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.

抽象的 自身免疫性溶血性贫血（AIHA）发生在针对红细胞（RBC）的病原自身抗体时 产生抗原并促进溶血。每年在美国报告9000例AIHA案例。 当前疗法，包括免疫抑制和/或脾切除术，具有可变的结果，不是 对某些患者有效。此外，在最初成功的患者中有80％的复发率 当前疗法。由于自身抗体通常反对无处不在的抗原，因此本质上是所有RBC单元 许多患者不兼容，从而防止输血足够的RBC治疗贫血。因此， 由于我们缺乏机械理解和缺乏有效性的研究，对AIHA发病机理的研究非常重要 一些AIHA患者的疗法。鉴于自身免疫的危险，免疫系统已经发展 对自我抗原的耐受性的多种途径，包括中央和外围耐受性检查点。尽管 aiha每年以9000例新病例发生，无症状的献血者中有0.1％可检测到 RBC自身抗体表明对RBC抗原的耐受性经常失效。但是，宽容 关于RBC抗原的机制知之甚少，代表了这两种临床的区域 意义，也是对免疫耐受性的重要新基本理解的来源。我们已经创新了 一种新型且可拖动的鼠系统，用于研究对RBC抗原的免疫耐受性，该系统允许测试 在其他系统中不可能的机械假设。该模型为1提供了独特的机会） 询问RBC特异性的公差机制，2）在发作之前评估潜在的预防疗法 自身免疫性和3）研究活跃自身免疫性疾病期间的潜在疗法。提议 研究利用这些新工具，旨在作为转化努力，以阐明如何 建立和维护对RBC抗原的耐受性，确定导致A的潜在途径 耐受机制的分解，并洞悉AIHA发病机理的机制。一个 了解免疫系统如何对RBC上的抗原做出反应将为不提供重大洞察力而不是 仅对RBC自身免疫性，但对RBC抗原的免疫反应一般（从而扩展到 炎症环境和由于输血等而暴露于同种异体RBC等）和 作为未来人类研究和新疗法潜在发展的合理基础。因此，我们 提出以下特定目的：目标1）确定抗原呈现细胞的子集和表型 参与RBC衍生抗原对淋巴细胞的抗原表现，目标2）确定T细胞如何 耐受性RBC特异性抗原，目标3）可以逆转RBC的测试因素 自动抗原并在AIHA发病机理中发挥作用。