Induction of Immune Tolerance by Neonatal Intravenous Injection of Human Factor VIII in Murine Hemophilia A

新生儿静脉注射人因子 VIII 对小鼠甲型血友病诱导免疫耐受

基本信息

  • 批准号:
    15591021
  • 负责人:
  • 金额:
    $ 2.24万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    2003
  • 资助国家:
    日本
  • 起止时间:
    2003 至 2004
  • 项目状态:
    已结题

项目摘要

Inhibitory antibody formation is the most serious complication of factor VIII replacement therapy in patients with hemophilia A. Factor VIII-deficient mice served as a model of severe hemophilia A to characterize the immune response to human factor VIII and to study new approaches for induction of immune tolerance. Neither anti-factor VIII inhibitory antibodies nor anti-factor VIII IgGs were observed in 13 of 14 adult mice that received 0.05 unit/g body weight of human factor VIII intravenously within 24 hours after birth, as well as repeated injections as adults. In contrast, high factor VIII antibody titers (>50 Bethesda units/mL) were found in 7 of 13 mice injected on day 3 post-partum and in all adult mice that had not been treated neonatally. One out of 9 mice and 3 of 17 mice developed high-titer anti-factor VIII inhibitory antibody, when they were initially treated with 2-fold (0.1 unit/g body weight) and 10-fold higher doses (0.5 unit/g body weight) factor VIII on day 0 respectively. A human factor VIII specific T cell proliferative response was absent in splenocytes obtained from neonatally treated mice. However, the tolerant mice immunized with tetanus toxoid developed high anti-tetanus toxoid antibody, demonstrating that tolerance is factor VIII specific. The splenocytes failed to proliferate or produce interferon-γ in response to factor VIII stimulation, yet still secreted significant amounts of interleukin-2 and were restored proliferation by the addition of exogenous interferon-γ or the interleukin-12, suggesting that the lack of inhibitor to factor VIII is due to interferon-γ dependent anergy. These studies indicate that exposure on day 0 to physiological levels of factor VIII antigen might be important for induction of immune tolerance. This immune tolerance model may provide a basis for new approaches regarding prevention of factor VIII inhibitors during replacement therapy.
抑制性抗体形成是血友病A患者凝血因子VIII替代治疗最严重的并发症。因子VIII缺陷小鼠作为严重血友病A的模型,以表征对人因子VIII的免疫应答,并研究诱导免疫耐受的新方法。在出生后24小时内接受0.05单位/g体重人因子VIII静脉注射以及成年后重复注射的14只成年小鼠中,有13只未观察到抗因子VIII抑制性抗体和抗因子VIII IgG。相比之下,在产后第3天注射的13只小鼠中的7只中以及在所有未接受生殖治疗的成年小鼠中发现了高因子VIII抗体滴度(>50 Bethesda单位/mL)。在第0天分别用2倍(0.1单位/g体重)和10倍高剂量(0.5单位/g体重)的因子VIII初始处理时,9只小鼠中的1只和17只小鼠中的3只产生高滴度抗因子VIII抑制性抗体。人因子VIII特异性T细胞增殖反应是不存在的脾细胞获得的pharmacatally治疗的小鼠。然而,用破伤风类毒素免疫的耐受小鼠产生了高的抗破伤风类毒素抗体,表明耐受是因子VIII特异性的。脾细胞不能响应于因子VIII刺激而增殖或产生干扰素-γ,但仍分泌显著量的白细胞介素-2,并且通过添加外源性干扰素-γ或白细胞介素-12而恢复增殖,这表明缺乏因子VIII的抑制剂是由于干扰素-γ依赖性无能。这些研究表明,在第0天暴露于生理水平的因子VIII抗原可能对诱导免疫耐受是重要的。这种免疫耐受模型可能为在替代治疗期间预防因子VIII抑制剂的新方法提供基础。

项目成果

期刊论文数量(84)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Naito M: "Defective sorting to secretory vesicles in the trans Golgi network is partly responsible for protein C deficiency : Molecular mechanism of impaired secretion of abnormal protein C R169W, R352W and G376D."Circ.Res.. 92. 865-872 (2003)
Naito M:“反式高尔基体网络中分泌囊泡的缺陷分选是蛋白质 C 缺乏的部分原因:异常蛋白质 C R169W、R352W 和 G376D 分泌受损的分子机制。”Circ.Res.. 92. 865-872 (2003)
  • DOI:
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  • 影响因子:
    0
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  • 通讯作者:
Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of gamma Ala327Thr : formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism.
γ-Ala327Thr 氨基酸取代的嗜血栓性纤维蛋白原东京 V:易碎但抗纤维蛋白溶解的纤维蛋白凝块的形成及其与动脉血栓栓塞的相关性。
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Sejima T;Sato Y;Shimizu H;Shimizu H;Madoiwa S;Iimura O;Kikuchi J;Sejima T;Hamano A
  • 通讯作者:
    Hamano A
Sustained transgene expression by human cord blood derived CD^+_<34> cells transduced with simian immunodeficiency virus agmTYO1-based vectors carrying the human coagulation factor VIII gene in NOD/SCID mice.
在NOD/SCID小鼠中,用携带人凝血因子VIII基因的基于猿猴免疫缺陷病毒agmTYO1的载体转导的人脐带血来源的CD 1 _ 34 细胞的持续转基因表达。
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Sejima T;Sato Y;Shimizu H;Shimizu H;Madoiwa S;Iimura O;Kikuchi J;Sejima T;Hamano A;Mimuro J;Ogata K;Sato Y;Kikuchi J;Hamano A;Sato Y;Madoiwa S;Madoiwa S;Iimura O;Kikuchi J
  • 通讯作者:
    Kikuchi J
Expression profiles of fibrinolytic components in nasal mucosa
  • DOI:
    10.1007/s00418-004-0664-2
  • 发表时间:
    2004-06
  • 期刊:
  • 影响因子:
    2.3
  • 作者:
    Takayuki Sejima;S. Madoiwa;J. Mimuro;T. Sugo;T. Ishida;K. Ichimura;Y. Sakata
  • 通讯作者:
    Takayuki Sejima;S. Madoiwa;J. Mimuro;T. Sugo;T. Ishida;K. Ichimura;Y. Sakata
Mimuro J: "Specific detection of human coagulation factor IX in cynomolgus macaques."J.Thromb.Haemost.. 2. 275-280 (2004)
Mimuro J:“食蟹猴中人凝血因子 IX 的特异性检测。”J.Thromb.Haemost.. 2. 275-280 (2004)
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    0
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MADOIWA Seiji其他文献

MADOIWA Seiji的其他文献

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{{ truncateString('MADOIWA Seiji', 18)}}的其他基金

Development of novel thymus-directed strategy for central immune tolerance induction in hemophilia A
开发用于血友病 A 中枢免疫耐受诱导的新型胸腺导向策略
  • 批准号:
    24591430
  • 财政年份:
    2012
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Regulation of plasminogen activator inhibitor-1 promotes the immune response to factor VIII in murine hemophilia A.
纤溶酶原激活剂抑制剂-1 的调节可促进小鼠 A 型血友病中对因子 VIII 的免疫反应。
  • 批准号:
    21591249
  • 财政年份:
    2009
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of immune-tolerance induction by continuous infusion of FactorVIII using micro-injection system in murine hemophilia A
使用显微注射系统连续输注因子 VIII 开发小鼠血友病 A 免疫耐受诱导
  • 批准号:
    19591133
  • 财政年份:
    2007
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Induction of factor VIII specific unresponsiveness by intrathymic factor VIII injection in murine hemophilia A
胸腺内注射因子 VIII 诱导小鼠血友病 A 诱导因子 VIII 特异性无反应
  • 批准号:
    17591006
  • 财政年份:
    2005
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Gene therapy for hemophilia A with simian immunodeficiency virus agmTYO1-based vectors carrying human factor VIII gene.
使用携带人类因子 VIII 基因的基于猿猴免疫缺陷病毒 agmTYO1 的载体对 A 型血友病进行基因治疗。
  • 批准号:
    13671078
  • 财政年份:
    2001
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

相似海外基金

Development of tolerogenic Factor VIII as immunotherapy to prevent inhibitor development in Hemophilia A
开发耐受性因子 VIII 作为免疫疗法来预防 A 型血友病抑制剂的产生
  • 批准号:
    10594819
  • 财政年份:
    2023
  • 资助金额:
    $ 2.24万
  • 项目类别:
Development of a non-Factor small molecule, oral, prophylactic and hemostasis balanced therapy for treatment of clotting disorders including hemophilia A/B
开发非因子小分子、口服、预防性和止血平衡疗法,用于治疗包括血友病 A/B 在内的凝血障碍
  • 批准号:
    10384995
  • 财政年份:
    2022
  • 资助金额:
    $ 2.24万
  • 项目类别:
Immunotherapy for Factor VIII Inhibition in Hemophilia A
血友病 A 中因子 VIII 抑制的免疫疗法
  • 批准号:
    10484774
  • 财政年份:
    2022
  • 资助金额:
    $ 2.24万
  • 项目类别:
A Severe Hemophilia A Intergenerational Cohort Research Program for the Study of Factor VIII Immunogenicity
严重血友病 因子 VIII 免疫原性研究的代际队列研究计划
  • 批准号:
    10512711
  • 财政年份:
    2022
  • 资助金额:
    $ 2.24万
  • 项目类别:
A Severe Hemophilia A Intergenerational Cohort Research Program for the Study of Factor VIII Immunogenicity
严重血友病 因子 VIII 免疫原性研究的代际队列研究计划
  • 批准号:
    10708183
  • 财政年份:
    2022
  • 资助金额:
    $ 2.24万
  • 项目类别:
SMART BIOELECTRONIC IMPLANTS FOR CONTROLLED DELIVERY OF THERAPEUTIC PROTEINS IN VIVO AND ITS APPLICATION IN LONG-TERM TREATMENT OF HEMOPHILIA A
用于体内治疗性蛋白质控制输送的智能生物电子植入物及其在血友病 A 长期治疗中的应用
  • 批准号:
    10446179
  • 财政年份:
    2022
  • 资助金额:
    $ 2.24万
  • 项目类别:
SMART BIOELECTRONIC IMPLANTS FOR CONTROLLED DELIVERY OF THERAPEUTIC PROTEINS IN VIVO AND ITS APPLICATION IN LONG-TERM TREATMENT OF HEMOPHILIA A
用于体内治疗性蛋白质控制输送的智能生物电子植入物及其在血友病 A 长期治疗中的应用
  • 批准号:
    10615840
  • 财政年份:
    2022
  • 资助金额:
    $ 2.24万
  • 项目类别:
Unleashing the power of AI to create a novel treatment for hemophilia A
释放人工智能的力量,创造 A 型血友病的新型治疗方法
  • 批准号:
    22K06119
  • 财政年份:
    2022
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Defining the therapeutic efficacy, tolerogenic potential, and genotoxicity of liver-targeted AAV gene therapy for hemophilia A
定义肝脏靶向 AAV 基因疗法治疗血友病 A 的疗效、耐受潜力和遗传毒性
  • 批准号:
    10704568
  • 财政年份:
    2022
  • 资助金额:
    $ 2.24万
  • 项目类别:
Toward Safer Gene Therapy for Hemophilia A
迈向更安全的 A 型血友病基因治疗
  • 批准号:
    10333185
  • 财政年份:
    2022
  • 资助金额:
    $ 2.24万
  • 项目类别:
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