Islet Cell Membrane Antibodies in Diabetes

糖尿病中的胰岛细胞膜抗体

• 批准号: 8369765
• 负责人: CHRISTIANE S HAMPE
• 金额: $ 36.64万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369765
• 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; 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. PUBLIC HEALTH RELEVANCE: To date no cure for Type 1 diabetes is available and new directions are necessary to identify pathogenic pathways to design prevention and intervention therapies. We identified a novel immune factor in the pathogenesis of Type 1 diabetes. While a protective role for similar factors has been described in other autoimmune diseases, this is a novel concept in Type 1 diabetes research.

描述（由申请人提供）：本申请的目的是a）研究针对人1型糖尿病（T1 D）中四种主要自身抗体的抗独特型抗体（抗Id），和B）开发抗Id，以选择性耗竭自身抗原反应性B淋巴细胞，作为预防T1 D的新型疗法。 T1 D中主要自身抗体（GAD 65 Ab）的抗Id存在于大多数健康个体中。这些抗Id特异性靶向GAD 65 Ab的抗原结合位点，从而阻断抗原识别。先前在T1 D患者和BB大鼠（T1 D的动物模型）中描述了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T1 D发病机制相关。在临床诊断时，与健康个体相比，患有TlD的患者具有显著较低的GAD 65 Ab特异性抗Id滴度。此外，抗Id活性与β细胞功能相关，正如在对新发T1 D儿童的纵向分析中观察到的那样，这些儿童的c肽水平经历了过渡性增加。这些数据强烈表明，GAD 65 Ab特异性抗Id是对GAD 65的调节性免疫应答的一部分，因此可以保护免受T1 D。最近的研究结果表明，NOD小鼠注射单克隆抗Id预防T1 D支持这种假设的保护性anti-Id。这种应用程序将确定何时抗Id活性在T1 D的发展过程中失去。将分析来自进展者和非进展者的纵向样本的抗Id，以确定进展者中抗Id活性的丧失是否先于T1 D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。抗 Id被描述为具有调节性免疫功能。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淋巴细胞耗竭。这些特征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T1 D中的作用，最近的利妥昔单抗试验表明，整体B淋巴细胞耗竭对β细胞功能的保护具有有益作用。然而，整体B淋巴细胞耗竭也消除了有益的B淋巴细胞，并且不是预防T1 D的现实选择。为了避免B淋巴细胞的整体耗竭，将使用自身抗原-Fc融合蛋白作为抗Id的模拟物。这些融合蛋白将耗竭对自身抗原的所有表位具有反应性的B淋巴细胞，而抗Id将仅靶向具有单一抗体表位特异性的B淋巴细胞。所有四种主要自身抗原（胰岛素、GAD 65、IA-2和ZnT 8）的自身抗原-Fc融合蛋白将用于该方法。这个项目的结果对小说的进一步发展至关重要 预防性治疗 公共卫生相关性：到目前为止，1型糖尿病还没有治愈方法，需要新的方向来确定致病途径，以设计预防和干预治疗。我们发现了一种新的免疫因子在1型糖尿病的发病机制。虽然在其他自身免疫性疾病中已经描述了类似因子的保护作用，但这在1型糖尿病研究中是一个新概念。