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（由适用提供）：肥胖已经达到流行比例，影响了近10％的美国人受2型糖尿病（T2D）影响的美国人中有三分之一以上。 T2D被认为是一种代谢性疾病，主要由目标引起，而1型糖尿病（T1D）是一种免疫介导的疾病。但是，在某些T2D患者中可以检测到T1D的多个标志，这表明肥胖和/或T2D中可能存在特定于胰岛的自身免疫成分。该应用将调查胰岛浸润淋巴细胞在肥胖中的作用，以了解淋巴细胞耐受性的断裂如何导致β功能的改变。我们发现T细胞和B细胞在高脂肪喂养的饮食诱导的肥胖模型中浸润，从而发展出胰岛素抵抗，从而导致T2D。这些胰岛浸润淋巴细胞的调节性T细胞比例很高。但是，肥胖期间胰岛内淋巴细胞的功能几乎一无所知。我们发现的人类疾病相关性得到了一项研究发现T2D患者胰岛中淋巴细胞浸润的研究。肥胖症也存在于全身性炎症中，我的特征是循环炎性细胞因子和局部胰岛和脂肪炎症，这是通过经典激活（M1）单核吞噬细胞的积累而促进的。 M1单核吞噬细胞可促进β细胞功能障碍和死亡，而替代激活（M2）单核吞噬细胞与正常胰岛和胰岛修复有关。在所有权中，也有证据表明，有一些淋巴细胞对脂肪组织抗原具有自身反应性。如果肥胖引起的炎症会引起免疫学耐受性的脂肪抗原的破裂，这还可以引起突破以检验这一假设，我们提出以下目的：（1）确定在肥胖，胰岛渗透效应效应子淋巴细胞中是否是胰岛细胞特异性和促进beta细胞淋巴细胞，是通过beta细胞的per per per per per，一部分通过激进的范围。但是，局部调节性淋巴细胞控制M1单核吞噬细胞介导的炎症以维持β细胞功能。为了检验该假设，我们提出以下目的：（1）确定在肥胖症中，胰岛浸润的T细胞和B细胞是特异性的； （2）确定胰岛浸润淋巴细胞子集对β细胞死亡和功能障碍的有效性； （3）确定胰岛浸润的淋巴细胞子集如何影响胰岛中单核吞噬细胞的数量，表型和功能。了解肥胖症中胰岛浸润淋巴细胞的功能可能会改变我们对肥胖症如何改变淋巴细胞耐受的理解，从而导致对T1D和T2D的敏感性，从而揭示热干预的新领域，以支持两种糖尿病形式的β细胞功能和生存。