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。

基本信息

  • 批准号:
    10711669
  • 负责人:
  • 金额:
    $ 39.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-10 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

RBC alloimmunization occurs when patients make antibodies to foreign antigens expressed on allogenic donor RBCs, and remains a significant cause of morbidity and mortality among chronically transfused patients. Though the vast majority of RBC transfusions express foreign antigens, only a subset of transfused patients will make alloantibodies. Indeed, patients tend to stratify into those who make multiple alloantibodies (responders) and those who never make an alloantibody despite multiple transfusions (non-responders). However, the molecular factors that regulate responder vs. non-responder status are poorly defined. RBCs have long been known to secrete of ATP and regulate endothelial cell function via resultant purinergic signaling, but the impact of purinergic signaling on RBC alloimmunization has not been previously addressed. We hypothesize that RBC driven purinergic signaling tends to suppress the antibody response to transfused RBCs, and further that inherent differences in purinergic signaling sensitivities among patients can impact their responder status. Using a mouse model of RBC alloimmunization, our preliminary data demonstrate that multiple different steps in the purinergic signaling pathway (P2X7R, CD73, and ADORA2b) do indeed regulate anti-RBC alloantibody production. This proposal sets out to determine the exact cellular and molecular mechanisms by which purinergic signaling regulates RBC alloimmunization, and further determine whether the known gain and loss of function polymorphisms of purinergic receptors can dictate whether a given patient will make anti-RBC IgG alloantibodies. Specifically, Aim1 of our proposal will test the hypothesis that B cell binding to transfused RBCs induces PANX1 mediated ATP secretion, and this extracellular ATP drives P2X7R activation. We further hypothesize that P2X7R activation suppresses IgG class-switching and germinal center formation by inducing ectodomain shedding of key B cell surface proteins. Aim2 of our proposal will test the hypothesis that CD73 expression on B cells regulates the balance of AMP and Adenosine signaling on responding B cells, ultimately altering B cells responses by regulating intracellular cyclic-AMP signaling. Finally, Aim3 of this proposal will test the hypothesis that known polymorphisms in the P2X7R, ADORA1 and ADORA2b genes can account for some of the phenotypic differences observed among responder and non- responder patient populations. Synergy between projects comes from crosstalk between our focus on purinergic signaling and (a) the known interactions between P2X7R signaling and immune complex signaling through TLR7 and TLR9 (Project 1), (b) the fact that P2X7R is highly expresses on RBC precursors but decreases as RBCs mature (Project 3), and (c) the known enhancement of soluble CD73 and increased levels of ATP, ADP, AMP and Adenosine in patients with sickle cell disease (Project 4).
当患者对异体供体上表达的外源抗原产生抗体时,就会发生红细胞异体免疫

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(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

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:
    $ 39.11万
  • 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:
    $ 39.11万
  • 项目类别:
Cyokine control of red blood cell alloimmunization
红细胞同种免疫的细胞因子控制
  • 批准号:
    9214994
  • 财政年份:
    2016
  • 资助金额:
    $ 39.11万
  • 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:
    $ 39.11万
  • 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:
    $ 39.11万
  • 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:
    $ 39.11万
  • 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:
    $ 39.11万
  • 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:
    $ 39.11万
  • 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:
    $ 39.11万
  • 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:
    $ 39.11万
  • 项目类别:
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