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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.

项目总结/摘要炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC），全世界有1000万人，患病率稳步上升。不幸的是，目前的IBD治疗方法不能维持长期的稳态免疫耐受。因此，仍然存在未满足的临床需求，维持IBD免疫耐受的策略。基本原理：用调节性T细胞（TCFs）治疗是一种有效的治疗方法。有吸引力的策略，以促进IBD的免疫耐受。在Treg扩增疗法中，低剂量的白细胞介素-2（IL-2）是令人兴奋的，因为它优先靶向具有高亲和力的T细胞，受体IL-2 RA，并已在IBD和其他疾病患者中显示出一定的疗效。然而，IL-2具有狭窄的治疗窗口，因为它也会扩增炎性T细胞和骨髓细胞。其他IL-2 其局限性在于其治疗效果限于扩展Treg，并且其不限制Treg不稳定性。因此，确定协同提高TcR的因素，同时防止低剂量TcR的任何不期望的作用， IL-2对炎症的扩展具有重要的临床意义。程序性死亡1（PD 1）途径作为控制T细胞应答和维持免疫稳态的关键抑制信号出现。改变的PD 1信号传导可以使小鼠和人类易患自身免疫。例如，PD 1阻断可导致小鼠和人类的结肠炎。最近，我们发现，Smad 7，一个与IBD有关的主要分子，通过限制PD 1信号传导，从而抑制PD 1诱导的TcR，从而抑制小鼠的肠道炎症。鉴于由于PD 1在限制组织炎症中的关键作用，PD 1代表了高度临床关注的治疗靶标。初步发现：对于这个提议，我们开始探索人类T细胞中的PD 1激动作用。我们发现令人痛苦的 PD 1通过重组人PDL 1-Fc和PDL 2-Fc促进从头诱导人Treg并限制Treg 可塑性有趣的是，我们还发现，在骨髓细胞中激动PD 1可以抑制炎性细胞因子，已知在IBD期间促进Th 1和Th 17发育并使Tcl 4不稳定。为了确认我们发现IL-2直接诱导人T细胞上的PD 1。令人兴奋的是，我们发现，低剂量IL-2与PD 1激动剂的组合协同促进人TcR。假设：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， Treg稳态，同时淬灭效应T细胞应答。此外，我们将研究是否结合低- 诱导T细胞上的PD 1的剂量IL-2与PDL 1/2-Fc将协同地促进Treg细胞，同时抑制T细胞上的PD 1。不希望的IL-2诱导的炎症，以更好地治疗IBD。在目标1中，我们将测试PD 1的翻译相关性激动剂单一疗法和与低剂量IL-2的联合疗法通过在体外处理IBD患者免疫细胞。在目标2中，我们将测试PD 1激动剂单药治疗和联合治疗的翻译相关性，剂量IL-2，治疗结肠炎的预防相关的人源化模型。总之，我们将探讨从未测试过的PD 1激动剂/低剂量IL-2联合疗法在IBD中的疗效。