The Role of Anti-Serpin B13 Autoantibody as a Biomarker of Slower Progression in Type 1 Diabetes Mellitus

抗丝氨酸蛋白酶抑制剂 B13 自身抗体作为 1 型糖尿病进展缓慢的生物标志物的作用

• 批准号: 9336062
• 负责人: Jan Czyzyk
• 金额: $ 15.36万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336062
• 关键词: Affect; Animals; Antibodies; Antibody Response; Autoantibodies; Autoimmune Process; Beta Cell; Binding; Biological Assay; Biological Markers; Cell Proliferation; Cell physiology; Cells; Child; Clinical; Coculture Techniques; Collaborations; Development; Diabetes Mellitus; Diabetes prevention; Disease; Duct (organ) structure; Ductal Epithelial Cell; Ductal Epithelium; Endocrine; Enrollment; Exocrine pancreas; Experimental Models; Gene Expression; Generations; Genes; Growth; Health; Homeostasis; Human; Humoral Immunities; Immune response; Immunity; In Vitro; Inbred NOD Mice; Individual; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Laboratories; Light; Measures; Modeling; Monoclonal Antibodies; Mus; Natural regeneration; Non obese; Onset of illness; Outcome; Output; Pancreas; Patients; Placebos; Prediabetes syndrome; Prevention trial; Process; Production; Protease Inhibitor; Registries; Research; Research Institute; Research Personnel; Residual state; Risk; Risk Factors; Role; Sampling; Serological; Serpins; Serum; Staging; T-Lymphocyte; Technology; Testing; Time; Tissues; Translating; Validation; Work; abstracting; animal data; base; diabetes risk; diabetic; disorder prevention; early onset; first phase insulin response; high risk; human disease; impaired glucose tolerance; improved; insulin dependent diabetes mellitus onset; islet; novel; novel marker; novel therapeutic intervention; potential biomarker; research study; response; self-renewal

Abstract The mechanisms responsible for protection against type 1 diabetes (T1D) are not completely understood. Our studies demonstrated that a subset of young T1D-prone non-obese diabetic (NOD) mice have elevated levels of autoantibodies (AAs) to the proteinase inhibitor serpin B13, and that this response correlated with protection from early onset diabetes. Experiments with serpin B13 monoclonal autoantibodies (mAbs) extended these observations by showing that anti-serpin activity is both a biomarker of protection from diabetes and an active contributor to the disease-prevention process. Specifically, we found that injecting serpin B13 mAb impeded islet-associated inflammation in the NOD model and induced the generation of approximately 80 islets per animals in normal Balb/c mice. Our additional analysis of human samples obtained from the Belgian Diabetes Registry demonstrated that early onset T1D is associated with low serpin B13 AA production, suggesting an inverse relationship between the serpin immunological response and the development of clinical diabetes. Importantly, our analysis of TrialNet placebo subjects indicated that baseline serpin antibody is associated with slower decline in residual beta cell function in children with recent onset T1D. Together, our findings in the mouse and humans consistently suggested that antibody response to serpin B13 promotes beneficial outcomes in T1D. To continue translating our findings to humans, we propose a study of individuals at risk for T1D who were followed to the time of disease onset. The successful completion of this project will require examination of serum samples obtained from approximately 600 individuals during their enrollment in the Diabetes Prevention Trial for Type 1 Diabetes (DPT-1). In Aim 1, we will examine subjects with high, intermediate, modest, and low risk for T1D and assess their serological binding activity to SERPIN B13 at baseline. In Aim 2, we will compare serum-binding activities between subjects with an intermediate-to- high risk for T1D who progressed to diabetes versus those that remained diabetes-free. Finally, in Aim 3 we will assess impact of antibodies to serpin B13 on beta cells proliferation in pancreatic islets isolated from humans. Serpin AAs will be detected with a Luminex-based technology that was developed in our laboratory and validated in collaboration with the Core for Assay Validaion (CAV) at the Benaroya Research Institute. This study will help to clarify whether humoral immunity to serpin molecules could be a biomarker of homeostasis resulting in improved beta cell health in the setting of autoimmune inflammation in human patients. It will also help us to verify the hypothesis that serpin B13 mAbs can be therapeutically beneficial by enhancing immunity against serpins.

抽象的 尚不完全了解负责保护1型糖尿病（T1D）的机制。 我们的研究表明，年轻T1D易于的非肥胖糖尿病（NOD）小鼠的子集具有 蛋白酶抑制剂SERPIN B13的自身抗体水平升高（AAS），并且这种反应 与免受早期糖尿病的保护相关。 Serpin B13单克隆的实验 自身抗体（mAb）通过表明抗serpin活性是一个 保护糖尿病保护的生物标志物和预防疾病过程的积极贡献者。 具体而言，我们发现注射SERPIN B13 mAb阻碍与胰岛相关的炎症 模型并诱导正常BALB/c小鼠中每只动物的大约80个胰岛的产生。我们的 对从比利时糖尿病登记处获得的人类样本的其他分析表明， 早期发作T1D与低SERPIN B13 AA产生有关，这表明是反相关关系的 在SERPIN免疫反应与临床糖尿病的发展之间。重要的是，我们的 试验网安慰剂受试者的分析表明，基线SERPIN抗体与较慢有关 最近发作T1D儿童的残留β细胞功能下降。一起，我们在 小鼠和人类始终提出抗体对SERPIN B13的反应会促进有益的 T1D的结果。 为了继续将我们的发现转化为人类，我们建议对有T1D风险的个体进行研究 遵循疾病发作时的人。该项目的成功完成将需要 检查在入学期间从大约600个人获得的血清样品 1型糖尿病（DPT-1）预防糖尿病试验。在AIM 1中，我们将检查高的受试者， T1D的中间，适中和低风险，并评估其与Serpin B13的血清学结合活性 基线。在AIM 2中，我们将比较受试者之间的血清结合活动 与糖尿病相比，T1D的高风险与仍然没有糖尿病的T1D。最后，在目标3中 我们将评估抗体B13抗体对分离的胰岛中β细胞增殖的影响 来自人类。 Serpin AAS将通过我们的基于Luminex的技术检测到我们 实验室并与Benaroya的Assay Validaion（CAV）核心合作进行了验证 研究所。 这项研究将有助于阐明对Serpin分子的体液免疫是否可能是生物标志物 在人类自身免疫性炎症的情况下，体内稳态导致β细胞健康的改善 患者。它还将帮助我们验证塞普蛋白B13 mAb可以治疗的假设 通过增强对SERPINS的免疫力来有益。