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.

摘要 自身免疫性溶血性贫血（AIHA）导致显著的发病率和死亡率;然而，我们仍然没有完全了解 了解如何建立或破坏对红细胞（RBC）的免疫耐受。因为RBC是 生命所需的，丰富的，并具有基本功能（例如，组织氧合），人们会预测 严格的免疫耐受;然而，耐受失败经常发生。0.1%的健康献血者 约8%的住院患者可检测到RBC自身抗体。这些自身抗体可以在临床上 通过诱导RBC清除、溶血、抗原调节和增加未来AIHA的风险， 癌AIHA患者表现为苍白、疲乏、血红蛋白尿、脾肿大和/或危及生命 溶血治疗策略的成功率各不相同，约11%的病例复发率和死亡率较高。 使用RBC输注的支持性护理具有挑战性，因为大多数自身抗体识别普遍存在的RBC 抗原;因此，实际上所有供体单位都是交叉配型不相容的。AIHA的病因通常是未知的 高达50%的AIHA病例没有可识别的原因（"原发性"）。继发性AIHA通常与 与其他自身免疫性疾病，最近已被观察到作为检查点抑制剂的并发症 免疫疗法治疗癌症。因此，对RBC自身抗原的耐受性丧失是一个重要的医学问题。 和科学问题。为了阐明RBC耐受机制，我们开发了一种创新的原发性AIHA， 一种密切反映人类疾病的鼠模型，一部分小鼠出现年龄发作性溶血性RBC 自身抗体、贫血、脾肿大和网织红细胞增多症。利用这个模型，我们确定了一个为期3周的 红细胞自身反应性近期胸腺移行细胞遇到红细胞抗原的发育时间表， 变得宽容。转录组学分析鉴定了其活性与自身反应相关的新途径。 T细胞耐受化，包括1）检查点分子，2）IL-10，和3）嘌呤能信号传导。因为AIHA是 由于癌症免疫治疗最常报告的血液学不良事件，我们开发了一种新的 检查点抑制剂的继发性AIHA模型。原发性和继发性AIHA小鼠的耐受性丧失 模型与调节性T细胞（TCLs）和促炎性TH17 T细胞之间的不平衡有关， 以及CD39 + T细胞的独特群体。在此，我们利用我们的临床前AIHA小鼠模型， 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AIHA预防所必需的，并阐明了生物因素，如性别， 和年龄，影响这些要求。独特的T细胞群体的功能（即，近期胸腺移出者，Treg 亚群和CD39 + T细胞）。了解免疫系统如何响应RBC 抗原将不仅提供对RBC的自身免疫的了解，而且还可以适用于其他免疫系统。 以高浓度存在的自身抗原（例如，血小板自身抗原，dsDNA），从而使其成为一种强大的 该平台用于研究一般对自身抗原耐受性的要求。