Cyokine control of red blood cell alloimmunization
红细胞同种免疫的细胞因子控制
基本信息
- 批准号:9214994
- 负责人:
- 金额:$ 51.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-15 至 2020-11-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAlloantigenAlloimmunizationAnimal ModelAntibodiesAntibody FormationAntibody ResponseAntigensB-LymphocytesBCL6 geneBiochemical GeneticsBiological ModelsBiological Response ModifiersBlocking AntibodiesBone MarrowCell Differentiation processCell SurvivalCellsCessation of lifeChronicClinicalClinical ResearchCytokine SignalingDataDetectionDiagnosticErythrocyte TransfusionErythrocytesExposure toFundingGenerationsGeneticHelper-Inducer T-LymphocyteHematological DiseaseHumanImmuneImmunizationImmunologicsInterleukin-6IsoantibodiesLeadLifeMaintenanceMediatingMedicineMemoryMemory B-LymphocyteMolecularMorbidity - disease rateMusMutant Strains MiceNational Heart, Lung, and Blood InstituteNaturePatientsPlasma CellsPlayPreventionProductionReactionResourcesRiskRoleSTAT3 geneSavingsSeriesSignal PathwaySignal TransductionSignaling MoleculeStimulusStructure of germinal center of lymph nodeSystemT-LymphocyteTestingTherapeuticTherapeutic InterventionTimeTransfusionTreatment EfficacyVaccinationWorkcellular targetingclinical developmentcytokinedifferentiated B cellexperimental studyfallshigh riskinterestmortalitymouse modelpatient populationplasma cell differentiationpre-clinicalpreventresponsevaccination strategy
项目摘要
Summary. Red blood cell (RBC) alloimmunization remains a significant clinical problem in transfusion
medicine, particularly among those patients who require chronic transfusions. For those who are unfortunate
enough to generate multiple alloantibodies, provision of compatible antigen negative RBCs can be both time
and resource intensive. In rare cases, this can result in an inability to locate an otherwise life-saving therapy.
RBC alloantibodies are also responsible for hemolytic transfusion reactions (HTRs), causing substantial
morbidity and occasional mortality. HTRs result from two important immunological phenomena. The first is
the uniquely evanescent nature of RBC antibodies, whose rapid disappearance leads to false negative
screens in alloimmunized patients. The second is the recall antibody response elicited by re-exposure to
antigen via subsequent transfusion, where the rapid and robust increase in circulating antibodies drive HTRs.
Despite the significant clinical consequences of these phenomena, our understanding of the fundamental
molecular and cellular mechanisms regulating anti-RBC antibody generation, maintenance and recall is
remarkably limited. Accordingly, there are no effective therapeutic interventions available to alloimmunized
patients other than antigen avoidance. Our previous work has identified IL-6 as a key cytokine signal that
regulates both the initial alloimmunization response to RBCs as well as early T follicular helper cell (TFH)
differentiation. We are now interested in extending our findings to investigate the role of IL-6 signals in
controlling RBC alloantibody evanescence and recall responses. Given the pleomorphic nature of IL-6
signaling, we are interested in determining both the cellular targets (B vs. T cell), downstream signaling
molecules (STAT3), and cellular consequences (short-lived plasma cell, long-lived plasma cell, memory B cell
and memory TFH cell differentiation) regulated by IL-6 and required for RBC alloimmunization. Accordingly,
we will employ cutting-edge conditional genetic mouse mutants of IL-6R, STAT3, and BCL6 to directly
compare antibody and cellular responses to two different mouse models of RBC alloimmunization as well as
standard vaccination approaches. In so doing, we will better understand how the fundamental cellular and
molecular immune regulators of RBC alloimmunization vary for different RBC antigen systems, and also how
they compare to traditional immune stimulation. Furthermore, we will develop a pre-clinical mouse model
system to determine the therapeutic efficacy of targeting the IL-6/IL-6R signaling pathway for the prevention
and/or treatment of RBC alloimmunization, serving as key data for the subsequent consideration of IL-6R
antibody blocking therapies (such as Tocilizumab) in select, high-risk alloimmunized patients.
总结。红细胞(RBC)同种异体免疫在输血中仍是一个重要的临床问题
药物,特别是那些需要长期输血的患者。对于那些不幸的人
足以产生多种同种异体抗体,可同时提供相容抗原阴性的红细胞
和资源密集型。在极少数情况下,这可能会导致无法找到原本可以挽救生命的疗法。
红细胞同种异体抗体也会引起溶血性输血反应(HTR),导致大量
发病率和偶尔的死亡率。HTRs由两种重要的免疫现象引起。第一个是
RBC抗体的独特的消逝性质,其迅速消失导致假阴性
对接受过同种免疫的患者进行筛查。第二种是重新暴露于病毒引起的召回抗体反应
通过随后的输血,循环抗体的快速而强劲的增加推动HTR。
尽管这些现象带来了重大的临床后果,但我们对基本情况的理解
调节抗RBC抗体产生、维持和召回的分子和细胞机制是
非常有限。因此,没有有效的治疗干预措施可用于同种免疫
除抗原回避外的患者。我们之前的工作已经确定IL-6是一种关键的细胞因子信号,
调节红细胞和早期T滤泡辅助细胞(TFH)的初始同种免疫反应
差异化。我们现在有兴趣将我们的发现扩展到研究IL-6信号在脑内的作用
控制红细胞同种异体抗体消逝和召回反应。鉴于IL-6的多形性
信号,我们感兴趣的是确定细胞靶点(B细胞与T细胞),下游信号
分子(STAT3)和细胞后果(短寿命浆细胞、长寿命浆细胞、记忆B细胞
和记忆TFH细胞分化)受IL-6调节,是红细胞同种异体免疫所必需的。因此,
我们将使用IL-6R、STAT3和BCL6的尖端条件遗传小鼠突变体来直接
比较两种不同的RBC同种免疫小鼠模型的抗体和细胞反应
标准的疫苗接种方法。通过这样做,我们将更好地理解基本的细胞和
RBC同种异体免疫的分子免疫调节因子因RBC抗原系统的不同而不同,以及如何
它们与传统的免疫刺激相比。此外,我们将开发一种临床前小鼠模型
系统确定靶向IL-6/IL-6R信号通路的治疗效果以预防
和/或红细胞同种异体免疫的治疗,作为随后审议IL-6R的关键数据
抗体阻断疗法(如Tocilizumab)用于选择的高危同种异体免疫患者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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CHANCE MARION JOHN LUCKEY其他文献
CHANCE MARION JOHN LUCKEY的其他文献
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{{ truncateString('CHANCE MARION JOHN LUCKEY', 18)}}的其他基金
Basic and Translational Mechanisms of Alloimmunization to RBC Transfusion. Project 2
红细胞输注同种免疫的基本和转化机制。
- 批准号:
10711669 - 财政年份:2023
- 资助金额:
$ 51.91万 - 项目类别:
Molecular determinants of anti-RBC alloantibody evanescence
抗红细胞同种抗体消失的分子决定因素
- 批准号:
10687424 - 财政年份:2022
- 资助金额:
$ 51.91万 - 项目类别:
Cellular and Molecular Determinants of RBC Alloimmunization Responder Status
红细胞同种免疫应答状态的细胞和分子决定因素
- 批准号:
10192795 - 财政年份:2017
- 资助金额:
$ 51.91万 - 项目类别:
Transcriptional Control of Memory Responses to Red Blood Cell Alloimmunization
红细胞同种免疫记忆反应的转录控制
- 批准号:
9017157 - 财政年份:2014
- 资助金额:
$ 51.91万 - 项目类别:
Transcriptional Control of Memory Responses to Red Blood Cell Alloimmunization
红细胞同种免疫记忆反应的转录控制
- 批准号:
8567036 - 财政年份:2013
- 资助金额:
$ 51.91万 - 项目类别:
Transcriptional Control of Memory Responses to Red Blood Cell Alloimmunization
红细胞同种免疫记忆反应的转录控制
- 批准号:
8703785 - 财政年份:2013
- 资助金额:
$ 51.91万 - 项目类别:
Cytokine control of Red Blood Cell Alloimmunization
红细胞同种免疫的细胞因子控制
- 批准号:
8228956 - 财政年份:2012
- 资助金额:
$ 51.91万 - 项目类别:
Cytokine control of Red Blood Cell Alloimmunization
红细胞同种免疫的细胞因子控制
- 批准号:
8424288 - 财政年份:2012
- 资助金额:
$ 51.91万 - 项目类别:
Pou6f1 transcriptional control of memory CD8+ T cells
Pou6f1 记忆 CD8 T 细胞的转录控制
- 批准号:
8164939 - 财政年份:2011
- 资助金额:
$ 51.91万 - 项目类别:
Pou6f1 transcriptional control of memory CD8+ T cells
Pou6f1 记忆 CD8 T 细胞的转录控制
- 批准号:
8264746 - 财政年份:2011
- 资助金额:
$ 51.91万 - 项目类别:
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