ANTIBODIES TO RECOMBINENT AUTOANTIGENS--PREDICT

DPT-1试验的临床部分由国家卫生研究院赞助， 卫生研究院，将初步测试的假设，胃肠外 胰岛素治疗可预防胰岛细胞中I型糖尿病 抗体（伊卡）阳性的一级亲属。作为这次审判的基础， 超过60，000名I型糖尿病患者的一级亲属 将进行伊卡筛查。伊卡阳性亲属将分期， 随机接受实验性胰岛素治疗或密切观察 （胃肠外试验）或口服胰岛素与安慰剂。该提案将采取 这种大规模和独特的筛查计划和进步的优势 在测定与生物化学定义的 重组自身抗原目前的提案将评估 这种“生化”筛查来预测I型糖尿病， 了解前I型糖尿病的自然史，探索 自身抗体表达免疫遗传学及其发展潜力 对治疗反应的自身抗体替代标志物。我们假设 单一自身抗体的存在将具有高灵敏度， 多种自身抗体（例如，等于或大于）减少，但 对糖尿病具有极好的敏感性和高阳性预测值。 此外，我们假设，在缺乏生物化学 自身抗体伊卡的阳性预测值较低。支持 确定“生物化学”确定的自身抗体，随访和 评估伊卡阴性亲属表达自身抗体和匹配 亲属和免疫遗传学分析（不属于当前DPT- 1资助的一部分） 寻求与三个中心划分自身抗体测定：抗- 胰岛素在乔斯林中心，抗GAD在盖恩斯维尔，抗ICA 512在 芭芭拉·戴维斯中心特别要求对自然人提供支助， 比较伊卡、IVGTT、HLA DQ等位基因生化检测的历史研究， 并发展为糖尿病值得注意的是，即使是随机化的未治疗的 （胃肠外试验）或安慰剂治疗（DPT的口服抗原试验）将 在数量上超过目前的“自然”历史研究。

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.