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: 8765948
• 负责人: BRIAN G ENGELHARDT
• 金额: $ 12.46万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8765948
• 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; 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; public health relevance; 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（由申请方提供）：异基因造血干细胞移植（HCT）受者代表了一个定义的人群，其中高达60%的患者将发生新发移植后糖尿病（PTDM），并且糖尿病的发生预示着后续发病率和死亡率较高。数据表明，传播胰岛素抵抗糖尿病的特点是增加频率的炎性Th 1细胞和消耗的免疫抑制调节性T细胞（T细胞）在内脏脂肪组织。在一组HCT接受者中，我们已经确定了具有肠道归巢（<$4 <$7+）表型的循环TcB亚群作为内脏组织炎症的标志物。在该队列中，PTDM的发展通过移植前空腹C肽水平升高和移植后Treg归巢表型改变来预测。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恶化，其表现为葡萄糖稳态受损和HCT前后组织特异性T细胞亚群频率的改变。利用2步正常血糖-高胰岛素钳夹和标准口服葡萄糖耐量试验，我们将分析匹配相关供体HCT前后的胰岛素抵抗和葡萄糖耐量，以确定新发PTDM发生的时间和机制（目的1）。接下来，我们将通过计数受体和供体中循环肠道归巢Th 1细胞来检查移植前后作为PTDM发生器的炎症环境（目的2）。在目标3中，我们将表征在初步数据中鉴定的循环Tcls的表型，以确定它们的GARP和Helios的表达，GARP和Helios是真正活化的胸腺衍生的（天然）Tcls的标志物。我们还将分析移植受者中循环T淋巴细胞的功能，以确定是否存在差异，在Treg抑制或T效应细胞增殖患者与PTDM或没有。这些研究，再加上一个新的职业发展计划，利用免疫学和内分泌学领域的共同导师，将提供最佳的培训环境，为发展高影响力的职业生涯，重点是HCT后代谢并发症的发病机制，预防和治疗。