Alloimmunization and Humoral Response to Hemolysis

摘要 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(地中海贫血)。然而，这些患者中有15%-50%会产生同种异体抗体，导致各种并发症。 从难以找到匹配单位到潜在威胁生命的延迟溶血性输血反应 (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起着核心作用 溶血性贫血的病理生理学，特别是在SCD。关于同种免疫，我们有 先前发现同种异体免疫中游离血红素的先天免疫调节功能减弱 提示溶血是潜在的同种异体免疫危险因素。我们的初步数据 提示游离血红素可直接抑制健康献血员和非献血员血浆B细胞分化。 同种免疫的SCD患者，但不是同种免疫的SCD患者。血红素/溶血导致T滤泡增强 非同种异体免疫的调节细胞(TFR)抑制活性，抑制B细胞反应的关键 对SCD患者进行同种免疫。因此，我们假设B细胞和TFR对血红素/溶血的缺陷反应 细胞增加了异体免疫的风险。我们假设关键体液中的血红素感知通路 免疫细胞在SCD红细胞同种异体免疫的调节中起着关键作用。我们将通过检验我们的假设 DOCK8/HO-1/ROS血红素基础水平和B细胞输注过程中的关键分子通路(Aim1) 和TFR细胞(AIM2)。使用体外和体内模型，我们还将测试 针对这些途径的药物，以关闭针对输血红细胞的体液免疫反应 溶血条件。我们认为，阐明与缺陷的血红素相关的分子途径 同种异体免疫患者体液免疫细胞的反应可能导致识别潜在的 溶血性疾病中同种异体免疫和DHTR的生物标志物和可预防的新治疗靶点 甚至抑制同种异体免疫/DHTR。

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.