Immune Response to RBC Antigens

对红细胞抗原的免疫反应

• 批准号: 9389295
• 负责人: Krystalyn E Hudson
• 金额: $ 45.7万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9389295
• 关键词: Adoptive Transfer; Aftercare; Allogenic; Anemia; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Atypical lymphocyte; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune hemolytic anemia; Autoimmunity; B-Lymphocytes; Blood donor; Breeding; Bypass; Cell physiology; Cells; Cellular biology; Chimeric Proteins; Clinical; Consumption; Data; Development; Disease; Education; Ensure; Erythrocytes; Exposure to; Future; Hemolysis; Hen Egg Lysozyme; Hepatic; Human; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunologics; Immunology; Immunosuppression; Immunosuppressive Agents; Infection; Integral Membrane Protein; Investigation; Lead; Life; Lymphocyte; Modeling; Molecular; Mus; Outcome; Ovalbumin; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral; Phagocytes; Phenotype; Plasma Cells; Play; Prevention; Prior Therapy; Prophylactic treatment; Proteins; Reagent; Relapse; Reporting; Research; Role; Self Tolerance; Source; Specificity; Splenectomy; System; T cell anergy; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; To autoantigen; Transfusion; Transgenes; Transgenic Mice; Wild Type Mouse; anergy; autoreactive B cell; autoreactive T cell; autoreactivity; base; blood group; cell type; central tolerance; clinically significant; cytokine; design; inflammatory milieu; innovation; insight; novel; novel therapeutics; peripheral tolerance; prevent; receptor; relapse patients; reverse tolerance; senescence; success; tool

Abstract Autoimmune hemolytic anemia (AIHA) occurs when pathogenic autoantibodies against red blood cell (RBC) antigens are generated and promote hemolysis. Each year, 9000 new cases of AIHA are reported in the USA. Current therapies, including immunosuppression and/or splenectomy, have variable outcomes and are not effective in certain patients. Additionally, there is an 80% relapse rate in patients who have initial success with current therapies. Because autoantibodies are often against ubiquitous antigens, essentially all RBC units incompatible for many patients, thereby preventing transfusion of sufficient RBCs to treat anemia. Thus, the study of AIHA pathogenesis is significant due to our lack of mechanistic understanding and lack of efficacious therapies for some AIHA patients. Given the dangers of autoimmunity, the immune system has evolved multiple pathways of tolerance to self-antigens, including central and peripheral tolerance checkpoints. While AIHA occurs at a rate of 9000 new cases a year, up to 0.1% of asymptomatic blood donors have detectable RBC autoantibodies, demonstrating that tolerance to RBC antigens fails frequently. However, tolerance mechanisms with respect to RBC antigens are poorly understood, and represent an area of both clinical significance and also a source of important new basic understanding of immune tolerance. We have innovated a novel and tractable murine system to study immune tolerance to RBC antigens that allows testing of mechanistic hypotheses not possible in other systems. This model provides unique opportunities to 1) interrogate RBC-specific tolerance mechanisms, 2) evaluate potential prophylaxis therapies prior to onset of autoimmunity and 3) investigate potential therapeutics during active autoimmune disease. The proposed studies take advantage of these new tools and are designed to serve as a translational effort to elucidate how tolerance to RBC antigens is established and maintained, identify potential pathways that result in a breakdown of tolerance mechanisms, and provide insight into mechanisms of AIHA pathogenesis. An understanding of how the immune system responds to antigens on RBCs will provide significant insight into not only autoimmunity to RBCs, but immune responses to RBC antigens in general (thereby extending to inflammatory environments and exposure to allogeneic RBCs as a consequence of transfusions etc.), and serve as a rational basis for future human studies and potential development of novel therapies. As such, we propose the follow specific aims: Aim 1) Determine the subset(s) and phenotype of antigen presenting cells that participate in antigen presentation of RBC-derived antigens to lymphocytes, Aim 2) Determine how T cells are tolerized to self-derived RBC-specific antigens, and Aim 3) Test factors that can reverse tolerance to RBC autoantigens and play a role in AIHA pathogenesis.

摘要 自身免疫性溶血性贫血（AIHA）发生时，致病性自身抗体对红细胞（RBC）， 产生抗原并促进溶血。美国每年报告9000例AIHA新病例。 目前的治疗，包括免疫抑制和/或脾切除术，具有可变的结果， 对某些患者有效。此外，有一个80%的复发率在患者谁有初步的成功， 目前的治疗。由于自身抗体通常是针对普遍存在的抗原，基本上所有的红细胞单位， 对于许多患者来说，这是不相容的，从而阻止输注足够的RBC来治疗贫血。因此 由于缺乏对AIHA发病机制的认识和有效的治疗手段， 治疗一些AIHA患者。鉴于自身免疫的危险性，免疫系统已经进化 对自身抗原耐受的多种途径，包括中枢和外周耐受检查点。而 AIHA以每年9000例新发病例的速度发生，高达0.1%的无症状献血者可检测到AIHA。 RBC自身抗体，表明对RBC抗原的耐受经常失败。然而，宽容 关于RBC抗原的机制知之甚少，并且代表了临床和免疫学的两个领域。 重要意义，也是对免疫耐受重要的新的基本理解的来源。我们创新 一种新的和易处理的小鼠系统，用于研究对RBC抗原的免疫耐受性， 机械假说在其他系统中是不可能的。这种模式提供了独特的机会1） 询问RBC特异性耐受机制，2）在发病前评价潜在预防性治疗， 自身免疫和3）研究活动性自身免疫疾病期间的潜在治疗方法。拟议 研究利用这些新工具，旨在作为一种翻译努力，以阐明如何 建立并维持对RBC抗原的耐受性，确定导致 破坏耐受机制，并提供对AIHA发病机制的深入了解。一个 了解免疫系统如何对红细胞上的抗原作出反应，将为我们提供重要的见解， 只有对RBC的自身免疫，但对RBC抗原的免疫应答一般（从而扩展到 炎症环境和由于输血等而暴露于同种异体RBC），和 作为未来人类研究和潜在开发新疗法的合理基础。因此我们 提出以下具体目标：目的1）确定抗原呈递细胞的亚群和表型 参与RBC衍生抗原向淋巴细胞的抗原呈递，目的2）确定T细胞如何 对自身衍生的RBC特异性抗原耐受，目的3）测试可逆转RBC耐受的因子 自身抗原，并在AIHA发病机制中发挥作用。