Responsiveness and non-responsiveness to transfused RBCs in mice and humans.

小鼠和人类对输注红细胞的反应性和无反应性。

基本信息

批准号：
9918440
负责人：
PATRICK G GALLAGHER
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918440
关键词：
Adjuvant Adoptive Transfer Alloimmunization Animals Antibodies Antibody Formation Antigen-Presenting Cells Antigens Bioinformatics Biological Blood Group Antigens Blood donor CD4 Positive T Lymphocytes Caring Cells Collaborations Consumption Dangerousness Development Environmental Risk Factor Erythrocyte Transfusion Erythrocytes Evaluation Event Exposure to Fetal Erythroblastosis GYPA gene Generations Genes Genetic Genomics Glycoproteins Goals Grant Helper-Inducer T-Lymphocyte Human Immunologics Immunologist Inflammation Inflammatory Interferon Receptor Interferons Investigation Isoantibodies Knowledge Laboratories Mediating Minority Modeling Mus Natural Immunity Outcome Pathway interactions Patients Pattern Phenotype Pilot Projects Population Process Production Public Health Publishing Reaction Reporter Risk Role Route Safety Sickle Cell Anemia Signal Pathway Signal Transduction T-Lymphocyte Subsets Testing Therapeutic Intervention Time Transcend Transfusion adaptive immunity cell type clinically significant differential expression hazard immune activation improved in vivo insight mouse model novel prevent receptor responders and non-responders response screening transcriptome transcriptome sequencing

项目摘要

Background: It remains unclear why certain transfusion recipients make clinically significant RBC alloantibody after antibody (“responders”), yet others are transfused hundreds of times without generating any detectable alloantibodies (“non-responders”). We have discovered that the recipient inflammatory status at the time of RBC transfusion, in combination with the ability of the recipients to sense type 1 interferons (IFN), are critical in determining responder/non-responder status in our reductionist murine models. Further, recent studies in humans suggest that the inflammation/alloimmunization connection transcends mice, though genetic variables must also be considered. Central Hypothesis: We hypothesize that inflammation (specifically type 1 IFN induction and sensing) and genetic factors together determine which transfusion recipients will form alloantibodies following RBC transfusion, with non-responders possibly being tolerant and not simply ignorant of RBC antigens. The proposed studies utilize reductionist murine models, with blood donors expressing the authentic human blood group antigens glycophorin A (hGPA) or KEL glycoprotein, and with genetically identical recipients generating RBC alloantibodies only when transfusion occurs in the presence of an adjuvant or an ability to sense IFNs. In depth in vivo studies of early immune activation events in responder and non-responder mice, in combination with ex vivo studies of CD4+ T-cell subset phenotype, function, and transcriptome in responder and non- responder humans, seek to increase knowledge of RBC alloimmunization. Specific Aim 1: To investigate which recipient cell population(s) in mice mediate responsiveness to transfused RBCs. Specific Aim 2: To investigate the mechanism(s) through which non-responsiveness in mice occurs following transfusion. Specific Aim 3: To investigate differences in CD4+ T-cells in responder and non-responder humans.

背景：目前尚不清楚某些输血接受者为何使临床意义的RBC同种抗体抗体（“响应者”）之后，其他人则被输掉数百次，而没有产生任何可检测到的同种抗体（“非响应者”）。我们已经发现，接受者炎症状态在 RBC输血与接收者感知1型干扰素（IFN）的能力相结合至关重要在我们的还原主义鼠模型中确定响应者/非反应性状态。此外，最近的研究人类认为注射/同种免疫连接超越了小鼠，尽管遗传变量还必须考虑。中央假设：我们假设注射（特别是1型IFN诱导和灵敏度）和遗传因素共同确定哪些输血接受者将在RBC之后形成同种抗体输血，无反应者可能是耐受性的，而不仅仅是对RBC抗原的一无所知。这拟议的研究利用还原主义的鼠模型，献血者表达了正宗的人类血液组抗原糖蛋白A（HGPA）或KEL糖蛋白，并与遗传相同的受体产生 RBC只有在进行调整或感知IFN的能力的情况下输血才会出现同抗体。响应者和非反应器小鼠的早期免疫激活事件的体内研究深度研究通过对CD4+ T细胞子集的表型，功能和转录组的体内研究，响应者和非 - 响应者人类，试图增加对RBC同种免疫的知识。特定目的1：调查小鼠媒体对哪些受体细胞人群对输血的RBC。特定目的2：研究小鼠无响应性的机制输血后。特定目的3：研究响应者和非反应者人类中CD4+ T细胞的差异。