IMMUNOTHERAPY FOR NEW ONSET TYPE-1 DIABETES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们提出了一个3臂随机，部分盲，安慰剂对照比较霉酚酸酯（MMF）单独，MMF与达利珠单抗，口服安慰剂。将研究治疗对b细胞功能丧失、糖尿病特异性免疫应答和全身免疫应答的影响。我们将确定这些治疗是否具有临床疗效，并试图通过定义药物如何改变糖尿病特异性和全身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应答的机制研究将包括自身抗体滴度研究、糖尿病特异性T细胞功能研究和回忆抗原反应性评估。如果药物被证明有效，本试验将开发可用于更大规模研究的信息。 具体目标1是一项检验假设的临床试验：从诊断时开始，单用MMF将使1型糖尿病患者的C肽水平保持2年或更长时间。本研究将入组60例受试者，在2年随访期内，将受试者随机分为30组，接受750 mg/m2或2000 mg/天的MMF口服给药，每日2次，或接受MMF安慰剂。B细胞功能终点是Sustacal？治疗后的基础和刺激C肽，其次是胰岛素剂量、HbA 1c和低血糖事件数量。 具体目标2将检查和开发拟议治疗的免疫学效应的替代标志物。这些是：疾病特异性终点：自身抗体测定，T细胞反应性和频率。有免疫学终点：T细胞对回忆抗原的反应性和活化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.