Prediction and Prevention of Type 1 Diabetes - TrialNet

描述（由申请人提供）：UPMC儿童医院和匹兹堡大学提交的本文件对TriaNet RFA DK-08-001进行了回应。这组研究者拥有丰富的经验，他们是之前的TrialNet中心，拥有资源，众多招募的附属机构和跟踪记录，证明他们有能力继续作为中心参与TrialNet。为了回答RFA的目的，我们提出了一项随机对照试验，以评估一种新的糖尿病抑制细胞疫苗的安全性和有效性，该疫苗由用反义硫代磷酸酯修饰的寡核苷酸离体处理的自体单核细胞衍生的树突状细胞组成，该寡核苷酸靶向CD 40、CD 80和CD 86共刺激分子的初级转录物（免疫调节DC; iDC）。在已确诊的1型糖尿病（T1 D）患者和灵长类动物中进行的1期试验已接近完成。本研究中待检验的假设是，基因工程化的自体DC可以减弱或抑制以下疾病中的自身免疫：a）新诊断的T1 D，保留残留的β细胞质量，通过刺激的C-肽水平评估具有胰岛素分泌的恢复，B）具有预测胰岛自身抗体的疾病的一级亲属，维持通过刺激的C肽水平评估的胰岛素分泌，并防止进展为临床T1 D。目前，除了具有相当大的潜在副作用的免疫抑制外，没有其他方法可以逆转或预防新发T1 D。这些研究将是有史以来第一次采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。 该提案的优势在于研究者的专业知识和经验，跨中心的良好合作以及新颖的干预策略

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