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。到目前为止，我们已经实施了8项协议。我们的特别优势是参加预防和干预试验，在这方面，我们是总招聘者中排名第一的。然而，我们在自然历史研究(NHS)中的招聘一直是平均的。为了改善这一点，我们与密歇根大学家庭医学和社区健康部门研究主任、明尼苏达家庭医生学院研究网络主任Kevin Peterson博士展开了新的合作。我们预计可以立即接触到1000多名患有T1D的患者，随着这个网络的发展，未来可以接触到的患者会越来越多。 在这项申请中，我们建议使用自体T调节细胞(Tregs)进行治疗。以前的方案曾试图通过药物增加内源性Treg数量。Tregs本身以前并没有足够数量的临床使用。我们的团队是第一个开发出一种临床适用的从外周血中大量培养Tregs的选择和培养方法。动物模型和人类白血病的初步数据表明，该产品是安全的。 这是一项单部位、单臂1期剂量递增试验。最近(3-12个月)出现T1D并持续分泌C-肽的成年受试者将使用UM分子和细胞治疗cGMP设施开发的新方法接受自体外周血源性Tregs(CD4/CD25/FoxP3)的输注。细胞将通过白细胞分离收集并在培养中扩增长达35天，然后冷冻保存。在白细胞分离后，受试者将立即接受一个疗程的胸腺球蛋白，在一周内注射4剂。解冻后的自体Tregs将在大约2个月后注入，此时循环中没有残留的可检测到的兔抗体。安全性、免疫学资料和C肽分泌情况将进行为期2年的跟踪观察。长期目标是收集初步数据，以期进行外周血来源的自体CD4/CD25/FoxP3治疗新发T1D的干预试验。

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.