Type 1 Diabetes-A Proposal for Prevention & Intervention

描述（由申请人提供）：明尼苏达大学是美国最初的14个TrialNet中心之一。迄今为止，我们已经实施了8项协议。我们的特别优势是在预防和干预试验中的招募，我们是总招募人数的第一名。然而，我们在自然历史研究（NHS）中的招募情况一直处于平均水平。为了改善这一点，我们已经开始与家庭医学和社区健康的UM部门和家庭医生研究网络明尼苏达学院主任研究主任凯文彼得森博士进行新的合作。我们预计将立即访问1000多名T1 D患者，随着该网络的发展，未来访问人数将增加。 在本申请中，我们提出用自体T调节细胞（Tregulatory cells，Tregulatory cells）进行治疗。先前的方案试图用药物增加内源性Treg数量。以前没有足够的数量可用于临床使用。我们的小组是第一个开发出一种临床上适用的选择和培养方法，用于从外周血中生产大量的THBE。动物模型和人类白血病患者的初步数据表明，该产品是安全的。 这是一项单中心、单组I期剂量递增试验。近期（3-12个月）发作T1 D和持续C肽分泌的成人受试者将使用UM分子和细胞治疗cGMP机构开发的新方法输注自体外周血来源的TlD（CD 4 +/CD 25 +/FoxP 3+）。将通过白细胞分离术收集细胞，并在培养物中扩增长达35天，然后冷冻保存。白细胞去除术后，受试者将立即接受一个疗程的胸腺球蛋白治疗，1周内4次给药。解冻后，将在约2个月后输注自体Tcl 4，此时循环中没有残留的可检测兔抗体。安全性和免疫学数据以及C肽分泌将随访2年。长期目标是收集预期的外周血来源的自体CD 4 +/CD 25 +/FoxP 3+治疗新发T1 D的干预试验的初步数据。

DESCRIPTION (provided by applicant): The University of Minnesota is one of the original 14 US TrialNet centers. We have implemented 8 protocols to date. Our particular strength has been enrollment in prevention and intervention trials, where we are the number 1 overall recruiter. Our recruitment in the Natural History Study (NHS), however, has been average. In order to improve this, we have embarked on a new collaboration with Dr. Kevin Peterson, Director of Research for the UM Department of Family Medicine and Community Health and Director of the Minnesota Academy of Family Physicians Research Network. We anticipate access immediately to more than 1000 patients with T1D, with increased future access as this network grows. In this application we are proposing therapy with autologous Tregulatory cells (Tregs). Previous protocols have attempted to increase endogenous Treg numbers with drugs. Tregs themselves have not previously been available in sufficient numbers for clinical use. Our group is the first to develop a clinically applicable selection and culture method for manufacturing large numbers of Tregs from peripheral blood. Preliminary data in animal models and in humans with leukemia suggest that this product is safe. This is a single site, single arm phase 1 dose escalation trial. Adult subjects with recent (3-12 months) onset T1D and persistent C-peptide secretion will receive an infusion of autologous peripheral blood- derived Tregs (CD4+/CD25+/FoxP3+) using new methodology developed at the UM Molecular and Cellular Therapeutics cGMP Facility. Cells will be collected by leukapheresis and expanded in culture for up to 35 days and then cryopreserved. Immediately following leukapheresis, subjects will receive a course of thymoglobulin, 4 doses over 1 week. Thawed, autologous Tregs will be infused approximately 2 months later, at a time when there is no residual detectable rabbit antibody in the circulation. Safety and immunologic data and C-peptide secretion will be followed for 2 years. The long-term goal is to gather preliminary data in anticipation of an intervention trial of peripheral-blood derived autologous CD4+/CD25+/FoxP3+ treatment of new onset T1D.