Type 2 cytokines and innate lymphoid cells in pediatric ulcerative colitis

小儿溃疡性结肠炎中的 2 型细胞因子和先天淋巴细胞

• 批准号: 10596871
• 负责人: Michael J Rosen
• 金额: $ 44.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596871
• 关键词: Address; Adrenal Cortex Hormones; American; Autologous; Biological; Biopsy; Caring; Cell Differentiation process; Cell Therapy; Cells; Child; Childhood; Chronic; Clinical; Coculture Techniques; Colitis; Colon; Crohn' s disease; Custom; Data; Data Set; Diagnosis; Diagnostic; Differentiation and Growth; Disease; Disease remission; Epithelial; Flow Cytometry; Gene Expression; Gene Expression Profile; Goblet Cells; Growth; Homeostasis; Human; IL5 gene; Immune; Immune Response Genes; Immune response; Immunologics; Immunophenotyping; Inflammation; Inflammatory; Interleukin-13; Interleukin-17; Large Intestine; Lymphocyte; Lymphoid Cell; Maintenance; Measures; Mediating; Microfluidics; Modeling; Morbidity - disease rate; Mucins; Mucous Membrane; Mucous body substance; Mus; Outcome; Oxazolone; Pathway interactions; Patients; Pediatric ulcerative colitis; Pharmaceutical Preparations; Production; Prognostic Factor; RNA; Source; Steroids; System; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Treatment outcome; Ulcerative Colitis; base; clinical predictors; clinical remission; cohort; cytokine; dextran sulfate sodium induced colitis; disorder control; epithelial repair; follow-up; healing; improved; individualized medicine; intestinal epithelium; mesenteric lymph node; microbial colonization; microbiome; mouse model; peripheral blood; predicting response; predictive signature; preservation; prognostic value; prospective; rectal; repaired; response; single-cell RNA sequencing; therapy development; transcriptome; treatment response

PROJECT SUMMARY This proposal addresses two critical gaps in the treatment of pediatric ulcerative colitis (UC). The first gap is the need for patient-specific immunologic profiles that inform precision UC treatments to achieve remission efficiently on the safest medication. The second gap is the need to investigate therapeutic mechanisms that promote epithelial homeostasis and, thereby, improve mucosal healing, one of the best predictors of sustained remission in UC. We previously demonstrated that treatment naïve pediatric UC can be distinguished from colon-only Crohn's disease by increased mucosal expression of type 2 and type 17 immune response genes, as measured by a custom real time RT-qPCR microfluidic array. Furthermore, we observed that high mucosal expression of the type 2 cytokines IL13 and IL5 was associated with 5-fold increased odds of 12-month clinical remission in pediatric UC. We have also shown that IL33, a cytokine that induces type 2 cytokine production by innate lymphoid cells (ILCs), is increased in pediatric UC and is protective in oxazolone colitis in mice, in part through preservation of mucin-producing goblet cells. Maintenance of the mucus layer is critical for epithelial barrier function and mucosal healing. Our preliminary data supports that IL33 induces goblet cell differentiation by promoting the production of IL13 by group 2 ILCs (ILC2s). Our overarching hypothesis is that the induction of mucosal type 2 cytokines by ILC2s in a subset of pediatric UC patients protects the epithelium in the setting of uncontrolled type 17 inflammation and leads to superior treatment outcomes. In Aim 1, we will apply our array to tissues from treatment-naïve patients in a large prospective pediatric UC inception cohort and validate the type 2 gene expression signature for predicting treatment-specific clinical and endoscopic outcome. We will also integrate our array data with microbiome and transcriptome data sets from this cohort to identify key associations between type 2 immunophenotype and microbial colonization/function and host epithelial homeostasis/repair pathways, respectively. In Aim 2, we will identify ILC2s as a key source of type 2 cytokines in pediatric UC using multicolor flow cytometry and single-cell RNA sequencing. We will also determine the effect of autologous peripheral blood ILC2s on human primary colonoid growth and differentiation using a colonoid-immune cell co-culture system. In Aim 3, we will determine the effect of ILC2s on epithelial repair and differentiation, and treatment response during chronic colitis in mice using the T cell transfer and chronic DSS models. Upon completion of Aim 1, we will have validated an assessment of UC immunophenotype for predicting clinical remission and mucosal healing in response to specific treatments in a large well-defined UC inception cohort, which will inform precision patient-specific treatment in UC. Upon completion of Aim 2 and 3, we will have determined whether ILC2s are capable of promoting epithelial growth and goblet cell differentiation in humans and relevant murine models of chronic colitis. This deliverable would support the development of therapies that promote ILC2s or ILC2 cellular therapy for advancing mucosal healing in UC.

项目摘要 该提案解决了小儿溃疡性结肠炎（UC）治疗的两个关键差距。第一个差距是 需要特定于患者的免疫学特征，以告知精度UC治疗以实现缓解 有效地使用最安全的药物。第二个差距是需要调查治疗机制 促进上皮稳态，从而改善粘膜愈合，这是持续的最佳预测指标之一 UC的缓解。我们先前证明了治疗幼稚的小儿UC可以区分 仅限于结肠Crohn的疾病，通过增加2型和17型免疫反应基因的粘膜表达， 通过自定义实时RT-QPCR微流体阵列测量。此外，我们观察到高粘膜 2型细胞因子IL13和IL5的表达与12个月临床的几率增加了5倍 小儿UC的缓解。我们还表明，IL33是一种通过影响2型细胞因子产生的细胞因子 先天淋巴样细胞（ILC）在小儿UC中增加，并在小鼠的恶唑酮结肠炎中受到保护，部分部分是 通过保存粘蛋白产生的杯状细胞。粘液层的维护对于上皮至关重要 障碍功能和粘膜愈合。我们的初步数据支持IL33诱导杯状细胞分化 通过第2组ILC（ILC2S）促进IL13的生产。我们的总体假设是归纳 ILC2在小儿UC患者一部分中通过ILC2S的粘膜2型细胞因子保护上皮。 不受控制的17型注射，并导致卓越的治疗结果。在AIM 1中，我们将应用我们的 在大型前瞻性小儿UC Inception队列中，未接受治疗的患者的组织阵列并验证 用于预测特定治疗特异性临床和内窥镜结果的2型基因表达特征。我们将 还将我们的数组数据与微生物组和转录组数据集整合在一起，以识别密钥 2型免疫表型与微生物定植/功能与宿主上皮之间的关联 稳态/维修途径。在AIM 2中，我们将确定ILC2是2型细胞因子的关键来源 在小儿UC中使用多色流式细胞术和单细胞RNA测序。我们还将确定 自体外周血ILC2s对人类原发性结构类别生长和分化的影响 结肠体免疫细胞共培养系统。在AIM 3中，我们将确定ILC2对上皮修复和 使用T细胞转移和慢性DSS的小鼠慢性结肠炎期间的分化和治疗反应 型号。 AIM 1完成后，我们将验证对UC免疫表型的评估 预测大型UC中特定治疗的临床缓解和粘膜愈合 Inception队列将为UC中的精确患者特定治疗提供信息。 AIM 2和3完成后， 我们将确定ILC2是否能够促进上皮生长和杯状细胞 人类的分化和相关的慢性结肠炎鼠模型。此交付将支持 开发促进ILC2S或ILC2细胞疗法的疗法，以推进UC中的粘膜愈合。

项目成果

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33.

• DOI: 10.1038/s41467-021-21113-7
• 发表时间: 2021-02-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Schumacher MA;Hsieh JJ;Liu CY;Appel KL;Waddell A;Almohazey D;Katada K;Bernard JK;Bucar EB;Gadeock S;Maselli KM;Washington MK;Grikscheit TC;Warburton D;Rosen MJ;Frey MR
• 通讯作者: Frey MR

Could a Small Population of Epithelial Cells Get "Tuft" With Crohn's Disease?

• DOI: 10.1053/j.gastro.2020.09.037
• 发表时间: 2020-12
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Rosen MJ