Cord Blood Immunoregulation of Type 1 Diabetes

1 型糖尿病的脐带血免疫调节

• 批准号: 7115415
• 负责人: MARK A. ATKINSON
• 金额: $ 19.73万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115415
• 关键词: CD4 molecule; T lymphocyte; antigen antibody reaction; autoimmunity; autotransfusion; cell population study; cellular immunity; children; clinical research; cord blood; diabetes mellitus genetics; diabetes mellitus therapy; diabetes risk; early /brief intervention /therapy; glucose metabolism; human subject; human therapy evaluation; humoral immunity; immune tolerance /unresponsiveness; immunoregulation; insulin dependent diabetes mellitus; interleukin 2; longitudinal human study; pancreatic islet function; pancreatic islets; pathologic process; patient oriented research

DESCRIPTION (provided by applicant): The development of a means for inducing immunological tolerance may have a dramatic impact not only on the way autoimmune disorders such as type 1 diabetes (T1D) are treated, but, in addition, towards therapeutic applications related to allergy, transplantation, and oncology. The focus of this application is to identify the therapeutic potential of umbilical cord blood as a means for inducing tolerance in an autoimmune setting and to define the role for a class of so-called regulatory T cells (Treg; identified by their coexpression of CD4 and CD25 molecules) in imparting immune regulation. We recently received FDA approval for a highly innovative study aimed at the reversal of recent onset T1D involving autologous umbilical cord blood transfusion (obtained from banked material). This current application seeks to test the hypothesis that T1D can be reversed or the rate of metabolic loss slowed by autologous umbilical cord transfusion. In addition to evaluating therapeutic efficacy, the project's specific aims are designed to provide a mechanistic understanding for the ability of cord blood to modulate immune reactivities and induce tolerance. 1) Determine whether autologous umbilical cord blood administered to children with recently diagnosed T1D will lead to the preservation and/or regeneration of insulin-producing beta cells. This notion will be assessed by longitudinal evaluation of metabolic function (e.g., blood glucose control, insulin usage, mixed-meal stimulated C-peptide production) from protocol subjects versus an age/gender/HLA-matched population of T1D patients. 2) Determine the influence of this therapy on immune responsiveness including tolerance induction. Specifically, whether alterations in the frequency and/or functional capacity of Treg in peripheral blood occur, the course of anti-islet cell immunity (production of T1D associated islet cell autoantibodies), and humoral and cellular immune response against immunization based, environmental, or insulin antigens. 3) Evaluate the frequency and function of Treg in cord blood from persons with T1D and by comparison to healthy, non-diabetic controls (age and gender matched), and identify their potential contributions to the risk of developing this disorder. The successful completion of these pilot studies could uncover an innovative method for tolerance induction and understand the contributions of Treg to both the process of tolerance induction as well as the pathogenic defects underlying the formation of T1 D.

描述（由申请人提供）：诱导免疫耐受的方法的开发可能不仅对自身免疫性疾病如1型糖尿病（T1 D）的治疗方式产生巨大影响，而且还对与过敏、移植和肿瘤学相关的治疗应用产生巨大影响。本申请的重点是鉴定脐带血作为在自身免疫环境中诱导耐受性的手段的治疗潜力，并确定一类所谓的调节性T细胞（Treg;通过其CD 4和CD 25分子的共表达鉴定）在赋予免疫调节中的作用。我们最近获得了FDA批准的一项高度创新的研究，旨在逆转最近发生的T1 D，涉及自体脐带血输血（从库存材料中获得）。本申请旨在检验T1 D可以通过自体脐带输血逆转或减缓代谢损失速率的假设。除了评估治疗效果外，该项目的具体目标旨在提供对脐带血调节免疫反应性和诱导耐受性能力的机制理解。1)确定对最近诊断为T1 D的儿童给予自体脐带血是否会导致产生胰岛素的β细胞的保存和/或再生。这一概念将通过代谢功能的纵向评价来评估（例如，血糖控制、胰岛素使用、混合餐刺激的C肽产生）与年龄/性别/HLA匹配的T1 D患者群体的比较。2)确定该疗法对免疫应答的影响，包括耐受诱导。具体而言，外周血中Treg的频率和/或功能能力是否发生改变，抗胰岛细胞免疫（产生T1 D相关胰岛细胞自身抗体）的过程，以及针对基于免疫的、环境的或胰岛素抗原的体液和细胞免疫应答。3)评估T1 D患者脐带血中Treg的频率和功能，并与健康的非糖尿病对照（年龄和性别匹配）进行比较，并确定其对发展这种疾病风险的潜在贡献。这些初步研究的成功完成可以揭示耐受性诱导的创新方法，并了解Treg对耐受性诱导过程以及TlD形成背后的致病性缺陷的贡献。