Immune Response to RBC Antigens

对红细胞抗原的免疫反应

• 批准号: 10733353
• 负责人: Krystalyn E Hudson
• 金额: $ 72.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733353
• 关键词: Adenosine; Adverse event; Affect; Age; Age of Onset; Aging; Anemia; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune hemolytic anemia; Autoimmunity; Automobile Driving; Binding; Biological Factors; Biological Testing; Blood Platelets; Blood donor; CD4 Positive T Lymphocytes; Cells; Clinical; Complication; Data; Development; Emigrant; Erythrocyte Transfusion; Erythrocytes; Etiology; Event; Failure; Fatigue; Female; Flow Cytometry; Frequencies; Functional disorder; Future; Hematology; Hemoglobinuria; Hemolysis; Hemolysis Induction; Hospitalization; Human; Immune; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immune system; Immunotherapy; Individual; Inflammatory; Interleukin-10; Knowledge; Life; Malignant Neoplasms; Mediating; Medical; Modeling; Morbidity - disease rate; Mus; Pallor; Pathogenesis; Pathway interactions; Patients; Platelet Glycoproteins; Population; Pre-Clinical Model; Prevention; Production; Publishing; Regulatory T-Lymphocyte; Relapse; Reporting; Research; Reticulocytosis; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Splenomegaly; Supportive care; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thrombocytopenic Purpura; Thymus Gland; Time; Tissues; autoreactive T cell; autoreactivity; cancer immunotherapy; cancer therapy; checkpoint therapy; clinically significant; cytokine; ds-DNA; experience; extracellular; human disease; immune checkpoint; innovation; insight; male; mortality; mouse model; novel; novel therapeutic intervention; pre-clinical; prevent; sex; success; tissue oxygenation; transcriptome sequencing; transcriptomics; treatment strategy; virtual

ABSTRACT Autoimmune hemolytic anemia (AIHA) causes significant morbidity and mortality; however, we still do not fully understand how immune tolerance to red blood cells (RBCs) is established or broken. Given that RBCs are required for life, are abundant, and have essential functions (e.g., tissue oxygenation), one would predict stringent immune tolerance; however, tolerance failure occurs frequently. Indeed, 0.1% of healthy blood donors and ~8% of hospitalized patients have detectable RBC autoantibodies. These autoantibodies can be clinically significant, by inducing RBC clearance, hemolysis, antigen modulation, and increased risk for future AIHA or cancer. Patients with AIHA present with pallor, fatigue, hemoglobinuria, splenomegaly, and/or life-threatening hemolysis. Treatment strategies have variable success, with high relapse rates and mortality in ~11% of cases. Supportive care using RBC transfusions is challenging as most autoantibodies recognize ubiquitous RBC antigens; thus, virtually all donor units are crossmatch incompatible. The etiology of AIHA is generally unknown and up to 50% of AIHA cases have no identifiable cause (“primary”). Secondary AIHA is frequently associated with other autoimmune diseases and has been recently observed as a complication of checkpoint inhibitor immunotherapies in the treatment of cancer. Thus, loss of tolerance to RBC autoantigens is an important medical and scientific problem. To elucidate RBC tolerance mechanisms, we developed an innovative primary AIHA murine model, which closely reflects human disease, a subset of mice develops age-onset hemolytic RBC autoantibodies, anemia, splenomegaly, and reticulocytosis. Using this model, we pinpointed a 3-week developmental timeframe during which RBC autoreactive recent thymic emigrants encounter RBC antigens and become tolerized. Transcriptomic analysis identified novel pathways whose activity correlates with autoreactive T cell tolerization, including 1) checkpoint molecules, 2) IL-10, and 3) purinergic signaling. Because AIHA is the most frequently reported hematological adverse event due to cancer immunotherapy, we developed a novel secondary AIHA model with checkpoint inhibitors. Loss of tolerance in the primary and secondary AIHA mouse models is associated with an imbalance between regulatory T cells (Tregs) and proinflammatory TH17 T cells, as well as a distinct population of CD39+ T cells. Herein, we leverage our preclinical AIHA mouse models to determine which signaling molecules and/or pathways (i.e., checkpoint molecules, IL-10, or purinergic signaling molecules) are required for T cell tolerance and AIHA prevention, and elucidate how biological factors, such as sex and age, affect these requirements. The function of unique T cell populations (i.e., recent thymic emigrants, Treg subsets, and CD39+ T cells) will also be defined. Understanding how the immune system responds to RBC antigens will provide insight into not only autoimmunity to RBCs but may also have applicability to other autoantigens present at high concentrations (e.g., platelet autoantigens, dsDNA) thereby making this a powerful platform to study the requirements for tolerance to self-antigens in general.

抽象的 自身免疫性溶血性贫血（AIHA）引起明显的发病率和死亡率；但是，我们仍然没有完全 了解如何建立或破坏对红细胞（RBC）的免疫耐受性。鉴于RBC是 生命所需 严格的免疫耐受性；但是，耐受性失败经常发生。确实，0.1％的健康献血者 约8％的住院患者具有可检测的RBC自身抗体。这些自身抗体可以在临床上进行 重要的是，通过诱导RBC清除，溶血，抗原调节以及未来AIHA或 癌症。患有AIHA的患者患有苍白，疲劳，血红蛋白尿症，全毛和/或威胁生命 溶血。治疗策略取得了可变的成功，在约11％的病例中，中继率和死亡率很高。 使用RBC输血的支持性护理具有挑战性 抗原；因此，几乎所有捐赠单元都是交叉匹配的不兼容。 aiha的病因通常是未知的 多达50％的AIHA病例没有鉴定原因（“主要”）。次级aiha经常相关 使用其他自身免疫性疾病，最近被视为检查点抑制剂的并发症 癌症治疗中的免疫疗法。那就是对RBC自动抗原的耐受性丧失是重要的医学 和科学问题。为了阐明RBC耐受性机制，我们开发了创新的原发性AIHA 密切反映人类疾病的鼠模型，一部分小鼠会发展出年龄发溶的RBC 自身抗体，贫血，脾肿大和网状细胞增多症。使用此模型，我们确定了一个3周 在此期间，RBC自动反应性最近的胸腺移民遇到RBC抗原和 变得容忍。转录组分析确定了活性与自动反应相关的新途径 T细胞的耐受性，包括1）检查点分子，2）IL-10和3）嘌呤能信号传导。因为艾哈是 由于癌症免疫疗法而导致的最常见的血液学不良事件，我们开发了一种新颖的 具有检查点抑制剂的次级AIHA模型。初级和次级AIHA小鼠的公差损失 模型与调节性T细胞（Treg）和促炎性Th17 T细胞之间的不平衡有关， 以及CD39+ T细胞的不同种群。在此，我们利用临床前aiha鼠标模型 确定哪些信号分子和/或途径（即检查点分子，IL-10或嘌呤能信号传导 分子）是T细胞耐受性和预防AIHA所必需的，并阐明了生物学因素（例如性别） 和年龄，影响这些要求。独特的T细胞种群的功能（即最近的胸腺移民，Treg 还将定义子集和CD39+ T细胞）。了解免疫系统如何响应RBC 抗原将不仅可以洞悉RBC的自身免疫性，而且还可以适用于其他 高浓度（例如血小板自动抗原，dsDNA）的自动抗原使其成为强大的 一般来说，研究对自我抗原的耐受性要求的平台。