Therapeutic targeting of PD1 signaling in inflammatory bowel disease

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 全球有1000万人，患病率稳步增长。不幸的是，目前的IBD治疗方法 未能维持长期的动态平衡免疫耐受。因此，新的临床需求仍未得到满足。 维持IBD免疫耐受的策略。原理：调节性T细胞(Tregs)治疗是一种 促进IBD免疫耐受的有吸引力的策略。在以下Treg扩展疗法中 低剂量白介素2(IL-2)的发展令人兴奋，因为它优先靶向具有高亲和力的Treg 受体IL-2RA，对IBD等疾病患者有一定疗效。然而，IL-2有一个 狭窄的治疗窗口，因为它还扩大了炎性T细胞和髓样细胞。其他IL-2 局限性是它的治疗效果仅限于扩大Treg，而且它不限制Treg的不稳定性。 因此，确定协同提高Tregs的因素，同时防止低剂量的任何不良作用 IL-2对扩张性炎症具有较高的临床意义。程序性死亡1(PD1)途径有 作为一种关键的抑制信号出现，它控制T细胞的反应并维持免疫平衡。 PD1信号的改变会使小鼠和人类容易产生自身免疫。例如，PD1封锁可能会导致 小鼠和人类的结肠炎。最近，我们发现与IBD有关的主要分子Smad7持续存在 通过限制PD1信号，从而抑制PD1诱导的Tregs，从而抑制小鼠的肠道炎症。给定 PD1在限制组织炎症中的关键作用，PD1代表了临床上高度感兴趣的治疗靶点。 初步发现：对于这一建议，我们开始探索人类T细胞中的PD1激动剂。我们发现令人痛苦的 PD1通过重组人PDL1-Fc和PDL2-Fc促进从头开始的人Treg诱导并限制Treg 可塑性。有趣的是，我们还发现，髓系细胞中刺激PD1的作用会抑制炎性细胞因子 已知在IBD期间促进Th1和Th17的发育并破坏Tregs的稳定。在我们努力确定 上调PD1的因素，我们发现IL-2直接诱导人T细胞上的PD1。令人兴奋的是，我们发现 小剂量IL-2与PD1激动剂联合使用可协同促进人Tregs。假设：我们将测试 我们的假设是，PD1激动剂单一疗法可以通过直接增强 Treg动态平衡，同时猝灭效应器T细胞反应。此外，我们将调查是否将低- 诱导T细胞表面PD1的IL-2与PDL1/2-Fc协同刺激Treg细胞，同时抑制其增殖 不受欢迎的IL-2诱导的炎症，以更好地治疗IBD。 在目标1中，我们将测试PD1的翻译关联性 激动剂单一疗法和小剂量IL-2联合疗法对IBD患者免疫细胞的体外作用。 在目标2中，我们将测试PD1激动剂单独治疗和联合治疗与低... 白介素2剂量 治疗翻译相关的人源化结肠炎模型。总而言之，我们将探索 从未测试过的PD1激动剂/小剂量IL-2联合治疗IBD的疗效。

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.