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

基本信息

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
项目类别：
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

项目摘要

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) 接受者代表了一个确定的人群，其中高达 60% 的患者会出现新发移植后糖尿病 (PTDM)，而在这些人群中，糖尿病的发生预示着糖尿病的发生。随后的高发病率和死亡率数据表明，胰岛素抵抗向糖尿病的传播以炎症 Th1 细胞频率增加和 Th1 细胞耗竭为特征。在一组 HCT 接受者中，我们发现了具有肠道归巢 (�4�7+) 表型的循环 T 细胞亚群，作为内脏组织炎症的标志物。，PTDM 的发展是通过移植前空腹 C 肽水平的增加和移植后 Treg 归巢表型的改变来预测的。慢性、移植前胰岛素抵抗和脂肪细胞炎症，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。利用两步正常血糖-高胰岛素钳夹和标准口服葡萄糖耐量测试，我们将分析匹配相关供体 HCT 前后的胰岛素抵抗和葡萄糖耐量，以确定新发 PTDM 发生的时间和机制（目标 1）。通过计数受体及其供体中的循环肠道归巢 Th1 细胞，在移植前后作为 PTDM 的生成者（目标 2），我们将表征初步数据中识别的循环 Tregs 的表型，以确定其表达。 GARP 和 Helios，真正激活的胸腺来源（天然）Treg 的标志物我们还将分析移植受者中循环 Treg 的功能，以确定 Treg 抑制或 T 效应细胞增殖是否存在差异。这些研究，加上利用免疫学和内分泌学领域的共同指导的新型职业发展计划，将为专注于发病机制、预防、以及 HCT 后代谢并发症的治疗。