Examining the Mechanisms of RBC Alloimmunization Hyperresponders

检查红细胞同种免疫高反应者的机制

• 批准号: 10483186
• 负责人: Connie M Arthur
• 金额: $ 43.23万
• 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: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483186
• 关键词: Adoptive Transfer; Alloantigen; Alloimmunization; Antibody Formation; Antigen Targeting; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; CD4 Positive T Lymphocytes; Cellular Structures; Chronic; Clinical; Data; Dendritic Cells; Development; Erythrocyte Transfusion; Erythrocytes; Event; Future; Genetic Polymorphism; Goals; Immune; Immune system; Immunologic Factors; Immunologics; Immunology; Individual; Inflammation; Interferon Type I; Interferons; Isoantibodies; Lead; Mediating; Medicine; Morbidity - disease rate; Pathway interactions; Patients; Poly I-C; Population; Pre-Clinical Model; Process; Reaction; Receptor Signaling; Risk; Role; Series; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Intervention; Toll-like receptors; Transfusion; Viral; Work; enhancing factor; imprint; innate immune pathways; insight; memory CD4 T lymphocyte; mortality; prevent; response; stem; trafficking

Summary: Red blood cell (RBC) alloimmunization can make it difficult to procure compatible RBCs for future transfusion, which can directly increase morbidity and mortality in transfusion-dependent individuals. While patients who develop multiple alloantibodies against distinct alloantigens are particularly challenging to manage, the immune events during initial alloimmunization that may increase the likelihood of generating additional alloantibodies following subsequent transfusion remain unknown. Our long-term goal is to identify immune factors that enhance subsequent alloimmunization events in previously alloimmunized individuals in order to prevent the accumulation of multiple alloantibodies in transfusion dependent individuals. Our central hypothesis is that initial alloimmunization events directly enhance subsequent RBC alloimmunization by inducing CD4 T cells that possess the ability to directly activate B cells against a completely unrelated RBC alloantigen following subsequent transfusion. Our hypothesis is formulated on the basis of our recent discovery that B cells specific for one antigen (the HOD (HEL, OVA and Duffy) antigen) not only internalize HOD following RBC engagement, but likewise remove and internalize additional RBC components, suggesting that B cells may possess the ability to remove multiple antigens following engagement of the target antigen. Consistent with this, adoptive transfer of CD4 T cells primed by KEL RBC transfusion in the presence of poly I:C, which induces viral-like inflammation, directly enhances alloantibody formation against the completely distinct HOD antigen following subsequent transfusion of RBCs expressing HOD and KEL. Depletion of marginal zone (MZ) B cells, a unique B cell population previously shown to be critical in the initiation of alloantibodies, inhibits KEL RBC priming and the HOD RBC boost following HOD x KEL RBC transfusion, suggesting that MZ B cells work in concert with previously recognized bridging channel 33D1+ dendritic cells (33D1+ DCs) shown to be critical in the initial activation of CD4 T cells following HOD RBC transfusion. In contrast, while KEL RBC-induced alloimmunization requires type I interferons (IFNab) and HOD RBC-induced alloimmunization requires toll-like receptor (TLR) signaling, KEL-induced alloimmunization in the presence of PIC requires both IFNab and TLRs, suggesting that while innate immune pathways may differ for KEL and HOD RBC-induced alloimmunization, PIC allows KEL RBCs to engage TLRs and prime a subsequent HOD boost. We will use a series of pre-clinical models to define the key priming and subsequent boosting pathways by testing the following specific aims: Aim 1: Define the role of MZ B cells, 33D1+ DCs, IFNab and TLRs in PIC/KEL RBC-induced priming. Aim 2: Define the role of MZ B cells, 33D1+ DCs, and TLRs in subsequent KEL-mediated HOD RBC boost. We think that successful completion of these aims will define key immunological priming and boosting events that facilitate alloimmunization and therefore will provide an important framework to develop rational approaches to prevent the development of RBC alloantibodies against multiple alloantigens in chronically transfused individuals.

摘要：红细胞（RBC）同种异体免疫可能会使未来难以获得相容的RBC 输血，这可以直接增加输血依赖个体的发病率和死亡率。而 产生针对不同同种异体抗原的多种同种异体抗体的患者的管理特别具有挑战性， 在初始同种异体免疫期间的免疫事件，其可能增加产生额外的免疫应答的可能性。 随后输血后的同种抗体仍然未知。我们的长期目标是识别免疫 增强先前同种免疫个体中随后同种免疫事件的因子， 防止多种同种抗体在输血依赖个体中的积累。我们的核心假设 最初同种异体免疫事件通过诱导CD 4 T直接增强随后的RBC同种异体免疫 具有针对完全无关的RBC同种异体抗原直接激活B细胞的能力的细胞， 随后输血。我们的假设是建立在我们最近发现的基础上的，即B细胞特异性 对于一种抗原（HOD（HEL，OVA和Duffy）抗原），不仅在RBC接合后内化HOD， 但同样地去除并内化额外的RBC成分，这表明B细胞可能具有这种能力， 以在靶抗原接合后去除多种抗原。与此相一致的是， 在多聚I：C存在的情况下，通过KEL RBC输注引发的CD 4 T细胞，其诱导病毒样炎症， 直接增强了针对完全不同的HOD抗原的同种抗体形成， 输注表达HOD和KEL的RBC。边缘区（MZ）B细胞耗竭，一种独特的B细胞 先前显示在同种抗体起始中起关键作用的细胞群抑制KEL RBC引发， HOD x KEL RBC输注后HOD RBC增强，表明MZ B细胞与 先前识别的桥接通道33 D1+树突状细胞（33 D1 + DC）显示在初始的免疫应答中起关键作用。 HOD RBC输注后CD 4 T细胞的活化。相反，KEL RBC诱导的同种免疫 需要I型干扰素（IFNab），HOD RBC诱导的同种异体免疫需要Toll样受体（TLR） 信号传导，在PIC存在下KEL诱导的同种免疫需要IFNab和TLR，这表明 虽然KEL和HOD RBC诱导的同种异体免疫的先天免疫途径可能不同，但PIC允许KEL 红细胞参与TLR并引发随后的HOD加强。我们将使用一系列临床前模型来定义 通过测试以下具体目标来确定关键的启动和随后的加强途径：目标1：定义角色 MZ B细胞、33 D1 + DC、IFN α B和TLR在PIC/KEL RBC诱导的致敏中的表达。目标2：确定MZ B的作用 细胞、33 D1 + DC和TLR在随后的KEL介导的HOD RBC加强中的表达。我们认为成功完成 这些目标将定义促进同种免疫的关键免疫引发和加强事件， 因此，将提供一个重要的框架，以制定合理的方法，以防止红细胞的发展 慢性输血个体中针对多种同种抗原的同种抗体。