Investigating the role for IL-21 in rabies virus vaccine-induced immunity.
Investigating the role for IL-21 in rabies virus vaccine-induced immunity.
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DOI：
10.1371/journal.pntd.0002129
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发表时间：
2013
影响因子：
3.8
通讯作者：
McGettigan JP
中科院分区：
文献类型：
--
作者：
Dorfmeier CL;Tzvetkov EP;Gatt A;McGettigan JP
超过三分之二的世界人口生活在狂犬病流行的地区，导致全球每年有超过1500万人接受多剂量暴露后预防（PEP），超过55，000人死亡。狂犬病病毒（RABV）研究的一个主要目标是开发一种单剂量PEP，以简化疫苗接种方案，降低与RABV预防相关的成本，并挽救生命。针对RABV感染的保护需要病毒中和抗体;然而，影响保护性RABV特异性B细胞应答发展的因素仍有待阐明。在这里，我们使用IL-21受体缺陷（IL-21 R −/−）的小鼠模型来表征IL-21在RABV疫苗诱导的免疫中的作用。用低剂量重组RABV活疫苗（rRABV）免疫的IL-21 R −/−小鼠仅产生低水平的一级或二级抗RABV抗体应答，而野生型小鼠产生了有效的抗RABV抗体。此外，用低剂量rRABV免疫的IL-21 R −/−小鼠对致病性RABV攻击仅具有最低限度的保护，而所有野生型小鼠均在攻击中存活，这表明IL-21 R信号传导是响应于低剂量基于RABV的疫苗接种产生抗体所必需的。用更高剂量的疫苗免疫的IL-21 R −/−小鼠产生了次优的抗RABV一级抗体应答，但在用致病性RABV攻击时显示出与野生型小鼠相似的有效的二级抗体和保护，表明当一级应答发展时，IL-21对于基于RABV的活疫苗的二级抗体应答是无效的。此外，我们表明，IL-21的产生Tfh细胞和记忆B细胞在引流淋巴结的免疫小鼠，但需要检测最佳的GC B细胞或浆细胞在淋巴结或骨髓，分别以疫苗剂量依赖性的方式。总的来说，我们的初步数据表明，IL-21是至关重要的最佳疫苗诱导的初级，但不是针对RABV感染的二次抗体反应的发展。超过三分之二的世界人口生活在狂犬病流行的地区，导致超过1500万人接受暴露后治疗。每20分钟就有一个人，尤其是儿童，死于狂犬病，每年预防狂犬病的费用超过10亿美元。单剂量人用狂犬病疫苗的开发将通过降低与狂犬病疫苗接种相关的成本和挽救生命，大大减轻全球狂犬病的负担。了解B细胞是如何发育产生保护性病毒中和抗体的，将大大有助于实现开发单剂量疫苗的目标。在这份报告中，我们表明，IL-21是至关重要的诱导初级疫苗诱导的抗RABV G抗体滴度和IL-21的影响是高度依赖于疫苗的剂量管理。在我们的狂犬病免疫原性和保护模型中，IL-21受体的缺乏分别影响了低剂量或高剂量疫苗免疫后淋巴结中生发中心B细胞或骨髓中浆细胞的检测。总体而言，这些初步结果表明，IL-21有可能影响B细胞的发育和功能的背景下，狂犬病疫苗诱导的免疫和保护。
Over two-thirds of the world's population lives in regions where rabies is endemic, resulting in over 15 million people receiving multi-dose post-exposure prophylaxis (PEP) and over 55,000 deaths per year globally. A major goal in rabies virus (RABV) research is to develop a single-dose PEP that would simplify vaccination protocols, reduce costs associated with RABV prevention, and save lives. Protection against RABV infections requires virus neutralizing antibodies; however, factors influencing the development of protective RABV-specific B cell responses remain to be elucidated. Here we used a mouse model of IL-21 receptor-deficiency (IL-21R−/−) to characterize the role for IL-21 in RABV vaccine-induced immunity. IL-21R−/− mice immunized with a low dose of a live recombinant RABV-based vaccine (rRABV) produced only low levels of primary or secondary anti-RABV antibody response while wild-type mice developed potent anti-RABV antibodies. Furthermore, IL-21R−/− mice immunized with low-dose rRABV were only minimally protected against pathogenic RABV challenge, while all wild-type mice survived challenge, indicating that IL-21R signaling is required for antibody production in response to low-dose RABV-based vaccination. IL-21R−/− mice immunized with a higher dose of vaccine produced suboptimal anti-RABV primary antibody responses, but showed potent secondary antibodies and protection similar to wild-type mice upon challenge with pathogenic RABV, indicating that IL-21 is dispensable for secondary antibody responses to live RABV-based vaccines when a primary response develops. Furthermore, we show that IL-21 is dispensable for the generation of Tfh cells and memory B cells in the draining lymph nodes of immunized mice but is required for the detection of optimal GC B cells or plasma cells in the lymph node or bone marrow, respectively, in a vaccine dose-dependent manner. Collectively, our preliminary data show that IL-21 is critical for the development of optimal vaccine-induced primary but not secondary antibody responses against RABV infections. Over two-thirds of the world's population lives in regions where rabies is endemic, resulting in over 15 million people receiving post-exposure treatment. A person, disproportionately a child, dies of rabies every 20 minutes and the cost of rabies prevention exceeds $1 billion US dollars per year. The development of a single-dose human rabies vaccine would greatly reduce the burden of rabies globally by lowering the cost associated with rabies vaccination and saving lives. Understanding how B cells develop to produce protective virus neutralizing antibodies would greatly help to achieve the goal of developing a single-dose vaccine. In this report, we show that IL-21 is critical for the induction of primary vaccine-induced anti-RABV G antibody titers and that the effects of IL-21 are highly dependent on the dose of vaccine administered. In our model of rabies immunogenicity and protection, the lack of IL-21 receptor influenced the detection of B cells in germinal centers in lymph nodes or of plasma cells in bone marrow after immunization with low or high doses of vaccine, respectively. Overall, these preliminary results indicate that IL-21 has the potential to influence B cell development and functions in the context of rabies vaccine-induced immunity and protection.
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影响因子：
2.4
作者：
Jackson, Alan C.
通讯作者：
Jackson, Alan C.
DOI：
10.1084/jem.20102065
发表时间：
2011-07-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lee SK;Rigby RJ;Zotos D;Tsai LM;Kawamoto S;Marshall JL;Ramiscal RR;Chan TD;Gatto D;Brink R;Yu D;Fagarasan S;Tarlinton DM;Cunningham AF;Vinuesa CG
通讯作者：
Vinuesa CG
DOI：
10.4049/jimmunol.1001703
发表时间：
2010-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
King IL;Mohrs K;Mohrs M
通讯作者：
Mohrs M
影响因子：
3.8
作者：
Holm, C;Nyvold, CG;Hokland, M
通讯作者：
Hokland, M
影响因子：
2.2
作者：
BUNSCHOTEN H;DIETZSCHOLD B;OSTERHAUS A
通讯作者：
OSTERHAUS A