Antibodies to Recombinant Autoantigens: Prediction

重组自身抗原的抗体：预测

• 批准号: 6405883
• 负责人: GEORGE S EISENBARTH
• 金额: $ 26.57万
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6405883
• 关键词: MHC class II antigen; autoantibody; autoantigens; diabetes mellitus genetics; diabetes mellitus therapy; diagnosis design /evaluation; disease /disorder prevention /control; early diagnosis; family genetics; glucose tolerance; high throughput technology; human subject; human therapy evaluation; immunogenetics; insulin dependent diabetes mellitus; oral administration; pancreatic islets; parenteral feedings; pathologic process; patient oriented research; prediabetic state; prognosis; recombinant proteins

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.

描述（由申请人提供）：OPT-1试验，其临床组成部分 由美国国立卫生研究院赞助， 胃肠外或口服胰岛素给药将延迟 1型糖尿病患者的胞浆伊卡阳性亲属中， 糖尿病该试验代表了对一级亲属的最大评估 有超过80，000名亲属接受了筛查，超过100，000名 分析血清样本的细胞质伊卡、GAO 65和ICA 512（IA-2） 自身抗体和3，000例胰岛素自身抗体分析（微量IAA测定） 在这笔资金的支持下。这项补助金的补充允许有限的 对具有“生化”自身抗体的亲属子集进行一次“分期” 但缺乏胞质伊卡。初步结果显示： 胞质伊卡阳性个体缺乏所有生化自身抗体， 在OPT -1试验的分期中合格的概率较低。 大约四分之一的亲属表达多种自身抗体， 胞质伊卡阴性。“生化”自身抗体的表达与 与先证者和HLA状态的关系。一种新的微量胰岛素自身抗体 检测（微量IAA）与多种自身抗体有较高的相关性 与标准抗胰岛素测定相比，DaB 1 *0602的子集 阳性个体发展为显性糖尿病。我们相信， 初步数据表明，“生化”自身抗体测定将是 对未来的1A型糖尿病预防试验至关重要。然而 具体的预测范例还不能被精确地指定（太少 微量IAA（胰岛素自身抗体）的测定，以及 伊卡阴性生化自身抗体阳性亲属）。现在必须 利用已经聚集的人群和新的屏幕 在未来几年内获得足够的前瞻性代谢和免疫 评价较新的检测（包括表位特异性检测和亚类 特异性检测）与独特的OPT临床研究相结合，将非常重要 既用于“生化”自身抗体预测的实际开发， 了解1A型糖尿病的“自然史”和发病机制， 对“胰岛素”疗法的反应。目前的赠款寻求支持，以继续 测定新样本中的GAO 65和ICA 512（IA-2）自身抗体，并应用于 新的检测方法，用最近开发的高通量胰岛素 对所有样本进行自身抗体检测，每年进行前瞻性评估 细胞质伊卡阴性，生化自身抗体阳性的个体， 分析自身抗体表型和代谢的遗传决定因素 进步，以及进一步分析积累的数据财富。