Metabolic and CD4+ T Cell Dysregulation in Post-Transplant Diabetes Mellitus

移植后糖尿病中的代谢和 CD4 T 细胞失调

• 批准号: 8894589
• 负责人: BRIAN G ENGELHARDT
• 金额: $ 7.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-18 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894589
• 关键词: Adipocytes; Adipose tissue; Affect; Aftercare; Allogenic; Biological Assay; C-Peptide; CD4 Positive T Lymphocytes; Cancer Survivor; Caring; Cell Proliferation; Cellular Immunity; Chronic; Clinical; Collaborations; Complex; Complication; Coupled; Data; Development; Development Plans; Diabetes Mellitus; Disease; Effector Cell; Endocrine; Endocrinology; Environment; Fasting; Frequencies; Glucose; Glucose Intolerance; Health; Hematological Disease; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hepatic; Homing; Human; Hyperglycemia; Immune; Immune System Diseases; Immunologics; Immunology; Immunosuppression; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interferons; Intervention; K-Series Research Career Programs; Mediating; Mentorship; Metabolic; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Pathogenesis; Patients; Peptides; Peripheral; Phenotype; Physicians; Population; Prevention; Procedures; Publishing; Regulatory T-Lymphocyte; Relative (related person); Research; Resistance; Risk; Role; Scientist; Stem cell transplant; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; Therapeutic Studies; Thymus Gland; Time; Tissues; Training; Translating; Transplant Recipients; Transplantation; United States; Visceral; Work; authority; blood glucose regulation; career; career development; cohort; experience; glucose tolerance; high risk; immunoregulation; mortality; novel; prevent; prospective; response; screening

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplant (HCT) recipients represent a defined population in which up to 60% of patients will develop new-onset post-transplant diabetes mellitus (PTDM) and in whom the development of diabetes presages a high rate of subsequent morbidity and mortality. Data suggests that the propagation of insulin resistance to diabetes is characterized by increased frequencies of inflammatory Th1 cells and the depletion of immunosuppresive regulatory T cells (Tregs) in visceral adipose tissue. In a cohort of HCT recipients, we have identified subsets of circulating Tregs with a gut-homing (�4�7+) phenotype as a marker for visceral tissue inflammation. In this cohort, the development of PTDM was predicted by increased levels of fasting c-peptide prior to transplant and an altered Treg homing phenotype after transplant. We hypothesize that PTDM is due to the exacerbation of chronic, pre-transplant insulin resistance and adipocyte inflammation, which manifests as impaired glucose homeostasis and altered frequencies of tissue-specific T cell subsets before and after HCT. Utilizing a 2-step euglycemic-hyerinsulinemic clamp and standard oral glucose tolerance testing, we will analyze insulin resistance and glucose tolerance before and after matched related donor HCT to determine the timing and mechanisms involved with the development of new-onset PTDM (Aim 1). Next we will examine the inflammatory environment before and after transplant as a generator of PTDM by enumerating circulating gut-homing Th1 cells in the recipient and their donor (Aim 2). In Aim 3 we will characterize the phenotype of the circulating Tregs identified in the preliminary data to determine their expression of GARP and Helios, markers of bona fide activated, thymus-derived (natural) Tregs. We will also analyze the function of circulating Tregs in transplant recipients to determine whether differences exist in Treg suppression or T effector cell proliferation among patients with or without PTDM. These studies, coupled with a novel career development plan utilizing co-mentorship within the fields of immunology and endocrinology, will provide the optimal training milieu for the development of a high-impact career focused on the pathogenesis, prevention, and treatment of metabolic complications following HCT.

描述（由应用提供）：同种异体造血干细胞移植（HCT）受体代表的人群，其中多达60％的患者将发展新的糖尿病后糖尿病（PTDM），其中糖尿病的发展预示着随后的疾病及时疾病的较高的糖尿病率。数据表明，胰岛素对糖尿病的耐药性的传播为特征是炎症性Th1细胞的频率增加以及在内脏脂肪组织中的免疫抑制调节T细胞（TREG）的部署。在HCT接受者的队列中，我们已经确定了带有肠道繁殖（4.7+）表型的循环Treg子集作为内脏组织注射的标记。在该队列中，PTDM的发展是通过移植前的禁食C肽水平升高和移植后Treg Housing表型改变的。我们假设PTDM是由于慢性，移植前胰岛素抵抗和脂肪细胞注射的加剧，这表现为葡萄糖稳态受损以及HCT前后组织特异性T细胞亚群的频率改变。利用两步的尿糖血症酶夹和标准的口服葡萄糖耐量测试，我们将在匹配相关的供体HCT之前和之后分析胰岛素抵抗和葡萄糖耐受性，以确定与新含量PTDM的开发有关的时间和机制（AIM 1）。接下来，我们将通过列举受体及其供体中的循环肠道Th1细胞来检查作为PTDM的发生前后的炎症环境（AIM 2）。在AIM 3中，我们将表征在初步数据中鉴定出的循环Treg的表型，以确定它们的GARP和HELIOS的表达，这是善良的，胸腺衍生的（自然）Tregs的善意的标记。我们还将分析移植受者中循环Treg的功能，以确定有或没有PTDM患者中Treg抑制或T效应细胞增殖中是否存在差异。这些研究再加上一项新的职业发展计划，利用免疫学和内分泌学领域内的会议制度，将为HCT后的发病机理，预防和代谢并发症的治疗提供最佳的培训环境。