Therapeutic targeting of PD1 signaling in inflammatory bowel disease

PD1信号传导在炎症性肠病中的治疗靶向

基本信息

批准号：
10647264
负责人：
Murugaiyan Gopal
金额：
$ 21.11万
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：
2023-02-03 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647264
关键词：
Address Affect Agonist Alpha Interleukin 2 Receptor Animal Model Autoimmune Diseases Autoimmunity Autologous Biological Models CD34 gene CD4 Positive T Lymphocytes Cells Chimeric Proteins Clinical Colitis Combined Modality Therapy Crohn&apos s disease Dendritic Cells Development Disease Dose Exploratory/Developmental Grant Functional disorder Goals Hematopoietic stem cells Homeostasis Human Immune Immune Tolerance Immune response Immunocompromised Host Immunoglobulins In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin 2 Receptor Interleukin-2 Interleukins Intestines Knock-in Mouse Ligands Modeling Mus Myeloid Cells Pathogenesis Pathogenicity Pathway interactions Patients Peripheral Peripheral Blood Mononuclear Cell Persons Prevalence Rag1 Mouse Recombinants Regulatory T-Lymphocyte Role Signal Transduction Sulfonic Acids T cell response T cell therapy T-Lymphocyte Testing Therapeutic Therapeutic Effect Tissues Ulcerative Colitis clinically significant cytokine dysbiosis effector T cell gut inflammation high reward high risk humanized mouse immunoregulation in vivo innovation insight interest mouse model nitrobenzene novel therapeutic intervention novel therapeutics prevent programmed cell death ligand 1 programmed cell death protein 1 reconstitution response restraint side effect single-cell RNA sequencing therapeutic target

项目摘要

Project Summary/Abstract Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), affect more than 10 million people worldwide with steadily growing prevalence. Unfortunately, current IBD therapeutic approaches fail to maintain long-term homeostatic immune tolerance. Thus, there remains an unmet clinical need for new strategies that sustain immune tolerance in IBD. Rationale: Treatment with regulatory T cells (Tregs) is an attractive strategy to promote immune tolerance in IBD. Among the Treg expansion therapies under development, low-dose interleukin-2 (IL-2) is exciting because it preferentially targets Tregs with high-affinity receptor IL-2RA, and it has shown some efficacy in patients with IBD and other diseases. However, IL-2 has a narrow therapeutic window given that it also expands inflammatory T cells and myeloid cells. Other IL-2 limitations are that its therapeutic effect is restricted to expanding Tregs, and it does not limit Treg instability. Therefore, identifying factors that synergistically boost Tregs while preventing any undesired action of low-dose IL-2 on expanding inflammation is of high clinical significance. The programmed death 1 (PD1) pathway has emerged as a critical inhibitory signal which controls T cell responses and maintains immune homeostasis. Altered PD1 signaling can predispose mice and humans to autoimmunity. For example, PD1 blockade can cause colitis in mice and humans. Recently, we identified that Smad7, a major molecule implicated in IBD, sustains intestinal inflammation in mice by limiting PD1 signaling, thereby dampening PD1-induced Tregs. Given the critical role of PD1 in limiting tissue inflammation, PD1 represents a therapeutic target of high clinical interest. Preliminary findings: For this proposal, we began exploring PD1 agonism in human T cells. We found agonizing PD1 via recombinant human PDL1-Fc and PDL2-Fc promotes de novo human Treg induction and limits Treg plasticity. Interestingly, we also found that agonizing PD1 in myeloid cells inhibits inflammatory cytokines that are known to promote Th1 and Th17 development and destabilize Tregs during IBD. In our effort to identify factors that upregulate PD1, we found that IL-2 directly induces PD1 on human T cells. Excitingly, we found that combination of low-dose IL-2 with PD1 agonist synergistically promotes human Tregs. Hypothesis: 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. Furthermore, we will investigate if combining low- dose IL-2, which induces PD1 on T cells, with PDL1/2-Fc will synergistically boost Treg cells while restraining undesired IL-2-induced inflammation to better treat IBD. In Aim 1, we will test the translational relevance of PD1 agonist monotherapy and combination therapy with low-dose IL-2 by treating IBD patient immune cells in vitro. In Aim 2, we will test the translational relevance of PD1 agonist monotherapy and combination therapy with low- dose IL-2 by treating translationally relevant humanized models of colitis. In summary, we will explore the efficacy of a never tested PD1 agonist/low-dose IL-2 combination therapy in IBD.

项目摘要/摘要炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC），影响超过全世界有1000万人，患病率不断增长。不幸的是，当前的IBD治疗方法无法保持长期稳态免疫耐受性。那仍然需要新的临床需求维持IBD免疫耐受性的策略。理由：调节性T细胞（TREG）的治疗是一种促进IBD免疫耐受性的有吸引力的策略。在Treg扩展疗法中开发，低剂量白介素2（IL-2）令人兴奋，因为它优先针对具有高亲和力的Treg 受体IL-2RA，它在IBD和其他疾病患者中表现出一些效率。但是，IL-2有一个鉴于它还扩大了炎症性T细胞和髓样细胞，狭窄的治疗窗口。其他IL-2 局限性是其治疗作用仅限于扩大Treg，并且不限制Treg的不稳定性。因此，识别有协同促进Treg的因素，同时预防低剂量的任何不希望的动作 IL-2对感染的扩张具有很高的临床意义。编程的死亡1（PD1）途径成为控制T细胞反应并保持免疫稳态的关键抑制信号。 PD1信号改变会使小鼠和人类易于自身免疫性。例如，PD1封锁可能导致小鼠和人类的结肠炎。最近，我们确定了IBD中实施的主要分子Smad7维持小鼠肠炎通过限制PD1信号传导，从而导致PD1诱导的Treg。鉴于 PD1在限制组织炎症中的关键作用，PD1代表了高临床兴趣的治疗靶点。初步发现：对于此提案，我们开始探索人类T细胞中的PD1激动剂。我们感到痛苦 PD1通过重组人PDL1-FC和PDL2-FC促进了从头treg诱导和限制Treg 可塑性。有趣的是，我们还发现，对髓样细胞中的PD1进行存档会抑制炎性细胞因子，这些因子是已知可以在IBD期间促进Th1和Th17的发展并破坏Treg。为了确定上调PD1的因素，我们发现IL-2直接影响人类T细胞的PD1。令人兴奋的是，我们发现低剂量IL-2与PD1激动剂的结合协同促进人类Tregs。假设：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，同时淬灭效应T细胞反应。此外，我们将研究是否合并低 - 剂量IL-2，诱导PD1在T细胞上，PDL1/2-FC会协同促进Treg细胞，同时限制Treg细胞不需要的IL-2引起的炎症可以更好地治疗IBD。在AIM 1中，我们将测试PD1的翻译相关性通过在体外治疗IBD患者免疫细胞治疗，对低剂量IL-2的激动剂单一疗法和联合疗法。在AIM 2中，我们将测试PD1激动剂单一疗法和组合疗法与低 - 剂量IL-2 治疗结肠炎的翻译相关人性化模型。总而言之，我们将探索 IBD中从未测试过的PD1激动剂/低剂量IL-2组合疗法的功效。