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

描述(由申请人提供)：异基因造血干细胞移植(HCT)接受者代表了一个特定的人群，在这个人群中，高达60%的患者将发展为新发的移植后糖尿病(PTDM)，在这些患者中，糖尿病的发展预示着随后的高发病率和死亡率。数据表明，胰岛素抵抗对糖尿病的传播特征是炎性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)耗尽。在一组红细胞移植受者中，我们确定了具有肠道归巢(�4�7+)表型的循环树突状细胞亚群作为内脏组织炎症的标志。在该队列中，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PTDM的发展。我们假设PTDM是由于移植前慢性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。利用两步正血糖-高胰岛素钳夹和标准的口服葡萄糖耐量试验，我们将分析匹配的亲属供者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(目标1)。接下来，我们将通过计数受者和供者体内循环中的肠道归巢Th1细胞来检查移植前后的炎症环境，作为PTDM的生成者(目标2)。在目标3中，我们将对初步数据中确定的循环Tregs的表型进行表征，以确定它们的GARP和Helios的表达，GARP和Helios是真正激活的胸腺来源(天然)Tregs的标志。我们还将分析移植受者循环中Treg的功能，以确定患有和不患有PTDM的患者在Treg抑制或T效应细胞增殖方面是否存在差异。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的职业发展计划，将为发展专注于HCT后代谢并发症的发病机制、预防和治疗的高影响力职业生涯提供最佳的培训环境。

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.