Cord Blood Immunoregulation of Type 1 Diabetes

描述(由申请人提供)：一种诱导免疫耐受的方法的发展不仅可能对1型糖尿病(T1D)等自身免疫性疾病的治疗方式产生重大影响，而且还可能对与过敏、移植和肿瘤学相关的治疗应用产生重大影响。这项应用的重点是确定脐带血作为在自身免疫环境中诱导耐受的手段的治疗潜力，并确定一类所谓的调节性T细胞(Treg；通过它们的CD4和CD25分子的共同表达来识别)在传递免疫调节中的作用。我们最近获得了FDA的批准，进行了一项高度创新的研究，旨在逆转最近发生的T1D，涉及自体脐带血输注(从库存材料中获得)。目前的应用是为了验证这样一个假设，即T1D可以通过自体脐带输血逆转或减缓代谢损失的速度。除了评估治疗效果外，该项目的具体目标是为脐带血调节免疫反应和诱导耐受的能力提供机制上的了解。1)确定给新近诊断为T1D的儿童使用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。这一概念将通过对方案受试者与年龄/性别/人类白细胞抗原相匹配的T1D患者群体的代谢功能(例如，血糖控制、胰岛素使用、混合餐刺激的C肽产生)的纵向评估来评估。2)确定该疗法对免疫应答的影响，包括诱导免疫耐受。具体地说，无论外周血中Treg的频率和/或功能能力是否发生变化，抗胰岛细胞免疫的过程(产生与T1D相关的胰岛细胞自身抗体)，以及针对基于免疫、环境或胰岛素抗原的体液和细胞免疫反应。3)评估T1D患者脐带血中Treg的频率和功能，并与健康的非糖尿病对照组(年龄和性别匹配)进行比较，确定他们对发生这种疾病的风险的潜在贡献。这些初步研究的成功完成可能会发现一种诱导耐受的创新方法，并了解Treg在耐受诱导过程中的贡献以及T1 D形成的致病缺陷。

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.