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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.

项目总结/摘要目前的多发性硬化症（MS）治疗方法不足以维持长期的免疫反应。体内平衡和有效地重新校准患者的T辅助细胞失衡。仍有未满足的临床需要恢复和维持MS免疫耐受的新策略。 PD 1信号在维持免疫耐受中起着关键作用 . PDL 1/PD 1表达改变，和/或阻断PD 1信号传导，导致免疫耐受性的破坏，并使小鼠和人类易于自身免疫和组织炎症的发展。例如，阻断PD 1及其配体可以事实上，我们最近发现，Smad 7，一种与MS有关的主要分子，自身免疫性，通过限制T细胞中的PD 1和T细胞中的PD 1配体来维持小鼠肠道和CNS炎症。 DC，从而抑制PD 1诱导的TcR。鉴于PD 1信号在限制组织中的关键作用，炎症和自身免疫，PD 1可以代表MS中高度临床感兴趣的治疗靶点。然而，在这方面，增强PD 1信号传导对EAE和MS的治疗益处的影响从未被测试过。对于这个提议，我们开始探索人类T细胞中的PD 1激动剂。我们发现了令人痛苦的PD 1，免疫球蛋白融合蛋白PDL 1-Fc或PDL 2-Fc促进从头人Treg诱导并限制Treg 可塑性有趣的是，我们还发现，在骨髓细胞内激动PD 1抑制炎症细胞因子，已知其在MS和EAE中促进Th 1/17发育并使Th 1/17不稳定。因此，我们将测试我们假设PD 1激动剂单药治疗可以通过直接增强免疫耐受来有效地恢复免疫耐受，在EAE和MS中，Treg稳态同时淬灭效应T细胞应答。发现IL-2直接诱导CD 4 + T细胞中的PD 1，并且将低剂量IL-2与PD 1激动剂组合，协同增强人Treg诱导，我们还将研究低剂量IL-2与PDL 1/2-Fc联合是否将协同促进MS患者Treg应答。因为IL-2仍然可以促进效应T细胞应答， PD 1激动剂与低剂量IL-2的组合也可以抑制低剂量IL-2对PD 1受体的任何不希望的直接作用。增强效应T细胞。此外，PD 1激动剂可能通过靶向其他细胞因子而进一步补充低剂量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，我们将测试通过在体外处理MS患者免疫细胞和通过在体外处理人源化PD 1敲除细胞来进行PD 1激动单一疗法，在EAE小鼠体内。在目标2中，我们将通过治疗来测试PDL 1/2-Fc和低剂量IL-2联合治疗。 MS患者免疫细胞体外培养，并通过治疗人源化PD 1/IL-2受体α（RA）双敲入小鼠与EAE在体内，包括单细胞RNA测序的免疫反应在治疗小鼠。总之，我们将探索从未测试过的PD 1激动剂/低剂量IL-2联合治疗策略在EAE中的疗效， MS到解决围绕PD 1激动如何促进人类免疫耐受的未回答的问题， PD 1激动剂治疗策略的翻译潜力，以及如何在CNS自身免疫中实施它们。