Development of novel PD1 agonist therapeutic strategies for multiple sclerosis

开发多发性硬化症的新型 PD1 激动剂治疗策略

基本信息

批准号：
10574191
负责人：
Murugaiyan Gopal
金额：
$ 22.35万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10574191
关键词：
Address Affect Agonist Animal Model Anti-Inflammatory Agents Autoimmune Diseases Autoimmunity Biological Models CD4 Positive T Lymphocytes CNS autoimmunity Calibration Cells Central Nervous System Chimeric Proteins Clinical Combined Modality Therapy Complement Dendritic Cells Development Disease Dose Experimental Autoimmune Encephalomyelitis Exploratory/Developmental Grant Goals Helper-Inducer T-Lymphocyte Homeostasis Human IL2RA gene Immune Immune Tolerance Immune response Immunoglobulins In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin 2 Receptor Interleukin-2 Intestines Knock-in Mouse Ligands Maintenance Mediating Modeling Multiple Sclerosis Mus Myeloid Cells Pathogenicity Pathway interactions Patients Peripheral Persons Pharmaceutical Preparations Play Regulatory T-Lymphocyte Role Signal Transduction Systemic Lupus Erythematosus T cell response T-Lymphocyte Testing Therapeutic Tissues autoreactive T cell cell type central nervous system demyelinating disorder clinically relevant clinically significant cytokine effector T cell enhancing factor high dimensionality high reward high risk immunoregulation improved in vivo innovation insight interest mouse model multiple sclerosis patient multiple sclerosis treatment novel novel therapeutic intervention prevent programmed cell death ligand 1 programmed cell death protein 1 response restraint single-cell RNA sequencing synergism therapeutic target translational potential

项目摘要

Project Summary/Abstract Current multiple sclerosis (MS) therapeutic approaches are insufficient to maintain long-term immune homeostasis and effectively recalibrate T helper cell imbalances in patients. There remains an unmet clinical need for new strategies that restore and sustain immune tolerance in MS. PD1 signaling plays a critical role in the maintenance of immune tolerance . Altered PDL1/PD1 expression, and/or blockade of PD1 signaling, results in the breakdown of immune tolerance and predisposes mice and humans to the development of autoimmunity and tissue inflammation. For example, blockade of PD1 and its ligands can exacerbate EAE, a mouse model of MS. In fact, we recently found that Smad7, a major molecule implicated in autoimmunity, sustains intestinal and CNS inflammation in mice by limiting PD1 in T cells and PD1 ligands in DCs, thereby dampening PD1-induced Tregs. Given the critical role of PD1 signaling in limiting tissue inflammation and autoimmunity, PD1 could represent a therapeutic target of high clinical interest in MS. However, the impact of enhancing PD1 signaling for therapeutic benefit in EAE and MS has never been tested. For this proposal, we began exploring PD1 agonists in human T cells. We found agonizing PD1 via immunoglobulin fusion proteins PDL1-Fc or PDL2-Fc promotes de novo human Treg induction and limits Treg plasticity. Interestingly, we also found that agonizing PD1 within myeloid cells inhibits inflammatory cytokines that are known to promote Th1/17 development and destabilize Tregs in MS and EAE. Therefore, we will test our hypothesis that PD1 agonist monotherapy could effectively restore immune tolerance by directly enhancing Treg homeostasis while quenching effector T cell responses in EAE and MS. Based on our exciting preliminary finding that IL-2 directly induces PD1 in CD4+ T cells and that combining low-dose IL-2 with PD1 agonists synergistically boosts human Treg induction, we will also investigate if combining low-dose IL-2 with PDL1/2-Fc will synergistically boost MS patient Treg responses. Because IL-2 can still promote effector T cell responses, combining PD1 agonist with low-dose IL-2 may also restrain any undesired direct effect of low-dose IL-2 on boosting effector T cells. In addition, PD1 agonist might further complement low-dose IL-2 by targeting other important cell types unaffected by IL-2 (e.g. myeloid cells). In Aim 1, we will test the translational relevance of PD1 agonism monotherapy by treating MS patient immune cells in vitro, and by treating humanized PD1 knock- in mice with EAE in vivo. In Aim 2, we will test PDL1/2-Fc and low-dose IL-2 combination therapy by treating MS patient immune cells in vitro, and by treating humanized PD1/IL-2 receptor alpha (RA) double knock-in mice with EAE in vivo, including single-cell RNA sequencing of immune responses in treated mice. In summary, we will explore the efficacy of a never tested PD1 agonist/low-dose IL-2 combination therapy strategy in EAE and MS to address unanswered questions around how PD1 agonism promotes human immune tolerance, the translational potential of PD1 agonist therapeutic strategies, and how to implement them in CNS autoimmunity.

项目概要/摘要目前的多发性硬化症 (MS) 治疗方法不足以维持长期免疫体内平衡并有效地重新调整患者 T 辅助细胞的失衡。临床上仍有未满足的问题需要恢复和维持多发性硬化症免疫耐受的新策略。 PD1信号传导在维持免疫耐受中发挥着关键作用。 PDL1/PD1 表达改变，和/或阻断 PD1 信号传导，导致免疫耐受性崩溃，并使小鼠和人类容易出现自身免疫和组织炎症的发展。例如，阻断 PD1 及其配体可以加剧 EAE（MS 小鼠模型）。事实上，我们最近发现 Smad7，一种与自身免疫，通过限制 T 细胞中的 PD1 和 T 细胞中的 PD1 配体来维持小鼠肠道和中枢神经系统炎症 DC，从而抑制 PD1 诱导的 Tregs。鉴于 PD1 信号传导在限制组织中的关键作用炎症和自身免疫，PD1 可能代表 MS 临床高度关注的治疗靶点。然而，增强 PD1 信号传导对 EAE 和 MS 治疗效果的影响尚未得到测试。对于这个提案，我们开始探索人类 T 细胞中的 PD1 激动剂。我们通过以下方式发现了令人痛苦的 PD1：免疫球蛋白融合蛋白 PDL1-Fc 或 PDL2-Fc 促进人 Treg 从头诱导并限制 Treg 可塑性。有趣的是，我们还发现，激动骨髓细胞内的 PD1 会抑制炎症细胞因子已知在 MS 和 EAE 中促进 Th1/17 发育并破坏 Tregs 的稳定性。因此，我们将测试我们的假设是 PD1 激动剂单一疗法可以通过直接增强免疫耐受来有效恢复免疫耐受。 EAE 和 MS 中 Treg 稳态同时淬灭效应 T 细胞反应。基于我们激动人心的初步结果发现 IL-2 直接诱导 CD4+ T 细胞中的 PD1，并将低剂量 IL-2 与 PD1 激动剂相结合协同促进人类 Treg 诱导，我们还将研究是否将低剂量 IL-2 与 PDL1/2-Fc 结合使用将协同增强多发性硬化症患者的 Treg 反应。因为IL-2仍然可以促进效应T细胞反应，将 PD1 激动剂与低剂量 IL-2 联合使用也可以抑制低剂量 IL-2 对细胞的任何不良直接影响。增强效应T细胞。此外，PD1激动剂可能通过靶向其他药物进一步补充低剂量IL-2。不受 IL-2 影响的重要细胞类型（例如骨髓细胞）。在目标 1 中，我们将测试以下内容的翻译相关性： PD1激动单一疗法通过在体外治疗多发性硬化症患者的免疫细胞，并通过治疗人源化PD1敲除体内患有 EAE 的小鼠。在目标 2 中，我们将通过治疗来测试 PDL1/2-Fc 和低剂量 IL-2 联合疗法体外 MS 患者免疫细胞，并通过治疗人源化 PD1/IL-2 受体 α (RA) 双敲入小鼠体内 EAE，包括对治疗小鼠的免疫反应进行单细胞 RNA 测序。综上所述，我们将探索从未测试过的 PD1 激动剂/低剂量 IL-2 联合治疗策略在 EAE 中的疗效女士至解决有关 PD1 激动如何促进人类免疫耐受的悬而未决的问题， PD1 激动剂治疗策略的转化潜力，以及如何在中枢神经系统自身免疫中实施它们。