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.

摘要：先前的同种免疫使患者面临以下同种抗体形成的风险： 同种异体抗原重新暴露可能导致红细胞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 很大程度上源于根本性的缺乏 了解控制记忆性红细胞同种抗体反应的关键免疫途径 驾驶 DHTR。我们的长期目标是确定并瞄准调节发展的关键途径 记忆同种抗体的形成。我们的中心假设是记忆性红细胞同种抗体的形成 通过独特的 Toll 样受体 (TLR)、桥接通道树突状细胞 (DC) 和滤泡 (FO) B 细胞发生 与原发性红细胞同种免疫有根本不同的依赖性途径。我们的假设已表述 基于我们的发现，与需要边缘区 (MZ) B 细胞的初始红细胞同种免疫不同， MZ B 细胞不是记忆同种抗体形成所必需的，但对于早期启动事件是必需的。 发生在初次接触红细胞同种抗原后。除了 MZ B 细胞要求的差异外，最初 同种抗体的形成不依赖于 CD4 T 细胞 (TI)，在 RBC 重新形成后观察到同种抗体水平增加 暴露完全依赖于 CD4 T 细胞 (TD)。此外，虽然滤泡辅助 T 细胞 (TFH) 和滤泡 (FO) 初始同种抗体形成不需要 B 细胞，初始红细胞输注确实会增加 TFH 和 FO B 细胞数量。再输血还会增加 33D1+ DC 激活和趋化因子受体表达。这些 结果表明，初始红细胞输注通过产生不同的同种异体抗原特异性 TFH 来启动受血者 FO B 细胞群在红细胞同种抗原重新暴露后又可以被 33D1+ DC 激活 独立于 MZ B 细胞。此外，虽然初级同种抗体需要 I 型干扰素 (IFNab) TLR 信号传导对于初始同种抗体的形成是可有可无的，但对于记忆来说是必需的 同种异体抗体的形成。鉴于 MZ B 细胞能够直接激活 CD4 T 细胞并将抗原运输至 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 CD4 T 细胞和 FO B 细胞 通过 IFNab 依赖性过程进行开发。然而，随着记忆同种抗体形成的发生 通过 MZ B 细胞独立途径，DC 还可以将抗原运输到 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同种抗体的形成。测试 根据这一假设，我们将追求以下具体目标： 具体目标 1：定义 MZ B 细胞的作用和 CD4 T 细胞和 FO B 细胞发育中的 IFNab 是后续记忆所需的 同种抗体反应。具体目标 2：定义 TLR 和 DC 在开发 红细胞同种抗原再次暴露后的记忆同种抗体反应。顺利完成这些 目标将确定调节记忆同种抗体反应的关键因素，并在此过程中提供重要的信息 防止导致 DHTR 的同种免疫的框架。