Islet Cell Membrane Antibodies in Diabetes

描述（由申请人提供）：本申请的目标是a)研究针对人类1型糖尿病（T1D）中四种主要自身抗体的抗独特型抗体（anti-Id），以及b)开发可选择性消耗自身抗原反应性b淋巴细胞的抗id，作为一种预防T1D的新疗法。在大多数健康个体中发现T1D主要自身抗体（GAD65Ab）的抗- id。这些anti-Id特异性靶向GAD65Ab的抗原结合位点，从而阻断抗原识别。先前在T1D患者和BB大鼠（T1D的动物模型）中都发现了另一种主要自身抗体（IAA）的抗Id抗体，这表明这些独特型网络可能与T1D的发病机制有关。在临床诊断时，与健康个体相比，T1D患者的gad65ab特异性抗- id滴度显著降低。此外，在对新发T1D儿童的纵向分析中观察到，抗- id活性与β细胞功能相关，这些儿童经历了c肽水平的过渡性增加。这些数据有力地表明，gad65ab特异性抗id是GAD65调节免疫应答的一部分，因此可能对T1D有保护作用。最近的研究发现，给NOD小鼠注射单克隆抗id可预防T1D，这支持了保护性抗id的假设。该应用程序将确定在T1D开发过程中何时失去抗id活性。将对进展者和非进展者的纵向样本进行抗id分析，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风险和保护性HLA基因型是否分别与低和高抗id活性相关。这种关联将支持HLA风险/保护部分由抗id活性介导的假设。反

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.