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: 10035713
• 负责人: Connie M Arthur
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10035713
• 关键词: Adoptive Transfer; Alloantigen; Alloimmunization; Antibody Formation; Antigen Targeting; Antigens; 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; Receptors, Antigen, B-Cell; 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）同种异体免疫可能使得未来兼容的RBC很难 输血，可以直接增加依赖输血依赖的个体的发病率和死亡率。尽管 针对不同同种抗原的多种同种抗体产生多种同种抗体的患者特别具有挑战性 初始同种免疫期间的免疫事件可能会增加产生其他的可能性 随后输血后的同种抗体仍然未知。我们的长期目标是确定免疫力 增强以前同种免疫的个体中随后的同种免疫事件的因素 防止在输血依赖的个体中积累多种同种抗体。我们的中心假设 是，初始同种免疫事件直接通过诱导CD4 T来直接增强随后的RBC同赋 具有直接激活B细胞针对完全无关的RBC同构成的细胞 随后的输血。我们的假设是根据我们最近发现的特定于B细胞的基础提出的 对于一种抗原（HOD（HEL，OVA和DUFFY）抗原），不仅在RBC互动后内化HOD， 但是同样，删除并内化了其他RBC组件，表明B细胞可能具有该能力 靶抗原参与后去除多种抗原。与此相一致的收养转移 在Poly I：C存在下，由KEL RBC输血引发的CD4 T细胞的CD4 T细胞，诱导病毒样炎症， 直接增强同种抗体形成，随后对完全不同的HOD抗原 RBC表达HOD和KEL的输血。边缘区（MZ）B细胞的耗竭，一个独特的B细胞 以前证明的人口对同种抗体的启动至关重要，抑制KEL RBC启动和 HOD RBC在HOD X KEL RBC输血后提升，表明MZ B细胞与 先前识别的桥接通道33d1+树突状细胞（33d1+ dcs）在初始 HOD RBC输血后CD4 T细胞的激活。相反，而KEL RBC诱导的同种免疫 需要I型干扰素（IFNAB）和HOD RBC诱导的同种免疫，需要类似收费的受体（TLR） 信号传导，在PIC存在下KEL诱导的同应释放需要IFNAB和TLR，这表明 尽管KEL和HOD RBC诱导的同种免疫可能会有所不同，但PIC允许KEL 加拿大皇家银行（RBC）参与TLR，并将随后的HOD提升。我们将使用一系列临床前模型来定义 通过测试以下特定目的：AIM 1：定义角色 Mz B细胞，33d1+ DC，IFNAB和TLR中的PIC/KEL RBC诱导的启动。目标2：定义MZ B的作用 随后KEL介导的HOD RBC增强中的细胞，33d1+ DC和TLR。我们认为成功完成 这些目的将定义关键的免疫启动和促进事件，以促进同种免疫和 因此，将提供一个重要的框架来开发理性方法以防止RBC的发展 在长期输血的个体中针对多种同种抗原的同种抗体。