Insulin vaccination for the prevention of anti islet autoimmunity

注射胰岛素疫苗预防抗胰岛自身免疫

• 批准号: 6227679
• 负责人: GEORGE S EISENBARTH
• 金额: $ 25.04万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6227679
• 关键词: T lymphocyte; autoantibody; autoimmune disorder; child (0-11); clinical research; clinical trials; diabetes mellitus; disease /disorder prevention /control; human subject; human therapy evaluation; immunotherapy; insulin; major histocompatibility complex; pancreatic islets; pathologic process

We believe it is likely that therapies for the prevention of type 1 diabetes will be most efficacious if administered before the development of "fixed" expression of anti-islet autoantibodies. We have evidence that we can now identify infants with a high risk of progressing to autoimmunity and diabetes. There are many avenues for primary preventive therapy and the current proposal will illustrate one such trial, which will likely be altered prior to implementation and likely be part of a collaborative effort to test a number of therapeutic options and regimens. Immunologic "vaccination" with insulin or insulin peptides prevents diabetes of NOD mice with the most dramatic protection associated with early therapy. Amongst islet autoantibody positive relatives of patients with type 1 diabetes, pilot trials of subcutaneous insulin therapy suggest that such therapy will delay progression to diabetes. A major determinant of progression to diabetes (despite therapy) appears to severe loss of insulin secretory capacity at trial entry. This suggests that the therapy is being tested late in the disease process. The results of our prospective DAISY study and the BABY-DIAB study from Germany indicate that DR3/4 (DQ8/DQ2) relatives of patients with type 1 diabetes have an extremely high risk of progression to anti-islet autoimmunity approximately (20- 40%) prior to age 2 (and to diabetes in early childhood). We will test the hypothesis that an "autoantigen" based trial for the prevention of anti-islet autoantibodies can be carried out (e.g. ability to identify high-risk relatives, significant progression to autoimmunity, adequate recruitment). The current proposal will initiate a trial of subcutaneous insulin "vaccination" for the prevention of anti-islet autoimmunity in high-risk children. High-risk individuals will be identified by family history and HLA typing. The major outcome variable of the trial will be the effect upon appearance of GAD65 and ICA512/IA-2 autoantibodies. In addition we will prospectively evaluate in the context of the trial specificity and isotype of anti-islet autoantibodies and characterize anti-insulin T lymphocytes, as well as analyze genetic determinants of anti-islet autoimmunity.

我们认为，如果在开发抗ISLET自身抗体的“固定”表达之前给药，预防1型糖尿病的疗法可能是最有效的。我们有证据表明，我们现在可以识别出患有高风险自身免疫和糖尿病风险的婴儿。主要的预防疗法有许多途径，当前的提案将说明一项此类试验，这可能会在实施之前进行更改，并可能是测试许多治疗选择和方案的合作努力的一部分。胰岛素或胰岛素肽的免疫学“疫苗接种”可防止与早期治疗相关的最明显保护的点头小鼠糖尿病。在1型糖尿病患者的胰岛自身抗体阳性亲属中，皮下胰岛素治疗的初步试验表明，这种疗法会延迟糖尿病的进展。进展到糖尿病的主要决定因素（尽管治疗）似乎严重损失了试验时胰岛素分泌能力。这表明该治疗在疾病过程后期正在测试。我们前瞻性雏菊研究的结果和来自德国的婴儿二氧化碳研究表明，1型糖尿病患者的DR3/4（DQ8/DQ2）亲戚的亲戚大约在2岁之前（以及儿童早期糖尿病）进展到抗ISLE的自身免疫的风险极高（20-40％）。我们将检验以下假设：可以进行基于“自身抗原”的基于“自身抗原”的试验，以预防反行语自身抗体（例如，鉴定高风险亲戚，对自身免疫性的显着发展，适当招募的能力）。当前的提案将启动皮下胰岛素“疫苗接种”试验，以预防高危儿童的抗ISLET自身免疫。高风险的人将通过家族史和HLA打字来识别。该试验的主要结果变量将是对GAD65和ICA512/IA-2自身抗体的出现影响。此外，我们将在试验特异性和抗ISLET自身抗体的试验特异性和同型中进行前瞻性评估，并表征抗胰岛素T淋巴细胞，并分析抗ISLET自身免疫性的遗传决定因素。