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.

项目摘要/摘要当前多发性硬化症（MS）治疗方法不足以维持长期免疫稳态并有效地重新校准患者的T辅助细胞失衡。仍然没有临床需要在MS中恢复和维持免疫力的新策略。 PD1信号在维持免疫耐受性中起着至关重要的作用。更改PDL1/PD1表达和/或封锁PD1信号传导，导致免疫耐受性的细分，使小鼠和人类易于自身免疫和组织炎症的发展。例如，封锁PD1及其配体可以 Averbate EAE，MS的鼠标模型。实际上，我们最近发现Smad7是一个与自身免疫性，通过限制T细胞中的PD1和PD1配体的PD1，在小鼠中炎症和中枢神经系统炎症 DC，从而抑制了PD1诱导的Treg。鉴于PD1信号在限制组织中的关键作用炎症和自身免疫性，PD1可以代表MS高临床兴趣的治疗靶点。然而，增强PD1信号传导对EAE和MS的治疗益处的影响从未进行过测试。为此，我们开始探索人类T细胞中的PD1激动剂。我们通过免疫球蛋白融合蛋白PDL1-FC或PDL2-FC促进了人类Treg诱导，并限制Treg 可塑性。有趣的是，我们还发现骨髓细胞中的痛苦PD1抑制炎症细胞因子已知可以促进Th1/17的发展并破坏MS和EAE中的Treg。因此，我们将测试我们假设PD1激动剂单药治疗可以通过直接增强有效恢复免疫耐受性 Treg稳态时，在EAE和MS中淬灭效应的T细胞反应。基于我们令人兴奋的初步发现IL-2直接诱导CD4+ T细胞中的PD1，并将低剂量IL-2与PD1激动剂组合协同促进人类的诱导，我们还将调查是否将低剂量IL-2与PDL1/2-FC相结合会协同增强MS患者Treg反应。因为IL-2仍然可以促进效应子T细胞反应，所以将PD1激动剂与低剂量IL-2组合也可能限制低剂量IL-2对增强效应T细胞。此外，PD1激动剂可能通过靶向其他重要的细胞类型不受IL-2（例如髓样细胞）的影响。在AIM 1中，我们将测试的转化相关性 PD1激动剂单一疗法通过在体外治疗MS患者免疫细胞，并通过治疗人源化的PD1敲击在带有eae in Vivo的老鼠中。在AIM 2中，我们将通过治疗来测试PDL1/2-FC和低剂量IL-2组合疗法 MS患者免疫细胞体外，并通过治疗人性化的PD1/IL-2受体α（RA）双敲门小鼠带有EAE体内，包括治疗小鼠中免疫反应的单细胞RNA测序。总而言之，我们将探索从未测试过的PD1激动剂/低剂量IL-2组合疗法策略的功效 MS TO 解决了关于PD1激动剂如何促进人类免疫耐受的问题， PD1激动剂治疗策略的转化潜力，以及如何在CNS自身免疫性中实施它们。