PREVENTION OF DIABETES PROGRESSION TRIAL (PDPT)

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 如果在B细胞被破坏之前，T辅助细胞I型(Th1)细胞及其分泌的细胞因子(包括干扰素-γ、肿瘤坏死因子-α和白介素2)所介导的自身免疫反应能够在B细胞被破坏之前被调节，那么胰岛素缺乏就有可能被预防。达利珠单抗(Zenapax)是一种人源化的针对IL-2受体的IgG1单抗，具有受体拮抗剂的作用。它的20天半衰期允许每2-3周静脉注射药物。Daclizumab被批准用于预防肾移植急性排斥反应。经过三年的随访，以全身输液反应、肾毒性、感染或恶性肿瘤的发生率来衡量，没有显示出毒性。我们提出了一项开放标签试验，以测试达利珠单抗治疗部分残留B细胞功能儿童的安全性和有效性。100名1-16岁的儿童将被招募到这项为期两年的试验中，并随机接受常规治疗或常规治疗与达利珠单抗联合治疗。疗效将通过蜜月期持续时间、胰岛素剂量、HgA1C、糖化白蛋白水平、C-肽水平、空腹胰岛素与葡萄糖比率和IVGTT进行评估。免疫学疗效将包括评估外周血、胰岛细胞、胰岛素和GAD抗体中CD25的表达，以及体外T细胞对GAD的增殖反应。安全性将通过评估输液相关毒性、感染频率和类型、Daclizumab抗体的发展以及化学和血液学特征进行监测。如果6个月后仍无临床反应，将停用达利珠单抗，但在研究期间将监测疗效和安全性参数。

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. If the Autoimmune response in Type I diabetes, mediated by T-helper Type 1 (Th1) cells and their secreted cytokines including IFN-y, TNF-a and IL-2, could be modulated prior to B cell destruction, insulin deficiency might be prevented. Daclizumab (Zenapax), a humanized IgG1 monoclonal antibody specific for IL-2 receptor, functions as a receptor antagonist. Its 20 day half-life permits IV drug dosing every 2-3 weeks. Daclizumab is approved for prevention of acute renal allograft rejections. No toxicity has been demonstrated as measured by rates of systemic infusion reaction, nephrotoxicity, infections, or malignancies with three years of follow-up. We propose an open label trial to test the safety and efficacy of daclizumab in children with partial residual B cell function. One hundred children, ages 1-16 years, will be recruited into the two year trial and randomized either to conventional therapy or conventional treatment in combination with daclizumab. Efficacy will be assessed by duration of the honeymoon period, dose of insulin, HgA1C, glycated albumin levels, C-peptide levels, fasting insulin to glucose ratios and IVGTT. Immunologic efficacy will include assessment of CD25 expression in peripheral blood, islet cell, insulin and GAD antibodies, and in vitro T cell proliferative response to GAD. Safety will be monitored by assessing infusion-related toxicities, frequency and type of infections, development of daclizumab antibodies, and chemistry and hematological profiles. If a clinical response is not demonstrated by 6 months, daclizumab will be discontinued, but efficacy and safety parameters will be monitored for the duration of the study.