ANTIBODIES TO RECOMBINENT AUTOANTIGENS--PREDICT

重组自身抗原的抗体——预测

• 批准号: 2887129
• 负责人: GEORGE S EISENBARTH
• 金额: $ 21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887129
• 关键词: MHC class II antigen; autoantibody; autoantigens; clinical research; diabetes mellitus therapy; family genetics; glucose metabolism; glucose tolerance; human subject; human therapy evaluation; immunogenetics; insulin dependent diabetes mellitus; oral administration; pancreatic islets; parenteral feedings; pathologic process; prognosis; recombinant proteins

The DPT-1 trial, whose clinical component is sponsored by the National Institutes of Health, will initially test the hypothesis that parenteral insulin therapy can prevent type I diabetes amongst cytoplasmic islet cell antibody (ICA) positive first degree relatives. As a basis for this trial, more than 60,000 first degree relatives of patients with type I diabetes will be screened for ICA. ICA positive relatives will be staged and randomized to experimental insulin therapy or close observation (parenteral trial) or oral insulin versus placebo. This proposal will take advantage of both this massive and unique screening program and advances in determination of autoantibodies reacting with biochemically defined recombinant autoantigens. The current proposal will evaluate the ability of such "biochemical" screening to predict type I diabetes in order to understand the natural history of pre-type I diabetes, probe the immunogenetics of autoantibody expression, and develop potential autoantibody surrogate markers of response to therapy. We hypothesize that the presence of a single autoantibody will have high sensitivity, and multiple autoantibodies (eg. equal to or greater than) reduced but excellent sensitivity and a high positive predictive value for diabetes. In addition we hypothesize that in the absence of biochemical autoantibodies ICA will have low positive predictive value. Support for determination of"biochemically" determined autoantibodies, followup and evaluation of ICA negative relatives expressing autoantibodies and matched relatives, and immunogenetic analysis (not part of current DPT- 1 funding) are sought with three centers dividing autoantibody determination: anti- insulin at the Joslin Center, anti-GAD in Gainesville, and anti-ICA512 at the Barbara Davis Center. Support is requested specifically for a natural history study comparing biochemical testing to ICA, IVGTT, HLA DQ alleles, and progression to diabetes. Of note, even the randomized non-treated (parenteral trial) or placebo treated (oral antigen trial of DPT) will exceed in numbers current "natural" history studies.

DPT-1试验，其临床成分由国家 将初步检验非肠道外注射的假说 胰岛素治疗可在胞浆胰岛细胞中预防I型糖尿病 抗体(ICA)阳性的一级亲属。作为这次审判的基础， 超过6万名I型糖尿病患者的一级亲属 将接受ICA筛查。ICA阳性亲属将上演 随机接受实验性胰岛素治疗或密切观察 (非肠道试验)或口服胰岛素与安慰剂。这项建议将需要 这一庞大而独特的筛查计划和先进的 在测定与生化定义的自身抗体反应中 重组自身抗原。目前的提案将评估这一能力 进行这种“生化”筛查来预测I型糖尿病，以便 了解前期I型糖尿病的自然病史，探索 免疫遗传学中自身抗体的表达和开发潜力 自身抗体替代治疗反应的标志物。我们假设 单一自身抗体的存在将具有高敏感性，并且 多种自身抗体(如等于或大于)减少，但 对糖尿病具有极高的敏感性和较高的阳性预测值。 此外，我们假设在没有生化物质的情况下 自身抗体ICA阳性预测值较低。支持 “生化”确定的自身抗体的测定、随访和 表达自身抗体和相合的ICA阴性亲属的评价 亲属和免疫遗传分析(不是当前DPT-1资金的一部分) 寻找三个划分自身抗体检测的中心：抗- 乔斯林中心的胰岛素，盖恩斯维尔的抗GAD和ICA512 芭芭拉·戴维斯中心。我们特别为一个自然的 生化检测与ICA、IVGTT、HLADQ等位基因比较的病史研究 并进展为糖尿病。值得注意的是，即使是随机未治疗的 (非肠道试验)或安慰剂治疗(DPT口服抗原试验)将 在数量上超过了当前的“自然”历史研究。