Tissue Resident Immune Cells in Human Pancreas.

人类胰腺中的组织驻留免疫细胞。

• 批准号: 9805950
• 负责人: Stuart P Weisberg
• 金额: $ 16.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805950
• 关键词: Activities of Daily Living; Antigen-Presenting Cells; Area; Biogenesis; Biology; CD58 gene; CD86 gene; CD8B1 gene; Cells; Clinical; Coculture Techniques; Computer Analysis; Data; Dependence; Diabetes Mellitus; Digestion; Disease; Duct (organ) structure; Ductal; Endocrine; Fibrosis; Gene Expression Profile; Genetic Transcription; Health; Homeostasis; Human; Image Analysis; Immune; Immune System Diseases; Immune response; Immunologic Surveillance; Immunology; In Situ; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Integrins; Islets of Langerhans; K-Series Research Career Programs; Knowledge; Ligands; Lymph Node Tissue; Lymphoid; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolic; Metabolism; Mitochondria; Morbidity - disease rate; Mus; Obesity; Organ Donor; PD-1/PD-L1; Pancreas; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Pancreatic duct; Pancreatitis; Pathologist; Pathway interactions; Pattern; Phenotype; Physicians; Play; Population; Property; Quantitative Microscopy; Regulation; Research; Resources; Rest; Risk; Risk Factors; Role; SLEB2 gene; Scientist; Shapes; Site; System; T cell regulation; T memory cell; T-Cell Activation; T-Lymphocyte; Tissues; Training; acute pancreatitis; career; chronic pancreatitis; density; dimensional analysis; experience; gastrointestinal; high dimensionality; human tissue; immune function; immunoregulation; islet; jejunum; lymph nodes; macrophage; metabolic profile; mortality; novel; novel strategies; prevent; residence; stressor; tissue repair; transcriptome sequencing

PROJECT SUMMARY ABSTRACT Dr. Weisberg is a Clinical Pathologist and Physician Scientist investigating the unique immune microenvironment within human pancreas. Immune regulation within tissues is highly dependent on non- recirculating resident immune cells. Tissue macrophages modulate local immune function, sense metabolic disturbances and participate in tissue repair and homeostasis, and tissue resident memory T cells (Trm) provide localized protective immune responses and tissue immune surveillance. Populations of Trm have now been identified in almost all tissues of the body. Human and murine studies show that Trm are phenotypically, transcriptionally and functionally distinct compared to circulating T cells. Although core properties of Trm common to most tissue sites have been identified, the differentiation state and functional profiles of Trm are also shaped by their microenvironment. These tissue specific properties of Trm and how they are altered by local stressors are less well defined. Due to the limited availability of healthy human pancreas tissue, relatively little is known about the resident immune cells of human pancreas. More knowledge is needed about these cells, because disruption of pancreatic immune homeostasis has severe consequences for human health, leading to diseases with high morbidity and mortality including acute and chronic pancreatitis, type I diabetes and pancreatic cancer. Obesity is associated with pro-inflammatory changes in pancreas and is a major risk factor for pancreatitis and pancreatic cancer. Elucidating the mechanisms that regulate pancreas resident immune cells and how they are influenced by metabolic stressors such as obesity may suggest novel strategies to prevent and treat pancreatic disease. Using a resource within Dr. Donna Farber’s lab which provides access to multiple gastrointestinal tissues from previously healthy organ donors, our preliminary studies have already defined several unique properties of pancreatic Trm. Within pancreas, networks of CD8 Trm cluster with macrophages in the exocrine and ductal areas, surrounding but not penetrating into the endocrine islets. The Trm are resting but with high functional capacity, and the macrophages express mediators of both positive and negative T cell regulation. Our central hypothesis is that pancreatic Trm are maintained in a state distinct from other sites by their local interactions with pancreatic macrophages; and due to their residence in a key tissue that regulates and senses metabolic changes, pancreatic Trm are uniquely sensitive to metabolic alterations such as obesity. The aims of the proposal are 1) Define the distinct properties of Trm in pancreas compared to neighboring tissues; 2) Identify mechanisms of pancreatic Trm-macrophage crosstalk; 3) Identify obesity-related changes in pancreas Trm functional profiles and localization. This career development award will provide critical training and experience in human T cell immunology research, and computational analysis of high dimensional immune data allowing Dr. Weisberg to establish an independent translational immunology research career studying mechanisms of tissue-specific immune regulation.

项目摘要摘要 Weisberg博士是一名临床病理学家和医师科学家，研究了独特的免疫 人类胰腺中的微环境。组织内的免疫调节高度取决于非 - 循环居民免疫细胞。组织巨噬细胞调节局部免疫功能，感觉代谢 干扰和参与组织修复和稳态，以及组织居民记忆T细胞（TRM） 提供局部保护的免疫血液和组织免疫检查。 TRM的种群现在有 他几乎在身体的所有组织中都被鉴定出来。人类和鼠的研究表明，TRM是表型的， 虽然TRM的核心特性 已经确定了大多数组织位点的共同点，TRM的分化状态和功能曲线是 也由它们的微环境塑造。这些TRM的这些组织特异性特性及其如何通过 当地压力源的定义不太明确。由于健康的人胰腺组织的可用性有限 关于人类胰腺的居民免疫小球知之甚少。需要更多知识 细胞，因为胰腺免疫稳态的破坏对人类健康造成了严重后果，所以 导致发病率高和死亡率的疾病，包括急性和慢性胰腺炎，I型糖尿病 和胰腺癌。肥胖与胰腺的促炎性变化有关，是主要风险 胰腺炎和胰腺癌的因素。阐明调节胰腺居住的机制 免疫细胞以及如何受到代谢应激源（例如肥胖）的影响可能表明新型 预防和治疗胰腺疾病的策略。在Donna Farber博士的实验室中使用资源 我们的初步提供了以前健康器官供体的多种胃肠道组织的访问 研究已经定义了胰腺TRM的几种独特特性。在胰腺中，CD8网络 TRM簇在外分泌区和导管区，周围但不穿透到 内分泌小岛。 TRM静止但功能高，巨噬细胞表达 阳性和负T细胞调节的介体。我们的中心假设是胰腺TRM是 通过与胰腺巨噬细胞的局部相互作用，保持在与其他地点不同的状态；并到期 居住在调节和感觉代谢变化的关键组织中，胰腺TRM是独特的 对肥胖等代谢改变敏感。提案的目的是1）定义不同的特性 与邻近组织相比，胰腺中的TRM； 2）确定胰腺TRM巨噬细胞的机制 相声; 3）确定与肥胖相关的胰腺功能分布和定位的变化。这个职业 开发奖将在人类T细胞免疫学研究中提供批判性培训和经验，以及 高维免疫数据的计算分析，允许Weisberg博士建立独立 翻译免疫学研究职业研究组织特异性免疫学调节机制。