Islet Cell Membrane Antibodies in Diabetes

糖尿病中的胰岛细胞膜抗体

• 批准号: 8868978
• 负责人: CHRISTIANE S HAMPE
• 金额: $ 36.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-01-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868978
• 关键词: Alleles; Animal Model; Animals; Anti-Idiotypic Antibodies; Antibodies; Antibody Specificity; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Beta Cell; Binding; Binding Sites; Biological Preservation; Cell membrane; Cell physiology; Characteristics; Child; Chimeric Proteins; Clinical; Data; Development; Diabetes Mellitus; Disease; Effector Cell; Elements; Epitopes; Frequencies; Genetic Predisposition to Disease; Genetic Risk; Genotype; Goals; Grant; Human; Immune; Immune response; In Vitro; Inbred BB Rats; Inbred NOD Mice; Individual; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Lymphocyte Depletion; Mediating; Monoclonal Antibodies; Pathogenesis; Pathway interactions; Patients; Peptides; Prevention; Prevention therapy; Reporting; Research; Risk; Role; Sampling; Specificity; Structure of beta Cell of islet; T cell response; Techniques; Testing; Therapeutic Intervention; To autoantigen; Umbilical Cord Blood; antigen binding; base; clinical Diagnosis; design; experience; high risk; human monoclonal antibodies; immune function; in vivo; innovation; insight; insulin dependent diabetes mellitus onset; longitudinal analysis; mimetics; novel; novel therapeutics; prevent; protein function; risk variant; rituximab

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.

描述（由申请人提供）：本申请的目的是 a) 研究针对人类 1 型糖尿病 (T1D) 的四种主要自身抗体的抗独特型抗体（抗 Id），以及 b) 开发抗 Id 来选择性消除自身抗原反应性 B 淋巴细胞，作为预防 T1D 的新疗法。 大多数健康个体中都存在针对 T1D 的主要自身抗体 (GAD65Ab) 的抗 Id 抗体。这些抗 Id 特异性靶向 GAD65Ab 的抗原结合位点，从而阻断抗原识别。先前已在 T1D 患者和 BB 大鼠（一种 T1D 动物模型）中描述了针对另一种主要自身抗体 (IAA) 的抗 Id，表明这些独特型网络可能与 T1D 发病机制相关。在临床诊断时，与健康个体相比，T1D 患者的 GAD65Ab 特异性抗 Id 滴度显着降低。此外，抗Id活性与β细胞功能相关，正如对新发T1D儿童的纵向分析所观察到的那样，这些儿童的C肽水平出现了过渡性增加。这些数据强烈表明，GAD65Ab 特异性抗 Id 是针对 GAD65 的调节性免疫反应的一部分，因此可以预防 T1D。最近的研究结果表明，给 NOD 小鼠注射单克隆抗 Id 可以预防 T1D，这支持了这种保护性抗 Id 的假设。 该应用程序将确定在 T1D 发展过程中抗 ID 活性何时丧失。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。这种关联支持 HLA 风险/保护部分由抗 Id 活性介导的假设。反对 Id被描述为具有调节免疫功能。它们中和自身抗体，下调自身抗体分泌，并诱导抗原特异性 B 淋巴细胞的消耗。这些特性已经用于治疗其他自身免疫性疾病。动物研究表明 B 淋巴细胞在 T1D 中发挥作用，最近的利妥昔单抗试验表明，整体 B 淋巴细胞耗竭对保存 β 细胞功能具有有益作用。然而，整体 B 淋巴细胞清除也会消除有益的 B 淋巴细胞，因此并不是预防 T1D 的现实选择。为了避免 B 淋巴细胞的整体耗尽，自身抗原-Fc 融合蛋白将被用作抗 Id 的模拟物。这些融合蛋白将耗尽对自身抗原的所有表位有反应的 B 淋巴细胞，而抗 Id 只会针对单一抗体表位特异性的 B 淋巴细胞。该方法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。该项目的结果对于小说的进一步开发至关重要 预防性治疗。