Examining Immune Circuits Responsible for Anamnestic RBC Alloimmunization

检查负责记忆性红细胞同种免疫的免疫回路

• 批准号: 10641025
• 负责人: Sean R Stowell
• 金额: $ 61.62万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641025
• 关键词: Acceleration; Alloantigen; Alloimmunization; Antibodies; Antibody Formation; Antibody Response; Antigens; Automobile Driving; B-Cell Development; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell Count; Clinical; Clinical Research; Critical Pathways; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Enrollment; Erythrocyte Transfusion; Erythrocytes; Event; Excision; Fetus; Goals; Helper-Inducer T-Lymphocyte; Immune; Immunologic Factors; Interferon Type I; Isoantibodies; Mediating; Mus; Newborn Infant; Pathway interactions; Patients; Population; Pre-Clinical Model; Prevention; Process; Reaction; Receptor Cell; Receptor Signaling; Risk; Role; Severities; Sickle Cell Anemia; Testing; Toll-like receptors; Transfusion; chemokine receptor; human subject; insight; interferon-alpha B; mortality; pre-clinical; preclinical study; prevent; receptor expression; response; stem

Summary: Prior alloimmunization places patients at risk for anamnestic alloantibody formation following alloantigen re-exposure that can result in accelerated RBC clearance and lead to a potentially fatal delayed hemolytic transfusion reaction (DHTR). The inability to prevent DHTRs largely stems from a fundamental lack of understanding regarding key immune pathways that govern anamnestic RBC alloantibody responses capable of driving DHTRs. Our long-term goal is to identify and then target critical pathways that regulate the development of anamnestic alloantibody formation. Our central hypothesis is that anamnestic RBC alloantibody formation occurs through a distinct toll-like receptor (TLR), bridging channel dendritic cell (DC) and follicular (FO) B cell- dependent pathway that fundamentally differs from primary RBC alloimmunization. Our hypothesis is formulated on the basis of our discovery that unlike initial RBC alloimmunization, which requires marginal zone (MZ) B cells, MZ B cells are not required for anamnestic alloantibody formation, but are required for early priming events that occur following initial RBC alloantigen exposure. In addition to differences in MZ B cell requirements, while initial alloantibody formation is CD4 T cell independent (TI), increased alloantibody levels observed following RBC re- exposure is entirely CD4 T cell dependent (TD). Furthermore, while T follicular helper cell (TFH) and follicular (FO) B cells are not required for initial alloantibody formation, initial RBC transfusion does increase TFH and FO B cell numbers. Re-transfusion also increases 33D1+ DC activation and chemokine receptor expression. These results suggest that initial RBC transfusion primes recipients by generating distinct alloantigen-specific TFH and FO B cell populations that can, in turn, be activated by 33D1+ DCs following RBC alloantigen re-exposure independent of MZ B cells. In addition, while type I interferons (IFNab) are required for primary alloantibody formation, TLR signaling is dispensable for initial alloantibody development, yet is required for anamnestic alloantibody formation. Given the ability of MZ B cells to directly activate CD4 T cells and traffic antigen to the B cell follicle, our data suggest that initial priming events require MZ B cell-mediated CD4 T cell and FO B cell development through an IFNab-dependent process. However, as anamnestic alloantibody formation occurs through a MZ B cell-independent pathway and DCs can also traffic antigen to B cells and directly activate CD4 T cells, DCs likely orchestrate anamnestic alloantibody formation through a TLR-dependent pathway. To test this hypothesis, we will pursue the following specific aims: Specific Aim 1: Define the role of MZ B cells and IFNab in the development of CD4 T cells and FO B cells required for a subsequent anamnestic alloantibody response. Specific Aim 2: Define the role of TLRs and DCs in the development of an anamnestic alloantibody response following RBC alloantigen re-exposure. Successful completion of these aims will define key factors that regulate anamnestic alloantibody responses and in so doing provide an important framework to prevent alloimmunization that leads to DHTRs.

总结：既往同种免疫接种使患者处于既往同种抗体形成的风险中， 同种异体抗原再暴露，可导致RBC清除加速，并导致潜在致命的延迟 溶血性输血反应（DHTR）。无法预防DHTR很大程度上源于缺乏一个基本的 了解关于关键免疫途径，管理记忆红细胞同种抗体反应， 驾驶DHTR。我们的长期目标是确定并瞄准调控发展的关键途径， 记忆性同种抗体的形成。我们的中心假设是记忆性红细胞同种抗体的形成 通过不同的toll样受体（TLR）、桥接通道树突细胞（DC）和滤泡（FO）B细胞发生。 依赖途径，从根本上不同于主要的红细胞同种异体免疫。我们的假设是 基于我们的发现，与需要边缘区（MZ）B细胞的初始RBC同种异体免疫不同， MZ B细胞不是记忆性同种抗体形成所必需的，但却是早期引发事件所必需的， 发生在最初的RBC同种异体抗原暴露后。除了MZ B细胞要求的差异外， 同种抗体的形成是CD4 T细胞非依赖性的（TI），在RBC再灌注后观察到同种抗体水平增加， 暴露完全是CD4 T细胞依赖性的（TD）。此外，虽然T滤泡辅助细胞（TFH）和滤泡 (FO)初始同种抗体形成不需要B细胞，初始RBC输注确实增加TFH和FO B细胞数量。回输还增加33D1+ DC活化和趋化因子受体表达。这些 结果表明，最初的红细胞输注通过产生不同的同种异体抗原特异性TFH来启动受体， FO B细胞群在RBC同种异体抗原再暴露后可被33 D1 + DC激活 不依赖于MZ B细胞。此外，虽然I型干扰素（IFNab）是一级同种抗体所必需的， 虽然TLR信号传导对于最初的同种抗体形成是必需的，但对于记忆性抗体形成是必需的。 同种抗体形成。考虑到MZ B细胞直接激活CD4 T细胞并将抗原运输至T细胞的能力， B细胞滤泡，我们的数据表明，初始启动事件需要MZ B细胞介导的CD 4 T细胞和FO B细胞 通过IFNab依赖的过程发展。然而，随着记忆性同种抗体的形成， DCs通过MZ B细胞非依赖性途径运输抗原至B细胞并直接激活CD4 T细胞、DC可能通过TLR依赖性途径协调记忆性同种抗体形成。测试 在这个假设中，我们将追求以下具体目标：具体目标1：定义MZ B细胞的作用， IFN α B在CD4 T细胞和FO B细胞的发育中为随后的回忆所需 同种抗体反应具体目标2：明确TLR和DC在肿瘤发生发展中的作用。 RBC同种异体抗原再暴露后的记忆性同种异体抗体应答。成功完成这些 aims将定义调节记忆性同种抗体应答的关键因素，并在此过程中提供重要的 框架，以防止同种异体免疫，导致DHTR。