Alloimmunization and Humoral Response to Hemolysis

同种免疫和溶血的体液反应

基本信息

批准号：
10220127
负责人：
Karina Yazdanbakhsh
金额：
$ 64.78万
依托单位：
NEW YORK BLOOD CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10220127
关键词：
Affect Alloimmunization Antioxidants B Cell Proliferation B cell differentiation B-Cell Activation B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Biliverdine Binding Blood Transfusion Cell Differentiation process Cell physiology Cells Chemicals Coculture Techniques Data Disease Drug Targeting Environment Equilibrium Event Frequencies Functional disorder Genetic Helper-Inducer T-Lymphocyte Heme Hemoglobin Hemoglobinopathies Hemolysis Hemolytic Anemia Humoral Immunities Immune Immune response In Vitro Inflammatory Innate Immune Response Isoantibodies Lead Life Mediating Modality Molecular Monitor Oxidants Oxidation-Reduction Pathway interactions Patients Peripheral Pharmaceutical Preparations Plasma Plasma Cells Play Prevention strategy Process Protocols documentation Quinine Reaction Regulation Reporting Risk Risk Factors Role Sickle Cell Anemia Signal Pathway Signal Transduction Small Interfering RNA T cell response Testing Thalassemia Transfusion Up-Regulation differential expression effectiveness testing efficacy testing heme a immunoregulation in vivo Model inhibitor/antagonist insight mouse model new therapeutic target novel peripheral tolerance plasma cell differentiation potential biomarker prevent response

项目摘要

Abstract Blood transfusions remain an important treatment modality for patients with sickle cell disease (SCD) and thalassemia (Thal). However, 15-50% of these patients develop alloantibodies causing complications ranging from difficulty in finding matched units to potentially life-threatening delayed hemolytic transfusion reactions (DHTR). Increasing evidence suggest that free hemoglobin (Hb) and heme play central roles in many aspects of the pathophysiology of hemolytic anemias, especially in SCD. With regards to alloimmunization, we have previously identified weakened innate immunoregulatory function in response to free heme in alloimmunized SCD patients with the implication that hemolysis is a potential alloimmunization risk factor. Our preliminary data indicate that free heme can directly inhibit B plasma B cell differentiation in healthy donors and non- alloimmunized but not alloimmunized SCD patients. Heme/hemolysis resulted in enhancement of T follicular regulatory cell (TFR) suppressive activity, key in inhibiting B cell responses, in non-alloimmunized but not alloimmunized SCD patients. We therefore posit that defective response to heme/hemolysis in B cells and TFR cell increases their risk of alloimmunization. We hypothesize that heme-sensing pathways in key humoral immune cells are critical in the regulation of SCD RBC alloimmunization. We will test our hypothesis by examining key DOCK8/HO-1/ROS heme molecular pathways at basal level and during RBC transfusion in B cells (Aim1) and TFR cells (Aim2) in patients with SCD. Using both in vitro and in vivo models, we will also test the efficacy of drugs that target these pathways to switch off humoral immune response against transfused RBCs under hemolytic conditions. We believe that elucidation of molecular pathways associated with the defective heme response in humoral immune cells in alloimmunized patients is likely to lead to identification of potential biomarkers of alloimmunization and DHTR in hemolytic disorders and novel therapeutic targets that can prevent or even inhibit alloimmunization/DHTR.

抽象的输血仍然是镰状细胞病（SCD）患者的重要治疗方式地中海贫血（Thal）。然而，这些患者中的 15-50% 会产生同种抗体，导致一系列并发症从难以找到匹配的单位到可能危及生命的迟发性溶血性输血反应（DHTR）。越来越多的证据表明游离血红蛋白 (Hb) 和血红素在许多方面发挥着核心作用溶血性贫血的病理生理学，特别是 SCD。关于同种免疫，我们有先前发现同种免疫中游离血红素的先天免疫调节功能减弱 SCD 患者暗示溶血是潜在的同种免疫危险因素。我们的初步数据表明游离血红素可以直接抑制健康供体和非正常供体的 B 浆 B 细胞分化。同种免疫但未同种免疫的 SCD 患者。血红素/溶血导致滤泡 T 增强调节细胞 (TFR) 抑制活性，在非同种免疫中抑制 B 细胞反应的关键，但在非同种免疫中则不然同种免疫的 SCD 患者。因此，我们假设 B 细胞和 TFR 对血红素/溶血反应有缺陷细胞增加了同种免疫的风险。我们假设关键体液中的血红素传感途径免疫细胞在 SCD RBC 同种免疫的调节中至关重要。我们将通过检查来检验我们的假设 B 细胞中基础水平和红细胞输注过程中的关键 DOCK8/HO-1/ROS 血红素分子通路 (Aim1) 和 SCD 患者的 TFR 细胞 (Aim2)。我们还将使用体外和体内模型来测试其功效针对这些途径的药物可以关闭针对输注红细胞的体液免疫反应溶血情况。我们相信，阐明与缺陷血红素相关的分子途径同种免疫患者体液免疫细胞的反应可能导致识别潜在的溶血性疾病中同种免疫和 DHTR 的生物标志物以及可以预防的新治疗靶点甚至抑制同种免疫/DHTR。