Immune Response to RBC Antigens

对红细胞抗原的免疫反应

基本信息

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
项目类别：
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

项目摘要

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) 会导致显着的发病率和死亡率；然而，我们仍然不完全了解。如何建立或破坏对红细胞 (RBC) 的免疫耐受。人们预测，生命所需的、丰富的、具有基本功能（例如组织氧合）的免疫耐受；然而，0.1% 的健康献血者经常发生耐受失败。约 8% 的住院患者可检测到红细胞自身抗体，这些自身抗体可用于临床。显着，通过诱导红细胞清除、溶血、抗原调节以及增加未来 AIHA 或 AIHA 患者表现为面色苍白、疲劳、血红蛋白尿、脾肿大和/或危及生命。治疗策略的成功率参差不齐，约 11% 的病例复发率和死亡率很高。使用红细胞输血进行支持治疗具有挑战性，因为大多数自身抗体可识别无处不在的红细胞抗原；因此，几乎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 病例没有明确的病因（“原发性”），通常与继发性 AIHA 有关。与其他自身免疫性疾病有关，最近被观察为检查点抑制剂的并发症因此，失去对红细胞自身抗原的耐受性是一个重要的医学问题。为了阐明红细胞耐受机制，我们开发了一种创新的初级 AIHA。小鼠模型密切反映了人类疾病，一部分小鼠出现老年性溶血性红细胞使用该模型，我们确定了 3 周的自身抗体、贫血、脾肿大和网织红细胞增多症。发育时间范围，在此期间红细胞自身反应性最近的胸腺移出者遇到红细胞抗原并转录组分析发现了其活性与自身反应相关的新途径。 T 细胞耐受，包括 1) 检查点分子、2) IL-10 和 3) 嘌呤能信号传导。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具有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 (Treg) 和促炎性 TH17 T 细胞之间的不平衡有关，以及独特的 CD39+ T 细胞群在此，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 细胞耐受和 AIHA 预防所必需的，并阐明了生物因素（例如性别）如何影响和年龄，影响独特 T 细胞群（即最近的胸腺迁移 Treg）的功能。还将定义免疫系统如何响应红细胞。抗原不仅可以深入了解红细胞的自身免疫，而且还可能适用于其他疾病自身抗原以高浓度存在（例如血小板自身抗原、dsDNA），从而使其成为一种强大的研究一般对自身抗原的耐受性要求的平台。