpoint Inhibition and humoral immune response in systemic autoimmunity

项目摘要/摘要 PD-1是一种关键的免疫检查点受体，可抑制T细胞功能。虽然广泛的研究已经 研究了PD-1如何在癌症环境中调节T细胞效应器的功能，PD-1如何调节全身 自身免疫和体液免疫仍然没有明确的定义。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与经典风湿性疾病之间的机制和关系尚不清楚。重要的是 不存在允许直接分析临床上使用的抗PD-1抗体的自身免疫动物模型，因为 它们不与小鼠PD-1相互作用。我们利用新的人源化PD-1和PD-L1小鼠模型 探讨临床使用的抗PD-1和抗PD-L1生物制品调节体液的机制 经典胶原蛋白诱导的关节炎模型的免疫反应。此外，通过对比分析，本文还提出了一种解决方案 抗PD-1诱导的IA-RAIL与类风湿关节炎的临床资料和免疫学特征 发现IA-IRAE和血清阴性类风湿性关节炎之间的显著相似之处，到目前为止还很少 被理解为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生物制品 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 信号是IA-IRAE和血清阴性类风湿性关节炎(RA)的一个促成因素。为了测试这一点 假设，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的失调是如何 在人类受试者中，信号转导有助于IA-RARE和血清阴性类风湿关节炎。建立在我们的临床和基础上 将新的小鼠模型、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、体液免疫和系统自身免疫，与临床的改善直接相关 实践和病人的福祉。此外，我们的研究还将提供一个有价值的动物模型作为研究工具 在伊拉克的战场上。

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.