Islet Cell Membrane Antibodies in Diabetes

描述(申请人提供)：本申请的目标是a)研究针对人类1型糖尿病(T1D)四种主要自身抗体的抗独特型抗体(anti-ID)，以及b)开发抗ID以选择性地耗尽自身抗原反应性B淋巴细胞作为预防T1D的新疗法。T1D中的一种主要自身抗体(GAD65Ab)的抗ID在大多数健康人中都存在。这些抗-ID特异性地靶向GAD65Ab的抗原结合部位，从而阻断抗原识别。针对另一种主要自身抗体(IAA)的抗ID在T1D患者和BB大鼠(T1D的动物模型)中都已被描述，表明这些独特型网络可能与T1D的发病相关。在临床诊断中，与健康人相比，T1D患者的GAD65Ab特异性抗ID效价显著降低。此外，抗ID活性与β细胞功能相关，正如在对新发T1D儿童的纵向分析中所观察到的那样，这些儿童经历了过渡性的C-肽水平上升。这些数据强烈表明，GAD65Ab特异性抗ID是GAD65调节性免疫反应的一部分，因此可能对T1D具有保护作用。最近的研究发现，给NOD小鼠注射单抗ID可以预防T1D，这支持保护性抗ID的假说。此应用程序将确定在开发T1D期间何时丢失反ID活动。进展者和非进展者的纵向样本将被分析抗ID，以确定进展者中抗ID活性的丧失是否先于T1D的发展。另一个目的是确定已知的高危和保护性基因型别是否分别与低和高抗-ID活性相关。这种关联将支持这样一种假设，即人类白细胞抗原风险/保护部分是由抗ID活性介导的。抗 ID被描述为具有调节免疫功能。它们中和自身抗体，下调自身抗体的分泌，并诱导抗原特异性B淋巴细胞的耗尽。这些特征已经被用于治疗其他自身免疫性疾病。B淋巴细胞在T1D中的作用已在动物研究中被提出，最近的Rituximab试验表明，全球B淋巴细胞枯竭对β细胞功能的保存有好处。然而，全球B淋巴细胞耗尽也会消除有益的B淋巴细胞，对于预防T1D来说，这并不是一个现实的选择。为了避免B淋巴细胞的全局性耗竭，将使用自身抗原-Fc融合蛋白作为抗-ID的模拟物。这些融合蛋白将耗尽对自身抗原所有表位有反应的B淋巴细胞，而抗ID只针对具有单一抗体表位特异性的B淋巴细胞。在这种方法中，将使用所有四种主要自身抗原(胰岛素、GAD65、IA-2和ZnT8)的自身抗原-Fc融合蛋白。这个项目的结果将对一部小说的进一步发展至关重要 预防性治疗。

DESCRIPTION (provided by applicant): The goal of this application is a) to investigate anti-idiotypic antibodies (anti-Id) directed to the four major autoantibodies in human Type 1 Diabetes (T1D), and b) to develop anti-Id to selectively deplete autoantigen-reactive B lymphocytes as a novel therapy to prevent T1D. Anti-Id to a major autoantibody in T1D (GAD65Ab) are found in the majority of healthy individuals. These anti-Id specifically target the antigen-binding site of GAD65Ab and thus block antigen recognition. Anti- Id to another major autoantibody (IAA) have been described previously in both T1D patients and the BB rat - an animal model for T1D- indicating that these idiotypic networks may be of relevance for T1D pathogenesis. At clinical diagnosis patients with T1D have significantly lower GAD65Ab-specific anti-Id titers as compared to healthy individuals. Moreover, anti-Id activity correlates with beta cell function, as observed in a longitudinal analysis of children with new onset T1D, who experienced a transitional increase in c-peptide levels. These data strongly suggest that GAD65Ab-specific anti-Id are part of the regulatory immune response to GAD65 and may therefore protect against T1D. Recent findings that injections of NOD mice with a monoclonal anti-Id prevented T1D support this hypothesis of protective anti-Id. This application will determine when anti-Id activiy is lost during development of T1D. Longitudinal samples from progressors and non-progressors will be analyzed for anti-Id to establish whether loss of anti-Id activity in progressors precedes T1D development. Another aim is to determine whether known high-risk and protective HLA genotypes are associated with low and high anti-Id activity, respectively. Such an association would support the hypothesis that HLA risk/protection is mediated in part by anti-Id activity. Anti Id are described to have regulatory immune functions. They neutralize autoantibodies, downregulate autoantibody secretion, and induce depletion of antigen-specific B lymphocytes. These characteristics are already employed in the treatment of other autoimmune diseases. A role of B lymphocytes in T1D has been suggested in animal studies, and the recent Rituximab trial demonstrated that global B lymphocyte depletion has a beneficial effect on the preservation of beta cell function. However global B lymphocyte depletion also eliminates beneficial B lymphocytes and is not a realistic option for the prevention of T1D. To avoid the global depletion of B lymphocytes, autoantigen-Fc fusion proteins will be used as mimetics of anti-Id. These fusion proteins will deplete B lymphocytes that are reactive to all epitopes of the autoantigen, while anti-Id will only target B lymphocytes of a single antibody epitope specificity. Autoantigen-Fc fusion proteins of all four major autoantigens (insulin, GAD65, IA-2, and ZnT8) will be used in this approach. The results from this project will be crucial for the further development of a novel preventative therapy.