The Role of Lymphocytes in Diet-Induced Metabolic Disease

淋巴细胞在饮食引起的代谢性疾病中的作用

• 批准号: 8495452
• 负责人: Barbara Nikolajczyk
• 金额: $ 19.26万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495452
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adult; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; B-Lymphocytes; Biological Assay; Biological Markers; Blood; Blood Cells; Blood Tests; Blood Vessels; Blood typing procedure; CD4 Positive T Lymphocytes; Cell Communication; Cell Count; Cell physiology; Cells; Chronic; Clinical; Coculture Techniques; Coupled; Data; Development; Diet; Disease; Enzyme-Linked Immunosorbent Assay; Equilibrium; FDA approved; Flow Cytometry; Glucose; Health; Healthcare Systems; Histocompatibility Testing; Human; Immune; Immune system; Individual; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interferons; Interleukin-17; Leptin; Link; Lymphocyte; Maintenance; Measures; Mediator of activation protein; Metabolic; Metabolic Diseases; Methods; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Play; Prevention; Process; Production; Proteins; Publishing; Regulatory T-Lymphocyte; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sampling; Serum; Source; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; Work; adiponectin; cell type; cost; cytokine; human subject; innovation; insight; macrophage; mouse model; novel; nutrition; prevent; response; subcutaneous; treatment strategy

DESCRIPTION (provided by applicant): The appreciation of insulin resistance (IR) and type 2 diabetes (T2D) as chronic inflammatory diseases has necessitated development of the new field of immunometabolism, which will define the role of the immune system in metabolic disease. Recent animal studies have shown that inflammatory T cells and B cells play key roles in the development of IR in T2D. For example, T cell skewing towards the pro-inflammatory Th17 and Th1 subsets and elevated Th17/Th1 numbers in the expanding diet-induced obesity (DIO) mouse adipose tissue (AT) promotes inflammation, thus IR (1, 5). Importantly, Th17 and Th1 cells are major sources of IL-17 and IFN-¿, respectively, two pro-inflammatory, anti-adipogenic, IR-linked cytokines. Complementary studies showed loss of anti-inflammatory regulatory T cells (Tregs) increases AT inflammation and serum insulin levels, while gain of Treg function decreases AT inflammation and rescues glucose sensitivity. Together, these studies show a pro-inflammatory T cell balance plays important roles in IR. Similar approaches also show B cells promote inflammation and IR. Like these murine studies, our pioneering human immunometabolism work identified a pro-inflammatory T cell subset balance in blood from T2D patients: pro-inflammatory Th17 and Th1 cells are elevated, and anti-inflammatory Tregs are reduced. Furthermore, we found that blood B cells from T2D patients are pro-inflammatory. Importantly, new data show T cell/B cell interaction is critical for elevated Th17 function in T2D; thus we have initiated some of the first mechanistic immunometabolism studies in human samples. Taken together, our work indicates that detailed human immune cell analysis will identify new mechanisms of IR/T2D thus introduce new concepts in assessment and treatment strategies. Furthermore, detailed analysis of the human immune system in IR/T2D individuals is absolutely essential to justify attempts to harness the power of the immune system as a biomarker and/or treatment for T2D. We hypothesize that the elevated pro-inflammatory T cell function we have found in T2D 1. is similar in blood and AT from a single individual; 2. Predicts IR and/or AT function in obesity patients; and 3. Requires support from B cells, which can be safely ablated with FDA-approved drugs. Testing these hypotheses would assess the innovative possibility that a simple blood test (T cell subset analysis) can identify risk of transition from insulin-sensitive to IR. The availability of such a test would be a major advance with immediate clinical impact. In addition to preliminarily identifying a biomarker for the IS/IR transition, outcomes will address the novel possibility that existing B cell depletion drugs may prevent the IS/IR transition.

描述（由申请人提供）：胰岛素抵抗（IR）和2型糖尿病（T2D）作为慢性炎症性疾病的认识使得免疫代谢这一新领域的发展成为必要，这将定义免疫系统在代谢疾病中的作用。最近的动物研究表明，炎性T细胞和B细胞在T2D的IR发展中起关键作用。例如，在饮食诱导肥胖（DIO）小鼠脂肪组织（AT）中，T细胞向促炎Th17和Th1亚群倾斜，Th17/Th1数量升高，从而促进炎症，从而促进IR（1,5）。重要的是，Th17和Th1细胞分别是IL-17和IFN-¿的主要来源，这是两种促炎、抗脂肪、ir相关细胞因子。补充研究表明，抗炎调节性T细胞（Treg）的缺失会增加AT炎症和血清胰岛素水平，而Treg功能的增强会降低AT炎症并恢复葡萄糖敏感性。总之，这些研究表明促炎T细胞平衡在IR中起重要作用。类似的方法也表明B细胞促进炎症和IR。像这些小鼠研究一样，我们开创性的人类免疫代谢工作确定了T2D患者血液中的促炎T细胞亚群平衡：促炎Th17和Th1细胞升高，抗炎Tregs细胞减少。此外，我们发现T2D患者的血B细胞具有促炎作用。重要的是，新数据显示T细胞/B细胞相互作用对于T2D中Th17功能的升高至关重要；