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)是指针对红细胞(RBC)的致病性自身抗体。 产生抗原并促进溶血。在美国，每年报告的AIHA新病例有9000例。 目前的治疗方法，包括免疫抑制和/或脾切除术，有不同的结果，而不是 对某些病人有效。此外，在治疗初期成功的患者中，有80%的复发率 目前的治疗方法。因为自身抗体通常是针对无处不在的抗原，基本上是所有的红细胞单位 许多患者血型不合，因此无法输注足够的红细胞来治疗贫血。因此， 由于我们对AIHA的发病机制缺乏认识，缺乏有效的治疗手段，因此对其发病机制的研究具有重要意义 对一些AIHA患者的治疗。考虑到自身免疫的危险，免疫系统已经进化 对自身抗原的多条耐受途径，包括中枢和外周耐受检查点。而当 AIHA以每年9000例新病例的速度发生，高达0.1%的无症状献血者可检测到 RBC自身抗体，表明对RBC抗原的耐受性经常失败。然而，宽容 与RBC抗原有关的机制知之甚少，在临床上是一个既有代表性的领域 这不仅具有重要的意义，而且也是对免疫耐受的新的基本理解的重要来源。我们创新了 一种新的、易处理的小鼠系统，用于研究对RBC抗原的免疫耐受性，允许检测 机械假说在其他系统中是不可能的。此模式为1)提供了独特的机会 询问RBC特异性耐受机制，2)在发病前评估潜在的预防治疗 自身免疫和3)研究活动性自身免疫性疾病的潜在治疗方法。建议数 研究利用这些新工具，旨在作为一种翻译努力，以阐明如何 建立和维持对RBC抗原的耐受性，识别导致 耐受机制的分解，并提供对AIHA发病机制的洞察。一个 了解免疫系统如何对红细胞上的抗原做出反应将为了解NOT提供重要的见解 仅对红细胞的自身免疫，但一般对红细胞抗原的免疫反应(从而扩展到 炎性环境和输血等导致的异基因红细胞暴露)，以及 为未来的人体研究和潜在的新疗法的开发提供了合理的基础。因此，我们 提出以下具体目标：1)确定抗原提呈细胞的亚群(S)和表型 参与将RBC来源的抗原呈递给淋巴细胞，目的2)决定T细胞如何 对自身衍生的RBC特异性抗原具有耐受性，并旨在测试可逆转对RBC的耐受性的因子 自身抗原，并在AIHA的发病机制中发挥作用。