Investigating the Role of IL-23R in Mucosal Regulatory T Cells

项目摘要 肠道对肠腔细菌的免疫反应失调是慢性肠炎的主要原因 炎症性肠病(IBD)的性质。通过免疫调节剂减轻炎症反应 和/或生物制剂是诱导缓解的主要治疗策略。然而，许多患者 要么是没有回应，要么是那些最初做出回应的人经常停止回应。通过以下方式恢复免疫耐受 增加调节性T细胞(Treg)数量或改善Treg功能可能是实现 长期缓解期。PI的K01奖侧重于在体内扩大Tregs的策略，以防止 人源化小鼠实验性结肠炎。在这些研究过程中，细胞因子白介素23(IL-23) 在小鼠和人类抗原提呈细胞中上调。与IL-23在IBD中的作用一致，变种在 IL23R与IBD易感性有关。此外，最近的一项3期临床试验显示， 克罗恩病的靶点是IL-23的p40亚单位(也与IL-12相同)，据报道 与安慰剂相比，在诱导和维持临床反应和缓解方面均有改善。虽然 肠内巨噬细胞和树突状细胞是IL-23的来源，IL-23R的表达一般是 仅限于淋巴细胞和3型先天淋巴样细胞(ILC3)。在这份提案中，我们将确定 IL-23R在肠道免疫稳态和炎症过程中IL-23R的表达 等位基因与内源Foxp3启动子驱动的Cre重组酶结合。在目标1中，我们将 确定IL-23R在FOXP3树突状细胞在炎症和炎症相关过程中的作用 致癌。在目标2中，我们将定义转录、代谢和信号网络/通路 肠道FOXP3细胞受IL-23R信号调控。总体而言，这些研究详细探讨了IL-23R是如何 对黏膜免疫的不同影响及其在炎症中的作用，将为未来的治疗提供信息 IBD和结肠癌的治疗策略。这项建议将进一步推动国际和平研究所的独立研究和 促进他转变为黏膜免疫学领域的成功研究者和领导者，并将 提供足够的已公布和初步数据，以促进竞争激烈的R01拨款申请 申请成为一名早期调查员。

Project Summary Dysregulated immune responses to luminal bacteria in the intestine are largely responsible for the chronic nature of inflammatory bowel disease (IBD). Attenuating the inflammatory response via immunomodulators and/or biologics represent the majority of therapeutic strategies to induce remission. However, many patients either do not respond and those that initially do often stop responding. Restoring immune tolerance by increasing regulatory T cell (Treg) numbers or improving Treg function may be a viable strategy to achieve long-term remission. The PI’s K01 award has focused on strategies to expand Tregs in vivo to prevent experimental colitis in humanized mice. In the course of these studies, the cytokine interleukin-23 (IL-23) was upregulated in murine and human antigen presenting cells. Consistent with a role for IL-23 in IBD, variants in IL23R have been linked to IBD susceptibility. Furthermore, a recent phase 3 clinical trial in patients with Crohn’s disease targeted the p40 subunit of IL-23 (also shared with IL-12) and reported significant improvement in both induction and maintenance of clinical response and remission over placebo. Although macrophage and dendritic cells in the intestine are the source of IL-23, expression of IL-23R is generally restricted to lymphocytes and type 3 innate lymphoid cells (ILC3s). In this proposal, we will determine the role of IL-23R in Tregs in intestinal immune homeostasis and during inflammation using mice harboring floxed Il23r alleles combined with a Cre recombinase driven by the endogenous Foxp3 promotor. In Aim 1, we will determine the role of IL-23R in FOXP3+ Tregs during inflammation and inflammation-associated carcinogenesis. In Aim 2, we will define the transcriptional, metabolic, and signaling networks/pathways modulated by IL-23R signaling in intestinal FOXP3+ cells. Overall, these studies explore in detail how IL-23R differentially impacts mucosal immunity and it’s role during inflammation that will inform future therapeutic strategies for IBD and colon cancer. This proposal will further advance the independent studies of the PI and facilitate his transition as a successful investigator and leader in the field of mucosal immunology and will provide sufficient published and preliminary data to facilitate a highly competitive application for a R01 grant application as an early-stage investigator.