Prediction and Prevention of Type 1 Diabetes - TrialNet

1 型糖尿病的预测和预防 - TrialNet

基本信息

批准号：
8076298
负责人：
DOROTHY J BECKER
金额：
$ 57.77万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-29 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8076298
关键词：
Adult Adverse effects Allogenic Antigens Attenuated Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity Autologous Autologous Dendritic Cells B-Lymphocytes Beta Cell Bone Marrow Bone Marrow Ablation C-Peptide CD80 gene CTLA4-Ig Cells Clinical Collaborations Control Groups Dendritic Cells Development Diabetes Mellitus Disease Double-Blind Method Effectiveness Engineered Gene First Degree Relative Glutamate Decarboxylase Goals Health Hematopoietic Human Immune Immunosuppression In Vitro Inbred NOD Mice Injection of therapeutic agent Insulin Insulin-Dependent Diabetes Mellitus Interleukin-4 Intervention Kinetics Maintenance Measures Natural History Newly Diagnosed Nucleic Acids Oligonucleotides Oral Organ Survival Outcome Patient Monitoring Patients Pediatric Hospitals Performance Peripheral Phase Phase I Clinical Trials Population Prevalence Prevention Primates Principal Investigator Process Property Protocols documentation Randomized Controlled Trials Recruitment Activity Research Design Research Personnel Residual state Resources Rodent Rodent Model Safety Seminal Signal Transduction Site Solid Students T-Lymphocyte TNFRSF5 gene Testing Transcript Universities Vaccination Vaccines base cell preparation comparative efficacy design experience insulin dependent diabetes mellitus onset insulin secretion islet migration monocyte non-diabetic nonhuman primate novel phase 1 study phosphorothioate pre-clinical prevent randomized placebo controlled trial reconstitution response restoration rituximab

项目摘要

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.

描述（由申请人提供）： UPMC 儿童医院和匹兹堡大学提交的这份文件是对 TriaNet RFA DK-08-001 的回应。这组研究人员拥有丰富的经验，曾是 TrialNet 中心的一员，拥有资源、招募的众多附属机构以及证明他们有能力继续作为中心参与 TrialNet 的能力。为了回答 RFA 的目标，我们提出了一项随机对照试验来评估新型糖尿病抑制细胞疫苗的安全性和有效性，该疫苗由经过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，该疫苗针对CD40、CD80 和 CD86 共刺激分子（免疫调节 DC；iDC）的初级转录本。针对已确诊的 1 型糖尿病 (T1D) 患者和灵长类动物的一期测试已基本完成。本研究要测试的假设是，基因工程自体 DC 可以减弱或抑制以下情况中的自身免疫：a) 新诊断的 T1D，保留残留的 β 细胞质量，并通过刺激的 C 肽水平评估恢复胰岛素分泌， b) 一级亲属患有预测胰岛自身抗体的疾病，以维持通过刺激的 C 肽水平评估的胰岛素分泌并防止进展为临床 T1D。目前，除了具有相当大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T1D。这些研究将首次采用自体树突状细胞移植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人员的专业知识和经验、跨中心良好的合作以及新颖的干预策略公众健康相关性：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，即使延迟糖尿病的发作和胰岛素需求也会带来巨大的好处。