Mechanisms underlying inflammation-induced alloimmunization to RBC antigens in lupus

狼疮中炎症诱导的红细胞抗原同种免疫的机制

• 批准号: 10281785
• 负责人: David R Gibb
• 金额: $ 8.35万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10281785
• 关键词: Acute; Adult; Allogenic; Alloimmunization; Anemia; Animals; Antibody Formation; Antigens; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Blood Transfusion; Cells; Child; Chronic; Chronic Disease; Clinical Research; Communities; Data; Dependence; Development; Disease; Erythrocyte Transfusion; Erythrocytes; Event; Future; Genes; Goals; Graft Rejection; High Prevalence; Human; IFNAR1 gene; Immune; Immune response; Immune signaling; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injections; Innate Immune Response; Interferon-alpha; Interferons; Investigation; Isoantibodies; Kidney Transplantation; Lead; Life; Lupus; Mediating; Mentorship; Modeling; Mus; Pathology; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Phenotype; Population; Pregnancy; Pristane; Production; Protocols documentation; Reporting; Risk; Role; Safety; Savings; Severity of illness; Signal Pathway; Signal Transduction; Stimulus; Stratification; Systemic Lupus Erythematosus; TLR7 gene; Testing; Toll-like receptors; Transfusion; United States; Viral; Virus Diseases; clinically significant; cytokine; genetic signature; improved; influenza infection; lupus-like; mimetics; molecular recognition; mouse model; novel; pre-clinical; receptor; response; transfusion medicine

Abstract Approximately 50% of patients with systemic lupus erythematosus (SLE) suffer from anemia, for which red blood cell (RBC) transfusion is a common therapy. While RBC transfusion can be life-saving, production of alloantibodies against non-self RBC antigens causes clinically significant hemolytic events during RBC transfusion, pregnancy, and renal transplant. Prior human and animal studies have demonstrated that inflammation in a transfusion recipient, including autoimmune-associated inflammation, can induce or enhance RBC alloantibody responses. For example, while 3-5% of hospitalized patients in the United States produce RBC alloantibodies, more than 20% of patients with SLE produce RBC alloantibodies, representing the second highest prevalence compared to all other studied disease populations. However, mechanisms underlying autoimmune- induced RBC alloimmunization are poorly understood. Using murine transfusion models, we previously reported that acute viral-like stimuli and influenza infection induce pro-inflammatory type 1 interferons (IFNα/β), which critically regulate alloimmunization to human RBC antigens expressed on mouse RBCs. Approximately two- thirds of adults and nearly all children with SLE express an IFNα/β gene signature, defined as the production of numerous interferon stimulated genes by innate immune cells. Thus, we hypothesized and recently reported that IFNα/β also promotes RBC alloimmunization during acute inflammation in a lupus mouse model, prior to development of autoimmunity. It is unclear, however, whether chronic inflammation, in the presence of autoantibodies and lupus-like pathology, promotes RBC alloimmunization. In addition, it is unclear whether the lupus phenotype or IFNα/β directly promotes alloimmunization in the chronic setting. In this application, we propose to utilize lupus models with chronic inflammation to generate preliminary data for a future R01. We will test the hypothesis that chronic inflammation in lupus promotes RBC alloantibody production by an IFNα/β-dependent mechanism by determining the role of the lupus phenotype and IFNα/β in regulating RBC alloantibody production (Aim1) and identifying innate immune signaling pathways that promote inflammation- induced alloimmunization in models of chronic lupus (Aim 2). While the K08 focused on basic mechanisms of IFNα/β production and IFNα/β-mediated alloimmunization in the absence of inflammation or disease, this application diverges by examining mechanisms of chronic inflammation-induced alloimmunization in lupus models. Findings will provide a potential mechanistic basis for past observations of autoimmunity-associated alloimmunization. In addition, results may uncover novel pathways underlying inflammation-induced alloimmunization and provide preclinical data to strengthen an R01 proposal that will include investigation of mechanisms underlying RBC alloimmunization in patients with SLE. With mentorship from experts in RBC alloimmunization, lupus, IFNα/β, and other innate immune responses, we are well-equipped to complete the proposed aims.

摘要 大约50%的系统性红斑狼疮（SLE）患者患有贫血，红细胞减少。 红细胞（RBC）输注是一种常见的治疗方法。虽然红细胞输注可以挽救生命， 针对非自身RBC抗原的同种抗体在RBC移植期间引起临床上显著的溶血事件。 输血怀孕和肾移植先前的人类和动物研究已经证明， 输血接受者中的炎症，包括自身免疫相关的炎症，可以诱导或增强 RBC同种抗体反应。例如，虽然美国3-5%的住院患者产生红细胞， 同种抗体，超过20%的SLE患者产生RBC同种抗体，占第二高 与所有其他研究的疾病人群相比。然而，自身免疫的潜在机制- 诱导的RBC同种异体免疫知之甚少。使用小鼠输血模型，我们先前报道 急性病毒样刺激和流感感染诱导促炎1型干扰素（IFNα/β）， 严格调节对小鼠RBC上表达的人RBC抗原的同种异体免疫。大约两个- 三分之一的成人和几乎所有的SLE儿童表达IFNα/β基因标签，定义为产生IFN α/β。 许多干扰素刺激基因的先天免疫细胞。因此，我们假设并在最近报告， IFNα/β还促进狼疮小鼠模型急性炎症期间的RBC同种异体免疫， 自身免疫的发展。然而，目前尚不清楚慢性炎症，在存在 自身抗体和狼疮样病理，促进RBC同种免疫。此外，目前还不清楚， 狼疮表型或IFNα/β直接促进慢性环境中的同种免疫。在本申请中，我们 建议利用慢性炎症狼疮模型为未来的R 01生成初步数据。我们将 测试狼疮的慢性炎症促进红细胞同种抗体产生的假设， 通过确定狼疮表型和IFNα/β在调节红细胞中的作用来确定IFNα/β依赖性机制 同种抗体产生（Aim 1）和识别促进炎症的先天免疫信号通路- 在慢性狼疮模型中诱导同种异体免疫（Aim 2）。虽然K 08侧重于基本机制， 在没有炎症或疾病的情况下，IFNα/β的产生和IFNα/β介导的同种异体免疫， 通过检查慢性炎症诱导的狼疮同种异体免疫的机制， 模型研究结果将为过去观察到的自身免疫相关性免疫缺陷提供潜在的机制基础。 同种免疫此外，研究结果可能揭示炎症诱导的新途径。 同种异体免疫，并提供临床前数据，以加强R 01提案，其中包括研究 SLE患者红细胞同种异体免疫的机制RBC专家的指导 同种异体免疫，狼疮，IFNα/β和其他先天免疫反应，我们有充分的准备来完成 提出的目标。