Mechanisms of IVIG Protection in Viral Encephalitis

IVIG 对病毒性脑炎的保护机制

基本信息

项目摘要

DESCRIPTION (provided by applicant): C57BL/6 (B6) mice are genetically resistant to fatal HSV encephalitis (HSE) compared to 129S6 (129) and BALB/c that are susceptible. We have shown that fatal HSE in 129 mice results from hyper-inflammatory responses involving macrophages and neutrophils and that acyclovir which inhibits HSV replication is largely ineffective in protection against HSE. B6-Rag mice lacking B and T cells are more resistant than 129-Rag that are only slightly more susceptible than 129 wild type (wt) mice. We report that a single dose of pooled human immunoglobulin (IVIG) given at 24 h post infection (PI) completely protected wild type 129 mice from fatal HSE. IVIG protected virtually all B6-Rag mice, while 129-Rag mice were not protected even when given multiple doses of IVIG or IVIG supplemented with acyclovir (ACV). We suggest that the mechanism(s) of IVIG protection differs fundamentally in B6 and 129 mice and further, that a cell type absent in Rag mice is required for long-term protection akin to that seen in IVIG treated wt 129. We propose a two-component model for IVIG protection involving a mechanism to suppress inflammation and a mechanism to suppress HSV replication in neurons; both mechanisms are operative in 129 mice whereas only the second mechanism is operative in B6 mice. We hypothesize that IVIG activates a 'sensor' DC that in turn modulates innate effector cells (macrophages and monocytes) either directly of via induced regulatory T cells (Tregs) to achieve controlled inflammatory responses that control infection without bystander immune pathology. Our Specific Aims are designed to test the hypothesis proposed to explain IVIG's anti-inflammatory activity. The mechanism whereby IVIG suppresses HSV replication will be studied in a separate application. In Aim 1, the inflammatory response to HSV will be characterized in untreated and mice treated with IVIG or its derivatives (sialylated IgG, antibody subclasses, etc). IVIG effects on survival, virus load, lesion formation will be assessed and additionally, biodistribution of IVIG will be compared in mock and HSV infected WT 129 and 129/B6-Rag. In Aim 3, the IVIG 'sensor' cells (sDC) will be identified using an adoptive transfer strategy, it's role in protection will be investigated, including induction of Tregs and modulation of expression of Fc?Rs, cytokines, chemokines and their receptors in hematopoietic cells to define the anti-inflammatory mechanism(s) of IVIG in this model of viral encephalitis caused by excessive inflammation. Results from studies done thus far suggest IVIG will be useful for treating HSE and other immune mediated HSV diseases such as herpes stromal keratitis (HSK). Results from studies proposed here will uncover the mechanisms of suppression of neuroinflammation revealing the potential for application of IVIG to treat a broad spectrum of CNS inflammatory diseases. PUBLIC HEALTH RELEVANCE: Herpes simplex virus (HSV) is widely distributed in the human population as result of its ability to cause latent infections and subsequently reactivate leading to further spread. HSV is the major cause of sporadic encephalitis, which despite treatment with antiviral drugs is still associated with high mortality (~20%) and serious neurological sequelae in many survivors. HSV infections are particularly dangerous in immunosuppressed individuals and neonates with compromised immunity. We have shown convincingly that fatal HSV encephalitis (HSE) in susceptible 129S6 mice results from pathogenic inflammatory responses. Most importantly, treatment of 129 infected mice with pooled human IgG (IVIG) totally protected the mice from death. IVIG treatment also protected >80% of resistant C57BL/6 (B6) Rag mice that lack B&T cells but it failed to protect 129-Rag mice even when multiple doses of IVIG or IVIG supplemented with acyclovir (ACV) were given. This unexpected result shows that genetic factors determine the efficacy of IVIG treatment and our unique model will allow us to dissect the mechanism(s) of IVIG protection in mice with different genetic backgrounds, including Rag mice representative of immunocompromized individuals. Results from these studies will be important for making the case for IVIG as a treatment for neuroinflammatory diseases including encephalitis caused by HSV and other viruses like West Nile virus that are potential bioterrorism agents.
描述(申请人提供):C57BL/6(B6)小鼠对致死性单纯疱疹病毒脑炎(HSE)具有遗传抵抗力,而129S6(129)和BALB/c小鼠是敏感的。我们已经证明,129只小鼠的致命性HSE是由涉及巨噬细胞和中性粒细胞的超炎症反应引起的,而抑制HSV复制的阿昔洛韦在保护HSE方面基本上无效。缺乏B和T细胞的B6-RAG小鼠比129-RAG小鼠更具抵抗力,而129-RAG小鼠仅比129野生型(Wt)小鼠稍敏感。我们报道,在感染后24小时给予单剂混合人免疫球蛋白(IVIG)完全保护野生型129小鼠免受致死性HSE的影响。IVIG几乎保护了所有B6-RAG小鼠,而129-RAG小鼠即使在给予多次IVIG或IVIG加阿昔洛韦(ACV)时也不受保护。我们认为静脉注射免疫球蛋白的保护机制(S)在B6和129型小鼠中有根本的不同,此外,RAG小鼠缺乏的细胞类型需要长期保护,类似于静脉注射免疫球蛋白治疗的wt129。我们提出了一个两组分的IVIG保护模型,包括一个抑制炎症的机制和一个抑制神经元中HSV复制的机制;这两种机制在129只小鼠中都有效,而只有第二种机制在B6小鼠中有效。我们假设IVIG激活一个“传感器”树突状细胞,反过来通过诱导的调节性T细胞(Treg)直接或间接地调节先天效应细胞(巨噬细胞和单核细胞),以实现受控的炎症反应,控制感染,而不是旁观者免疫病理。我们的具体目标是测试提出的解释IVIG抗炎活性的假说。IVIG抑制HSV复制的机制将在另一项应用中进行研究。在目标1中,将在未治疗和静脉注射丙种球蛋白或其衍生物(唾液酸化的免疫球蛋白、抗体亚类等)治疗的小鼠中表征对HSV的炎症反应。将评估IVIG对存活、病毒载量、病变形成的影响,并将比较IVIG在模拟和HSV感染的WT129和129/B6-RAG中的生物分布。在目的3中,将采用一种过继转移策略来鉴定静脉注射免疫球蛋白的感受器细胞(SDC),研究其在保护中的作用,包括诱导Tregs和调节造血细胞中Fc?Rs、细胞因子、趋化因子及其受体的表达,以明确静脉注射免疫球蛋白在这种过度炎症所致的病毒性脑炎模型中的抗炎机制(S)。到目前为止所做的研究结果表明,IVIG将用于治疗HSE和其他免疫介导的HSV疾病,如疱疹间质角膜炎(HSK)。本文提出的研究结果将揭示抑制神经炎症的机制,揭示静脉注射免疫球蛋白用于治疗广泛的中枢神经系统炎症性疾病的潜力。与公共卫生相关:单纯疱疹病毒(HSV)在人类人群中广泛分布,因为它能够引起潜伏感染,然后重新激活,导致进一步传播。单纯疱疹病毒(HSV)是散发性脑炎的主要病因,尽管接受了抗病毒药物的治疗,但许多幸存者仍有较高的死亡率(~20%)和严重的神经后遗症。单纯疱疹病毒感染在免疫抑制的个人和免疫功能受损的新生儿中尤其危险。我们已经令人信服地表明,在易感的129S6小鼠中,致死性单纯疱疹病毒脑炎(HSE)是致病性炎症反应的结果。最重要的是,用混合人免疫球蛋白(IVIG)治疗129只受感染的小鼠,完全保护了小鼠免于死亡。IVIG治疗也保护了80%缺乏B&T细胞的耐药C57BL/6(B6)RAG小鼠,但即使给予多次IVIG或IVIG加阿昔洛韦(ACV)也未能保护129-RAG小鼠。这一意想不到的结果表明,遗传因素决定了静脉注射免疫球蛋白治疗的效果,我们独特的模型将使我们能够剖析静脉注射免疫球蛋白在不同遗传背景的小鼠中的保护机制(S),包括免疫受损个体的代表RAG小鼠。这些研究的结果将对IVIG作为治疗神经炎症性疾病的理由非常重要,包括由HSV引起的脑炎和其他病毒,如西尼罗河病毒,这些病毒是潜在的生物恐怖主义因子。

项目成果

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EDOUARD M CANTIN其他文献

EDOUARD M CANTIN的其他文献

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{{ truncateString('EDOUARD M CANTIN', 18)}}的其他基金

Role for the Microbiota in Development of Herpes Stromal Keratitis
微生物群在疱疹性基质性角膜炎发展中的作用
  • 批准号:
    9361033
  • 财政年份:
    2016
  • 资助金额:
    $ 41.5万
  • 项目类别:
Immunotherapy Ameliorate Neurological Deficits in Encephalitis
免疫疗法可改善脑炎的神经功能缺陷
  • 批准号:
    8771312
  • 财政年份:
    2014
  • 资助金额:
    $ 41.5万
  • 项目类别:
TNF SIGNALING IN THE ABSENCE OF FUNCTIONAL TNF RECEPTORS.
缺乏功能性 TNF 受体时的 TNF 信号传导。
  • 批准号:
    8524148
  • 财政年份:
    2012
  • 资助金额:
    $ 41.5万
  • 项目类别:
Mechanisms of IVIG Protection in Viral Encephalitis
IVIG 对病毒性脑炎的保护机制
  • 批准号:
    7876803
  • 财政年份:
    2009
  • 资助金额:
    $ 41.5万
  • 项目类别:
A Genetic Determinant of Resistance to HSV
HSV 耐药性的遗传决定因素
  • 批准号:
    6616812
  • 财政年份:
    2002
  • 资助金额:
    $ 41.5万
  • 项目类别:
A Genetic Determinant of Resistance to HSV
HSV 耐药性的遗传决定因素
  • 批准号:
    6543198
  • 财政年份:
    2002
  • 资助金额:
    $ 41.5万
  • 项目类别:
A Genetic Determinant of Resistance to HSV
HSV 耐药性的遗传决定因素
  • 批准号:
    6927797
  • 财政年份:
    2002
  • 资助金额:
    $ 41.5万
  • 项目类别:
A Genetic Determinant of Resistance to HSV
HSV 耐药性的遗传决定因素
  • 批准号:
    6778187
  • 财政年份:
    2002
  • 资助金额:
    $ 41.5万
  • 项目类别:
A Genetic Determinant of Resistance to HSV
HSV 耐药性的遗传决定因素
  • 批准号:
    7100200
  • 财政年份:
    2002
  • 资助金额:
    $ 41.5万
  • 项目类别:
MECHNISM OF HERPES ST ROMAL KERATITIS
疱疹病毒性角膜炎的机制
  • 批准号:
    6078884
  • 财政年份:
    1999
  • 资助金额:
    $ 41.5万
  • 项目类别:

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