Examination of Initiating Factors that Regulate Red Blood Cell Alloimmunization

调节红细胞同种免疫的起始因素的检查

• 批准号: 10218737
• 负责人: Sean R Stowell
• 金额: $ 12.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218737
• 关键词: Examination; Initiating; Factors; Regulate; Red

Project Summary Although Landsteiner's discovery of ABO(H) blood group antigens over a century ago allowed predictions of red blood cell (RBC) compatibility prior to transfusion, in the 1930s several studies demonstrated that RBC transfusion itself can also induce additional RBC alloantibodies capable of causing incompatible transfusion reactions. RBC-induced alloantibodies against a variety of distinct RBC alloantigens can become particularly problematic in individuals who require repeat transfusions, often making it difficult, if not impossible, to find compatible RBCs. As a result, RBC alloantibody formation can significantly increase the mortality and morbidity of patients who require chronic transfusions. However, no current strategies exist to actively inhibit RBC-induced alloantibody formation following RBC transfusion therapy. This in part reflects a lack of understanding regarding key initiating factors that regulate RBC-induced alloantibody formation. In order to develop strategies with the potential to inhibit RBC-induced alloantibody formation, we used recently developed mouse models of RBC alloimmunization to define key initiating events required for the production of RBC alloantibodies following exposure to two disparate RBC alloantigens. Our preliminary results demonstrate that removal of marginal zone (MZ) B cells or macrophages within the MZ prevents alloantibody formation following exposure to two distinct RBC alloantigens. However, these unique RBC alloantigens appear to differentially induce MZ constituents to engage type 1 interferon (INFαβ) or toll-like receptor pathways. Furthermore, our preliminary data demonstrate that RBC alloantigens also possess the capacity to induce CD4+ T cell-independent or CD4+ T cell-dependent antibody formation following RBC transfusion. As previous studies suggest that marginal zone macrophages (MZM) and MZ B cells can work in a coordinated fashion to induce CD4+ T cell-independent or CD4+ T cell-dependent immune responses, these results suggest a critical link between MZM and MZ B cells in the generation of anti-RBC alloantibodies through both CD4+ T cell-independent and CD4+ T cell-dependent processes, depending on the type of RBC alloantigen presented. As a result, we hypothesize that MZ constituents play a central role in the initiation and orchestration of immune responses induced by RBC transfusion. To test this hypothesis, we propose the following specific aims: 1) Define the role of MZ B cells and MZM in IFNαβ-induced T cell-independent RBC alloantibody formation. 2) Define the role of MZM and MZ B cells in CD4+ T cell-dependent RBC alloantibody formation. We believe each of these aims provides a unique opportunity to identify common initiating factors key to the immune response to distinct RBC alloantigens. In doing so, these studies will provide valuable insight into potential targets for therapeutic mitigation of alloimmune responses to multiple RBC antigens in patients who require chronic transfusion therapy.

项目摘要 尽管Landsteiner在世纪前发现了ABO（H）血型抗原， 红细胞（RBC）的相容性，在20世纪30年代的几项研究表明，RBC 输血本身也可以诱导额外的红细胞同种抗体，能够引起不相容的输血 反应. RBC诱导的针对多种不同RBC同种抗原的同种抗体可以变得特别 在需要重复输血的个体中存在问题，通常很难（如果不是不可能的话）找到 相容的红细胞因此，RBC同种抗体的形成可显著增加死亡率， 需要长期输血的患者的发病率。然而，目前还没有积极抑制 RBC输注治疗后RBC诱导的同种抗体形成。这在一定程度上反映了缺乏 了解调节RBC诱导的同种抗体形成的关键起始因子。为了 开发具有抑制RBC诱导的同种抗体形成潜力的策略，我们最近使用 开发了RBC同种免疫小鼠模型，以确定产生 暴露于两种不同的RBC同种抗原后的RBC同种抗体。我们的初步结果 证明去除边缘区（MZ）内的B细胞或巨噬细胞可防止同种抗体 在暴露于两种不同的RBC同种异体抗原后形成。然而，这些独特的红细胞同种异体抗原 似乎差异诱导MZ成分参与1型干扰素（INFαβ）或Toll样受体 途径。此外，我们的初步数据表明，红细胞同种异体抗原也具有能力， 在RBC输注后诱导CD4+ T细胞非依赖性或CD4+ T细胞依赖性抗体形成。作为 以前的研究表明，边缘区巨噬细胞（MZM）和MZ B细胞可以协同工作， 以诱导CD4+ T细胞非依赖性或CD4+ T细胞依赖性免疫应答，这些结果表明 MZM和MZ B细胞之间通过CD4+ T细胞和CD4+ T细胞产生抗RBC同种异体抗体的关键联系。 细胞非依赖性和CD4+ T细胞依赖性过程，取决于所呈递的RBC同种异体抗原的类型。 因此，我们假设MZ成分在启动和协调 红细胞输注诱导的免疫应答。为了验证这一假设，我们提出了以下具体的 目的：1）明确MZ B细胞和MZM在IFNαβ诱导的T细胞非依赖性红细胞同种抗体中的作用 阵2)确定MZM和MZ B细胞在CD4+ T细胞依赖性RBC同种抗体中的作用 阵我们认为，这些目标中的每一个都为确定共同的启动因素提供了独特的机会 对不同RBC同种异体抗原的免疫应答的关键。在这样做的过程中，这些研究将提供有价值的 深入了解治疗性缓解对多种RBC抗原的同种免疫应答的潜在靶点， 需要长期输血治疗的患者。

项目成果

Factor H autoantibodies contribute to complement dysregulation in multisystem inflammatory syndrome in children (MIS-C).

H 因子自身抗体会导致儿童多系统炎症综合征 (MIS-C) 中的补体失调。

• DOI: 10.1002/ajh.26868
• 发表时间: 2023
• 期刊: American journal of hematology
• 影响因子: 12.8
• 作者: Zerra,PatriciaE;Stowell,Jennifer;Verkerke,Hans;McCoy,James;Jones,Jayre;Graciaa,Sara;Lu,Austin;Hussaini,Laila;Anderson,EvanJ;Rostad,ChristinaA;Stowell,SeanR;Chonat,Satheesh
• 通讯作者: Chonat,Satheesh

Enhanced IgG immune response to COVID-19 vaccination in patients with sickle cell disease.

镰状细胞病患者对 COVID-19 疫苗接种的 IgG 免疫反应增强。

• DOI: 10.1111/bjh.18899
• 发表时间: 2023
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Nakahara,Hirotomo;Cheedarla,Narayanaiah;Verkerke,HansP;Cheedarla,Suneethamma;Wu,Shang-Chuen;Hendrickson,JeanneE;Chang,Andres;McLemore,MorganL;ElRassi,Fuad;Roback,JohnD;Neish,AndrewS;Fasano,RossM;Stowell,SeanR
• 通讯作者: Stowell,SeanR