Autoantibody-induced type 1 interferons and RBC alloimmunization in sickle cell disease

镰状细胞病中自身抗体诱导的 1 型干扰素和红细胞同种免疫

• 批准号: 10504262
• 负责人: David R Gibb
• 金额: $ 41.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504262
• 关键词: Address; Allogenic; Alloimmunization; Antibodies; Antigens; Autoantibodies; Autoimmunity; Blocking Antibodies; Blood; Blood Transfusion; Cell Culture Techniques; Cells; Coculture Techniques; Cytokine Activation; Data; Disease; Erythrocyte Transfusion; Erythrocytes; Erythrophagocytosis; Evaluation; Event; Exposure to; Flow Cytometry; Frequencies; Genes; Goals; Human; Immune response; Incidence; Inflammation; Inflammatory; Interferon-alpha; Interferons; Intervention; Investigation; Isoantibodies; Kinetics; Lead; Leukocytes; Life; Ligands; Liver; Measures; Mediating; Mediator of activation protein; Modeling; Mus; Nucleic Acid Binding; Nucleic Acids; Pathway interactions; Patients; Phagocytosis; Play; Population; Pre-Clinical Model; Process; Production; Protocols documentation; Reporter; Reporting; Reticulocyte count; Reticulocytes; Reticulocytosis; Risk; Role; Safety; Savings; Serum; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Spleen; Testing; Transfusion; Virus Diseases; antiviral immunity; cytokine; disorder control; genetic signature; improved; insight; macrophage; mouse model; pre-clinical; receptor; receptor binding; response; risk stratification

Project Summary RBC alloimmunization in patients with sickle cell disease (SCD) can lead to potentially fatal hemolytic events. Patients with SCD have the highest incidence of RBC alloimmunization, compared to all other disease populations including those with similar transfusion burdens. Factors explaining this high incidence are poorly understood. Identifying such factors would allow for identification of patients with SCD who may benefit from personalized transfusion protocols and rare antigen-matched units. Inflammation in the transfusion recipient has been shown to promote RBC alloantibody responses. We previously reported that proinflammatory type 1 interferons (IFNα/β) induced by viral infection or autoimmunity promote RBC alloimmunization in pre-clinical transfusion models. Recent studies, including preliminary data included in this application, have revealed that many patients with SCD have an IFNα/β gene signature, defined by leukocyte expression of IFNα/β stimulated genes. However, mechanisms leading to IFNα/β activation, including signaling pathways, receptors, and ligands, are poorly understood. Nearly all IFNα/β-inducing receptors are intracellular receptors for nucleic acids. Thus, phagocytosis of nucleic acid containing cells, including reticulocytes which are elevated in SCD, has the potential to activate IFNα/β pathways. Anti-RBC autoantibodies facilitate erythrophagocytosis, with alloimmunized patients with SCD having an increased incidence of such autoantibodies. While the RBC alloantibody/RBC autoantibody association is poorly understood, our preliminary data indicate that reticulocyte counts correlate with IFNα/β gene scores and erythrophagocytosis of autoantibody-opsonized reticulocytes from patients with SCD induces IFNα/β activation in human macrophages. Preliminary data also show that anti-RBC autoantibodies induce IFNα/β activation and RBC alloimmunization in a pre-clinical transfusion model. In this proposal, we aim to test the hypothesis that RBC autoantibodies promote IFNα/β-mediated RBC alloimmunization in SCD by identifying inflammatory pathways that induce IFNα/β (Aim 1) and determining the effects of autoantibody-induced IFNα/β inflammation on RBC alloimmunization in SCD mice (Aim 2). In Aim 1, IFNα/β pathways induced by autoantibodies will be identified in co-cultures of human macrophages and reticulocytes from patients with and without SCD, and the extension of findings will be tested in pre-clinical murine models. Identified pathways and receptors will inform ligands that induce IFNα/β in SCD. Aim 2 represents the first investigation of IFNα/β-regulated RBC alloimmunization in pre-clinical models of SCD and has the potential to reveal a mechanism that may contribute to the elevated incidence of RBC alloimmunization. Long term goals of this project include improved understanding of proinflammatory interferons in SCD, with the possibility that targeted IFNα/β-modulated therapy may be beneficial. Findings may also have applicability beyond SCD, with inflammatory interferons playing a critical role in autoimmunity and other disease processes.

项目摘要 镰状细胞疾病（SCD）患者的RBC同种免疫可导致潜在的致命溶血事件。 与所有其他疾病相比 种群包括那些输血相似的人群。解释这一高事件的因素很差 理解。确定此类因素将允许识别可能从中受益的SCD患者 个性化的输血方案和罕见的抗原匹配单元。输血接受者的炎症具有 我们先前报道了促炎1类 因病毒感染或自身免疫性诱导的干扰素（IFNα/β）促进临床前的RBC同种免疫 输血模型。最近的研究，包括本应用程序中包含的初步数据，表明 许多SCD患者具有IFNα/β基因特征，由IFNα/β刺激的白细胞表达定义 基因。但是，导致IFNα/β激活的机制，包括信号通路，受体和配体， 知之甚少。几乎所有IFNα/β诱导的受体都是核酸的细胞内受体。那， 含核酸的细胞的吞噬作用，包括升高SCD中的网状细胞具有潜力 激活IFNα/β途径。抗RBC自身抗体促进红细胞增多，并具有同种异体抗体。 SCD患者患有这种自身抗体的事件增加。而RBC同种抗体/RBC 自身抗体关联知之甚少，我们的初步数据表明网状细胞计数相关 来自IFNα/β基因评分和自身抗体的红细胞的红细胞增多，来自患者 SCD诱导人类巨噬细胞中的IFNα/β激活。初步数据还表明抗RBC自身抗体 在临床前输血模型中诱导IFNα/β激活和RBC同种免疫。 在此提案中，我们旨在检验RBC自身抗体促进IFNα/β介导的RBC的假设 通过鉴定影响IFNα/β的炎症途径（AIM 1）并确定SCD中的同种异体免疫 自身抗体诱导的IFNα/β炎症对SCD小鼠中RBC同种异体免疫化的影响（AIM 2）。在AIM 1中， 由自身抗体诱导的IFNα/β途径将在人类巨噬细胞的共培养中鉴定 来自有或没有SCD的患者的网状细胞以及发现的扩展将在临床前鼠中进行测试 型号。鉴定出的途径和接收器将告知在SCD中影响IFNα/β的配体。目标2代表 首次研究IFNα/β调节的RBC在SCD前临床模型中的AlloMunization，具有潜力 揭示一种可能导致RBC同种异体免疫入口升高的机制。 该项目的长期目标包括对SCD中促炎干扰素的了解，并与 靶向IFNα/β调节治疗的可能性可能是有益的。调查结果也可能具有适用性 除了SCD之外，炎症干扰素在自身免疫和其他疾病过程中起着至关重要的作用。