Antibodies to Recombinant Autoantigens: Prediction

描述(申请人提供)：OPT-1试验，其临床成分 由美国国立卫生研究院赞助，正在检验这一假说 注射或口服胰岛素会延缓糖尿病的发展 1型糖尿病患者胞浆ICA阳性亲属中的研究 糖尿病。这次审判是对一级亲属进行的最大规模的评估 曾与8万多名亲属进行过筛查，其中10万多人 细胞质ICA、GAO65和ICA512(IA-2)的血清样本分析 分析自身抗体和3000例胰岛素自身抗体(微量LAA试验) 在这笔赠款的支持下。这笔赠款的一项补充允许有限的 一次“分期”具有“生化”自身抗体的亲属亚群 但缺乏胞浆ICA。初步结果表明：一半的人 胞浆ICA阳性个体缺乏所有生化自身抗体， 在OPT-1试验阶段获得资格的可能性很低。 在表达多种自身抗体的亲属中，约有四分之一是 胞浆ICA阴性。“生化”自身抗体的表达与 与先证者和人类白细胞抗原状态的关系。一种新型微量胰岛素自身抗体 微量LAA检测与多种自身抗体相关性较高 与标准的抗胰岛素检测结果进行比较。DAB 1*0602的子集 阳性个体进展为显性糖尿病。我们相信，从 初步数据显示，“生化”自身抗体的测定将 对未来预防1型糖尿病的试验至关重要。尽管如此， 具体的预测范例还不能被精确地指定(太少了 微量IAA(胰岛素自身抗体)测定，随访太少 ICA阴性、生化自身抗体阳性亲属)。现在，这一点至关重要 为了利用已经集结的队伍和新的银幕 在未来几年内获得足够的预期代谢和免疫学 评估。较新的分析(包括表位特异性分析和亚类 与独特的OPT临床研究相结合，将是重要的 为了“生化”自身抗体预测的实用化发展 对1A型糖尿病“自然病史”和发病机制的认识 对“胰岛素”治疗的反应。目前的赠款寻求支持，以继续 新标本中GAO65和ICA512(IA-2)自身抗体的检测及应用 新的分析方法，用最近开发的高通量胰岛素进行测量 对所有样本进行自身抗体检测，每年进行前瞻性评估 细胞质ICA阴性、生化自身抗体阳性的个体， 自身抗体表型和代谢的遗传决定因素分析 进阶，以及进一步分析积累数据的财富。

DESCRIPTION (provided by applicant): The OPT -1 trial, whose clinical component is sponsored by the National Institutes of Health, is testing the hypothesis that parenteral or oral insulin administration will delay the development of type 1 diabetes amongst cytoplasmic ICA positive relatives of patients with diabetes. The trial represents the largest evaluation of first degree relatives ever undertaken with more than 80,000 relatives screened, and more than 100,000 sera samples analyzed for cytoplasmic ICA, GAO65 and ICA512 (IA-2) autoantibodies and 3,000 analyzed for insulin autoantibodies (micro-lAA assay) under the aegis of this grant. A supplement to this grant has allowed limited one time "staging" of a subset of relatives with "biochemical" autoantibodies but lacking cytoplasmic ICA. Preliminary results indicate: One half of cytoplasmic ICA positive individuals lack all biochemical autoantibodies and have a low probability of being eligible on Staging for the OPT -1 trial. Approximately one fourth of relatives expressing multiple autoantibodies are cytoplasmic ICA negative. Expression of "biochemical" autoantibodies is related to relationship to proband and HLA status. A new micro-insulin autoantibody assay (micro-lAA) has a higher correlation with multiple autoantibody expression compared to the standard anti-insulin assay. A subset of DaB 1 *0602 positive individuals progress to overt diabetes. We believe from the preliminary data that "biochemical" autoantibody determination will be essential for future trials of type 1 A diabetes prevention. Nevertheless specific predictive paradigms cannot yet be precisely specified (too few determinations of micro-IAA (insulin autoantibody), and too little follow up of ICA negative biochemical autoantibody positive relatives). It is now essential to take advantage of the cohorts already assembled and new screenees over the next several years to obtain adequate prospective metabolic and immunologic evaluation. Newer assays (including epitope specific assays and subclass specific assays) combined with the unique OPT clinical study, will be important both for the practical development of "biochemical" autoantibody prediction and understanding of the "natural history" and pathogenesis of type 1A diabetes and response to "insulin" therapy. The current grant seeks support to continue to determine GAO65 and ICA512 (IA-2) autoantibodies on new samples and to apply new assays, to measure with the recently developed high-throughput insulin autoantibody assay all samples, to prospectively evaluate on an annual basis cytoplasmic ICA negative, biochemical autoantibody positive individuals, to analyze genetic determinants of autoantibody phenotype and metabolic progression, as well as further analyze the wealth of accumulating data.