Role of Islet-Infiltrating Lymphocytes in Obesity

胰岛浸润淋巴细胞在肥胖中的作用

• 批准号: 8953834
• 负责人: Rachel S Friedman
• 金额: $ 19.81万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-24 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8953834
• 关键词: Adipose tissue; Affect; American; Antigen Receptors; Antigens; Area; Autoimmune Process; Autoimmunity; B-Lymphocytes; Beta Cell; Biological Assay; C-Peptide; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; DNA; Data; Development; Diabetes Mellitus; Diet; Disease; Environment; Epidemic; Fatty acid glycerol esters; Figs - dietary; Frequencies; Functional disorder; Future; Glucose tolerance test; Goals; Immune; Immune response; In Vitro; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Islets of Langerhans; Lead; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; Lymphocyte Subset; Mediating; Metabolic Diseases; Modeling; Mononuclear; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Patients; Phagocytes; Phenotype; Population; Predisposition; Production; Reactive Oxygen Species; Receptor Signaling; Regulatory T-Lymphocyte; Reporter; Resistance; Role; Specificity; T-Lymphocyte; Testing; Therapeutic Intervention; Time; cytokine; feeding; human disease; improved; in vivo; insulin secretion; islet; mouse model; public health relevance; repaired

 DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions, affecting more than one third of Americans with almost 10 percent of Americans affected by type 2 diabetes (T2D). T2D is considered a metabolic disease that is largely induced by obesity, while type 1 diabetes (T1D) is an immune-mediated disease. However, multiple hallmarks of T1D can be detected in some T2D patients, suggesting that an islet-specific autoimmune component could be present in obesity and/or T2D. This application will investigate the role of islet-infiltrating lymphocytes in obesity with the goal of understanding how breaks in lymphocyte tolerance lead to altered beta function. We discovered that T cells and B cells infiltrate the isles in the high fat fed, diet induced obesity model which develops insulin resistance resulting in pre-T2D. These islet-infiltrating lymphocytes had a high percentage of regulatory T cells. However, virtually nothing is known about the function of lymphocytes within the islets during obesity. The human disease relevance of our finding is supported by a study that found lymphocyte infiltration in the islets of T2D patients. Also present in obesity is systemic inflammation that i characterized by circulating inflammatory cytokines and local islet and adipose inflammation that is promoted by the accumulation of classically activated (M1) mononuclear phagocytes. M1 mononuclear phagocytes promote beta cell dysfunction and death, while alternatively activated (M2) mononuclear phagocytes are associated with normal islets and islet repair. In obesity, there is also evidence to suggest that there are lymphocytes that are autoreactive for adipose tissue antigens. If obesity-induced inflammation can induce a break in immunological tolerance to adipose antigens can it also induce a break in tolerance to islet antigens? We hypothesize that in obesity, islet-infiltrating effector lymphocytes are islet-specific and promote beta cell dysfunction and death, in part through activation of M1 mononuclear phagocytes; however, local regulatory lymphocytes control M1 mononuclear phagocyte- mediated inflammation to maintain beta cell function. To test this hypothesis we propose the following aims: (1) to determine if in obesity, islet-infiltrating T cells and B cells are islet-antigen specific; (2) to determine the efect of islet-infiltrating lymphocyte subsets on beta cell death and dysfunction; and (3) to determine how islet- infiltrating lymphocyte subsets affect the number, phenotype and function of mononuclear phagocytes in the islets. Understanding the function of islet-infiltrating lymphocytes in obesity could change our understanding of how obesity alters lymphocyte tolerance leading to susceptibility to both T1D and T2D, thereby revealing new areas of therapeutic intervention to support beta cell function and survival in both forms of diabetes.

 描述（由申请人提供）：肥胖已达到流行病的程度，影响了超过三分之一的美国人，其中近 10% 的美国人患有 2 型糖尿病 (T2D)。 1 型糖尿病 (T1D) 是一种免疫介导的疾病，然而，在一些 T2D 患者中可以检测到 T1D 的多种特征，这表明肥胖中可能存在胰岛特异性自身免疫成分。该应用将研究胰岛浸润淋巴细胞在肥胖中的作用，目的是了解淋巴细胞耐受性的破坏如何导致β功能改变。我们发现T细胞和B细胞浸润​​高脂肪喂养的胰岛。饮食诱导的肥胖模型会产生胰岛素抵抗，从而导致 T2D 前期。这些胰岛浸润淋巴细胞具有高比例的调节性 T 细胞，但实际上，人们对肥胖期间胰岛内淋巴细胞的功能一无所知。我们的发现与人类疾病的相关性得到了一项研究的支持，该研究发现 T2D 患者的胰岛中存在淋巴细胞浸润，肥胖症中还存在全身性炎症，其特征是循环炎症细胞因子以及局部胰岛和脂肪炎症，而炎症细胞因子的积累会促进这种炎症。经典激活的（M1）单核吞噬细胞促进β细胞功能障碍和死亡，而选择性激活的（M2）单核吞噬细胞与正常胰岛和胰岛修复相关。肥胖，也有证据表明存在对脂肪组织抗原具有自身反应的淋巴细胞，如果肥胖引起的炎症可以引起对脂肪抗原的免疫耐受性的破坏，那么它是否也可以引起对胰岛抗原的耐受性的破坏？在肥胖症中，胰岛浸润效应淋巴细胞是胰岛特异性的，部分通过 M1 单核吞噬细胞的激活促进 β 细胞功能障碍和死亡；然而，局部调节淋巴细胞控制 M1 单核细胞；为了检验这一假设，我们提出以下目标：（1）确定胰岛浸润性 T 细胞和 B 细胞是否具有胰岛抗原特异性。胰岛浸润淋巴细胞亚群对β细胞死亡和功能障碍的影响；（3）确定胰岛浸润淋巴细胞亚群如何影响胰岛中单核吞噬细胞的数量、表型和功能。肥胖中胰岛浸润淋巴细胞的功能可能会改变我们对肥胖如何改变淋巴细胞耐受性从而导致对 T1D 和 T2D 易感性的理解，从而揭示支持两种类型糖尿病中 β 细胞功能和存活的治疗干预的新领域。