Prediction and Prevention of Type 1 Diabetes - TrialNet

描述(由申请人提供)：这份来自UPMC儿童医院和匹兹堡大学的意见书是对Trianet RFA DK-08-001的回应。这组拥有丰富经验的调查人员以前是TrialNet中心的成员，他们拥有资源，招募了许多分支机构，并有记录表明他们有能力继续作为中心参与TrialNet。为了回答RFA的目标，我们提出了一项随机对照试验来评估一种新的糖尿病抑制细胞疫苗的安全性和有效性，该疫苗由自体单核细胞来源的树突状细胞与针对CD40、CD80和CD86协同刺激分子(免疫调节DC；IDC)初级转录的反义硫代修饰寡核苷酸体外治疗。在确诊的1型糖尿病(T1D)患者和灵长类动物中进行的第一阶段测试几乎完成。本研究中要检验的假设是，基因工程自体DC可以在以下方面减弱或抑制自身免疫：a)新诊断的T1D，保留残留的β细胞团，通过刺激C肽水平评估胰岛素分泌恢复，b)疾病预测胰岛自身抗体的一级亲属，通过刺激C肽水平评估维持胰岛素分泌，防止进展到临床T1D。目前，除了免疫抑制具有相当大的潜在副作用外，还没有其他方法来逆转或防止新的T1D发作。这些研究将是有史以来第一次使用自体树突状细胞转移来抑制自身免疫性疾病，并可能在临床过程的早期逆转它。 这一提议的优势在于调查人员的专业知识和经验、跨中心的良好合作以及新颖的干预策略 公共卫生相关性：TrialNet的最终目标是预防临床1型糖尿病的发展。如果做不到这一点，即使推迟糖尿病的发病和胰岛素需求也有巨大的好处。

DESCRIPTION (provided by applicant): This submission from the Children's Hospital of UPMC and the University of Pittsburgh responds to the TriaNet RFA DK-08-001. This group of investigators, with extensive experience who were a prior TrialNet center, has the resources, numerous recruited affilliates and a track record demonstrating their ability to continue TrialNet participation as a center. In order to answer the objective of the RFA, we propose a randomized controlled trial to evaluate the safety and efficacy of a new diabetes-suppressive cell vaccine, consisting of autologous monocyte-derived dendritic cells treated ex vivo with antisense phosphorothioate-modified oligonucleotides targeting the primary transcripts of the CD40, CD80 and CD86 co-stimulatory molecules (immunoregulatory DC; iDC). Phase 1 testing in patients with established Type 1 diabetes (T1D) and primates are almost completed. The hypotheses to be tested in this study are that gene-engineered autologous DC can attenuate or suppress the autoimmunity in: a) newly-diagnosed T1D, sparing residual beta cell mass, with restoration of insulin secretion as assessed by stimulated C-peptide levels, b) first degree relatives with disease predicting islet autoantibodies, to sustain insulin secretion assessed by stimulated C-peptide levels and to prevent progression to clinical T1D. Currently, other than immune suppression with considerable potential side effects, there is no other means to reverse or prevent new-onset T1D. These studies will be the first ever to employ autologous dendritic cell transfer to suppress an autoimmune disease and to possibly reverse it early in the clinical process. The strength of this proposal is the expertise and experience of the investigators,well established collaborations across centers and a novel intervention strategy PUBLIC HEALTH RELEVANCE: The ultimate goal of TrialNet is to prevent the development of clinical type 1 diabetes. Failing this, even a delay in the onset of diabetes and insulin requirements has enormous benefits.