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

项目摘要 对肠腔细菌的免疫应答失调是导致慢性腹泻的主要原因。 炎症性肠病（IBD）的性质。通过免疫调节剂减弱炎症反应 和/或生物制剂代表了诱导缓解的大多数治疗策略。然而，许多患者 要么不响应，而那些最初响应的通常停止响应。恢复免疫耐受， 增加调节性T细胞（Treg）数量或改善Treg功能可能是实现以下目标的可行策略： 长期缓解。PI的K 01奖重点关注在体内扩大TcR的策略，以防止 人源化小鼠的实验性结肠炎。在这些研究的过程中，细胞因子白细胞介素-23（IL-23）被 在鼠和人抗原呈递细胞中上调。与IL-23在IBD中的作用一致， IL 23 R与IBD易感性有关。此外，最近的一项在患有 克罗恩病靶向IL-23的p40亚单位（也与IL-12共享），并报告了显著性差异。 与安慰剂相比，在诱导和维持临床应答和缓解方面均有改善。虽然 肠中的巨噬细胞和树突状细胞是IL-23的来源，IL-23 R的表达通常是 仅限于淋巴细胞和3型先天淋巴样细胞（ILC 3）。在本提案中，我们将确定 IL-23受体在肠道免疫稳态和炎症过程中的表达 等位基因与由内源性Foxp 3启动子驱动的Cre重组酶组合。在目标1中，我们 确定IL-23 R在炎症和炎症相关性炎症过程中FOXP 3 + T细胞中的作用 致癌作用在目标2中，我们将定义转录，代谢和信号网络/途径 在肠FOXP 3+细胞中通过IL-23 R信号传导调节。总的来说，这些研究详细探讨了IL-23 R 差异影响粘膜免疫及其在炎症过程中的作用，这将为未来的治疗提供信息。 IBD和结肠癌的治疗策略。这一建议将进一步推动PI的独立研究， 促进他作为粘膜免疫学领域的成功研究者和领导者的转变，并将 提供足够的已发布和初步数据，以促进竞争激烈的R 01赠款申请 作为一个早期的调查员。

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.