IMMUNOTHERAPY FOR NEW ONSET TYPE-1 DIABETES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。我们提出了一项3组随机、部分盲、安慰剂对照的研究，分别对霉酚酸酯（Mycophenolate mofetil， MMF）单独、MMF联合Daclizumab和口服安慰剂进行比较。将研究治疗对b细胞功能丧失、糖尿病特异性免疫反应和一般免疫反应的影响。我们将确定这些治疗是否具有临床疗效，并试图通过确定药物如何改变糖尿病特异性和一般免疫反应来确定潜在的作用机制。本试验中糖尿病特异性免疫反应的机制研究将包括自身抗体滴度的研究、糖尿病特异性t细胞的功能研究和召回抗原反应性的评估。如果这些药物被证明是有效的，该试验将提供可用于更大规模研究的信息。Specific Aim 1是一项临床试验，旨在验证这一假设：MMF可以在1型糖尿病患者诊断时维持2年或更长时间的c肽水平。该研究将招募60名受试者，他们将被随机分为30组，接受750 mg/m2或2000 mg/天的MMF口服治疗，每天两次，或在2年的随访期间服用MMF安慰剂。b细胞功能终点是基础和刺激c肽，其次是胰岛素剂量、糖化血红蛋白和低血糖事件的次数。特异性目标2将检查和开发替代标记物，用于拟议治疗的免疫效应。它们是：疾病特异性终点、自身抗体测定、t细胞反应性和频率。有免疫终点：t细胞对抗原的反应性和激活t细胞的频率。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose a 3-arm randomized, partially-blind, placebo-controlled comparison of Mycophenolate mofetil (MMF)alone, MMF with Daclizumab, and oral placebo only. The effects of the treatment on the loss of b-cell function, diabetes-specific immune responses and general immune responses will be studied. We will determine whether these treatments have clinical efficacy and attempt to determine the potential mechanism of action by defining how the drug alters both diabetes-specific and general immune responses. The mechanistic studies of diabetes-specific immune responses in this trial will include studies of titers of autoantibodies, functional studies of diabetes specific T-cells and assessment of recall antigen reactivity. This trial will develop information which can be used in larger studies should the agent(s) prove to be effective. Specific Aim 1 is a clinical trial to test the hypothesis: MMF alone will preserve C-peptide levels in Type-1 Diabetics for 2 or more yrs when started at diagnosis. The study will enroll 60 subjects who will be randomized into groups of 30 to receive 750 mg/m2 or 2000 mg/day of MMF by mouth twice daily or a placebo for the MMF over the 2 yr follow-up period. The b-cell function endpoints are basal and stimulated C-peptide following Sustacal¿ and, secondarily, insulin dose, HbA1c and number of hypoglycemic events. Specific Aim 2 will examine and develop surrogate markers for immunologic effects of the proposed treatments. These are: disease-specific endpoints: autoantibody determinations, T-cell reactivity and frequency. There are immunological endpoints: T-cell reactivity to recall antigens and frequency of activated T-cells.