Intestinal Dendritic Cell Modulation of Regulatory T Cell Function in IBD

IBD 中调节性 T 细胞功能的肠道树突状细胞调节

• 批准号: 8317680
• 负责人: James Daniel Lord
• 金额: $ 14.75万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-25 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317680
• 关键词: Autoimmune Process; Biological Assay; Blocking Antibodies; CD4 Positive T Lymphocytes; Cell physiology; Cell surface; Cells; Cellular Immunology; Chronic; Clinical; Coculture Techniques; Communities; Data; Dendritic Cells; Development Plans; Doctor of Medicine; Doctor of Philosophy; Educational Curriculum; Exercise; Fostering; Gastroenterology; Human; Human Resources; Immune system; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Ligands; Link; Mediating; Medical center; Mentorship; Molecular; Molecular Immunology; Pacific Northwest; Patients; Pattern; Physicians; Public Health; Recombinants; Recruitment Activity; Regulatory T-Lymphocyte; Reporting; Research; Research Institute; Research Personnel; Resected; Resistance; Signal Transduction; Sorting - Cell Movement; Study Subject; Surface; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; Testing; Universities; Virginia; Washington; career; career development; cytokine; design; forging; in vivo; prevent; programs; receptor; research facility; research study; symposium; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Project Summary: Dr. James Lord, M.D., Ph.D., is a motivated senior gastroenterology fellow with a strong background in basic immunology research. His immediate career plans involve understanding how regulatory T cells (Tregs) fail to prevent inflammation in inflammatory bowel disease. He proposes to study dendritic cells (DC) in the surgically resected bowels of patients with IBD, to determine if and how certain subtypes of DC prevent Tregs from inhibiting other T cells. He plans to identify the surface receptors and soluble cytokines produced by these DC, and determine if these may impair Treg function. He also will determine if DC indirectly impair Treg function by altering the differentiation of other T cells to become less responsive to Treg-mediated inhibition. This research will be performed under the mentorship of Steven Ziegler, a well-established Treg biologist. The Ziegler lab is well equipped for molecular and cellular immunology research, and exists within the Benaroya Research Institute (BRI). The BRI is an academic research facility dedicated to the study of autoimmune and chronic inflammatory conditions, and as such contains many material and human resources vital to the study of human immunology. The BRI is itself affiliated with the University of Washington, which represents a large, prestigious and vibrant reseach [sic] community. The BRI is also affiliated with, and recruits study subjects from, the Virginia Mason Medical Center, which is one of the busiest tertiary referral centers for IBD in the Pacific Northwest. Dr. Lord's long-term career plans involve building upon his dual backgrounds in clinical gastroenterology and basic immunology to forge a link between the large clinical gastroenterology community and the strong basic immunology research community currently present in Seattle. His career development plan outlines a curriculum of research, didactic coursework, and local and national conference attendance, designed to foster his maturation into a successful translational researcher. Relevance to Public Health: Despite significant advances in our understanding of the immune system, IBD remains incurable, poorly understood, and both challenging and expensive to treat. If the proposed experiments reveal a fundamental mechanism by which IBD occurs, they may not only reveal new potential treatment strategies for tomorrow, but also allow physicians to better target the treatments they have today.

描述（由申请人提供）： 项目概要：James Lord博士，医学博士，哲学博士、是一个积极的高级胃肠病学研究员，在基础免疫学研究方面有很强的背景。他近期的职业计划包括了解调节性T细胞（Tcells）如何无法预防炎症性肠病中的炎症。他建议研究IBD患者手术切除的肠道中的树突状细胞（DC），以确定某些DC亚型是否以及如何阻止T细胞抑制其他T细胞。他计划鉴定这些DC产生的表面受体和可溶性细胞因子，并确定这些是否会损害Treg功能。他还将确定DC是否通过改变其他T细胞的分化来间接损害Treg功能，从而降低对Treg介导的抑制的反应。这项研究将在著名Treg生物学家Steven齐格勒的指导下进行。齐格勒实验室配备了良好的分子和细胞免疫学研究，并存在于贝纳罗亚研究所（BRI）。BRI是一个致力于研究自身免疫和慢性炎症的学术研究机构，因此包含许多对人类免疫学研究至关重要的材料和人力资源。BRI本身隶属于华盛顿大学，该大学代表了一个大型，有声望和充满活力的研究社区。BRI还隶属于弗吉尼亚梅森医学中心，并从该中心招募研究对象，该中心是太平洋西北部最繁忙的IBD三级转诊中心之一。洛德博士的长期职业计划涉及建立在他的双重背景，在临床胃肠病学和基础免疫学，以建立一个大型临床胃肠病学社区和强大的基础免疫学研究社区目前在西雅图之间的联系。他的职业发展计划概述了研究课程，教学课程，以及当地和国家会议的出席，旨在促进他成为一个成功的翻译研究人员的成熟。 与公共卫生的相关性：尽管我们对免疫系统的理解取得了重大进展，但IBD仍然无法治愈，了解甚少，治疗既具有挑战性又昂贵。如果拟议的实验揭示了IBD发生的基本机制，它们不仅可以揭示未来新的潜在治疗策略，而且还可以让医生更好地瞄准他们今天的治疗。

项目成果

Human Blood and Mucosal Regulatory T Cells Express Activation Markers and Inhibitory Receptors in Inflammatory Bowel Disease.

• DOI: 10.1371/journal.pone.0136485
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lord JD;Shows DM;Chen J;Thirlby RC
• 通讯作者: Thirlby RC

Paradoxically increased FOXP3+ T cells in IBD do not preferentially express the isoform of FOXP3 lacking exon 2.

• DOI: 10.1007/s10620-012-2292-3
• 发表时间: 2012-11
• 期刊: DIGESTIVE DISEASES AND SCIENCES
• 影响因子: 3.1
• 作者: Lord, James D.;Valliant-Saunders, Karine;Hahn, Hejin;Thirlby, Richard C.;Ziegler, Steven F.
• 通讯作者: Ziegler, Steven F.

T-cell receptor sequencing reveals the clonal diversity and overlap of colonic effector and FOXP3+ T cells in ulcerative colitis.

• DOI: 10.1097/mib.0000000000000242
• 发表时间: 2015-01
• 期刊: Inflammatory bowel diseases
• 影响因子: 4.9
• 作者: Lord J;Chen J;Thirlby RC;Sherwood AM;Carlson CS
• 通讯作者: Carlson CS