Prevention Center U01: Early Targets for Antigen-Specific Tolerance Induction for

预防中心 U01：抗原特异性耐受诱导的早期目标

• 批准号: 8373734
• 负责人: Vernon Michael Holers
• 金额: $ 50.27万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8373734
• 关键词: Address; Affinity; Antibodies; Antibody Specificity; Antigen Targeting; Antigens; Arthritis; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Automobile Driving; B-Lymphocytes; Binding; Biocompatible Materials; Biological Markers; Blood; C-reactive protein; Cells; Characteristics; Chronic Disease; Clinical; Development; Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Epitopes; Etiology; Exhibits; Family; Flow Cytometry; Frequencies; Future; Goals; Immune response; Immunoblotting; Immunoglobulin Light Chain Genes; Immunoglobulins; Immunologic Factors; Immunologics; Individual; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intervention; Knowledge; Lead; Mass Spectrum Analysis; Modeling; Modification; Mus; National Institute of Allergy and Infectious Disease; Natural History; Participant; Pathogenesis; Patients; Pattern; Peptides; Phase; Plasma; Plasmablast; Prevention; Prevention strategy; Primary Prevention; Process; Production; Proteins; Public Health; Recombinant Antibody; Research; Research Personnel; Research Support; Rheumatoid Arthritis; Rheumatoid Factor; Risk; Sampling; Self Tolerance; Signs and Symptoms; Specificity; Staining method; Stains; Sushi Domain; Systemic Lupus Erythematosus; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; T-Lymphocyte Epitopes; Techniques; Time; To autoantigen; Trees; Work; base; chemokine; cohort; cytokine; design; high risk; improved; mouse model; novel; novel strategies; pre-clinical; preclinical study; response; tool

DESCRIPTION (provided by applicant): Studies over the last decade have dramatically changed our understanding of the early natural history of rheumatoid arthritis (RA) by demonstrating convincingly that RA-related autoantibodies are elevated in asymptomatic individuals for at least several years prior to the development of clinically apparent signs and symptoms of RA. This autoantibody positive but asymptomatic phase is then followed shortly before the onset of clinically apparent signs and symptoms of arthritis by the development of increased systemic inflammation that is manifest by elevated serum/plasma levels of cytokines and chemokines. Because of these findings, we now have a general conceptual framework of how the disease develops in its earliest phases. However, despite these gains in knowledge, the initial citrullinated epitopes to which pathogenic B and T cells respond are unknown. This knowledge is critical to our understanding of the immunologic mechanisms that underlie disease development as well as the future design of tolerance-based therapies. We have established a unique cohort of individuals under the umbrella of the Studies of the Etiology of Rheumatoid Arthritis (SERA) who are at the highest definable risk for the future development of RA. Two Co-Investigators in this project application, Drs. Robinson and Buckner, have developed novel approaches to identify and characterize antigen-specific B and T cell responses to citrullinated and other RA-related autoantigens. To advance our understanding of the autoimmune response at the earliest time points in the development of RA, we propose to utilize these techniques in high-risk SERA participants and pursue the following Specific Aims: Specific Aim #1. Identify the innate and adaptive immune response modifications that are causally associated with the break in tolerance to citrullinated autoantigens and progression to active disease; Specific Aim #2. Use novel single-B-cell expression techniques to identify the RA-related autoantigens that are targeted in the initial preclinical phases of disease development; and Specific Aim #3. Determine what peptide autoantigens are recognized by T cells in the initial phases of the loss of self tolerance in the preclinical period of disease development. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it utilizes a unique cohort of subjects and biomaterials and is focused on a strategy that will improve our understanding of the mechanisms whereby individuals develop preclinical autoimmunity and then subsequently transition to clinically apparent rheumatoid arthritis (RA). Unique antigens and epitopes recognized by subjects who are progressing to the development of RA will be defined. The proposed research will address questions directly bearing on the programmatic goals of NIAID that are focused on supporting research into the causes, treatment and prevention of autoimmune diseases.

描述（由申请人提供）：过去十年的研究极大地改变了我们对类风湿性关节炎 (RA) 早期自然史的理解，令人信服地证明，在无症状个体中，RA 相关自身抗体在发病前至少几年内就已升高。 RA 的临床明显体征和症状。在这种自身抗体阳性但无症状的阶段之后，在临床上明显的关节炎体征和症状出现之前不久，系统性炎症的发展加剧，表现为细胞因子和趋化因子的血清/血浆水平升高。由于这些发现，我们现在对这种疾病在最早阶段如何发展有了一个总体概念框架。然而，尽管知识取得了这些进展，致病性 B 和 T 细胞响应的最初瓜氨酸表位仍不清楚。这些知识对于我们理解疾病发展的免疫机制以及基于耐受的疗法的未来设计至关重要。我们在类风湿关节炎病因研究 (SERA) 的框架下建立了一个独特的人群，这些人群未来发展为 RA 的风险最高。该项目申请的两名联合研究员，博士。 Robinson 和 Buckner 开发了新方法来识别和表征抗原特异性 B 和 T 细胞对瓜氨酸和其他 RA 相关自身抗原的反应。为了加深我们对 RA 发展最早时间点自身免疫反应的理解，我们建议在高风险 SERA 参与者中使用这些技术，并追求以下具体目标：具体目标#1。确定与瓜氨酸自身抗原耐受性破坏和进展为活动性疾病有因果关系的先天性和适应性免疫反应修饰；具体目标#2。使用新型单 B 细胞表达技术来识别疾病发展的初始临床前阶段的目标 RA 相关自身抗原；和具体目标#3。确定在疾病发展的临床前阶段自我耐受丧失的初始阶段，T 细胞识别哪些肽自身抗原。 公共健康相关性：拟议的研究与公共健康相关，因为它利用了一组独特的受试者和生物材料，并重点关注一种策略，该策略将提高我们对个体发展临床前自身免疫性然后转变为临床明显的类风湿性关节炎的机制的理解（RA）。将定义正在发展为 RA 的受试者所识别的独特抗原和表位。拟议的研究将解决与 NIAID 的规划目标直接相关的问题，该目标的重点是支持对自身免疫性疾病的原因、治疗和预防的研究。