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（由申请人提供）：同种异体造血干细胞移植（HCT）受者代表了一个确定的人群，其中高达60%的患者将发展为移植后新发糖尿病（PTDM），糖尿病的发展预示着随后的高发病率和死亡率。数据表明，糖尿病胰岛素抵抗的传播特点是炎症性Th1细胞频率增加和内脏脂肪组织中免疫抑制调节性T细胞（Tregs）的消耗。在HCT受体队列中，我们已经确定了具有肠道归巢（4 - 7+）表型的循环treg亚群，作为内脏组织炎症的标志物。在这个队列中，通过移植前空腹c肽水平的升高和移植后Treg归巢表型的改变来预测PTDM的发展。我们假设PTDM是由于慢性移植前胰岛素抵抗和脂肪细胞炎症的加剧，表现为HCT前后葡萄糖稳态受损和组织特异性T细胞亚群频率改变。利用两步正糖-高胰岛素钳和标准口服糖耐量测试，我们将分析匹配相关供体HCT前后的胰岛素抵抗和糖耐量，以确定新发PTDM的发生时间和机制（目的1）。接下来，我们将通过列举受体及其供体的循环肠道归巢Th1细胞来检查移植前后的炎症环境作为PTDM的产生者（目的2）。在Aim 3中，我们将描述在初步数据中鉴定的循环treg的表型，以确定其GARP和Helios的表达，这是真正激活的胸腺来源（天然）treg的标记。我们还将分析移植受者循环Treg的功能，以确定是否存在Treg抑制或T效应细胞增殖的差异。这些研究，再加上利用免疫学和内分泌学领域的共同指导的新的职业发展计划，将为HCT后代谢并发症的发病机制、预防和治疗的高影响力职业的发展提供最佳的培训环境。