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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/文摘