Intra-and inter-cellular vaccine-induced signaling pathways

细胞内和细胞间疫苗诱导的信号通路

• 批准号: 21390152
• 负责人: ISHII Ken
• 金额: $ 11.81万
• 依托单位: 独立行政法人医薬基盤研究所 (2010-2011)Osaka University (2009)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390152/
• 关键词: ワクチン; アジュバント; 自然免疫; インフルエンザ; シグナル伝達; TLR7; 核酸; ベータ グルカン; CpG

Optimal vaccine efficacy requires not only a protective antigen, but also a strong immune activator as an adjuvant. Most viral vaccines, such as influenza vaccines and non-viral genetic vaccines(e. g., DNA vaccines), contain nucleic acids, which appear to act as essential "built-in" adjuvants. Specific receptors, including toll-like receptors(TLR), retinoic-acid-inducible protein I(RIG-I)-like receptors(RLR), and nucleotide-binding oligomerization domain(NOD)-like receptors(NLR), can detect specific nucleic acid patterns, such as sequence, structure and modification, which are also influenced by the immunized tissue, cell type, and intracellular localization. The resultant immune activation is uniquely regulated by intra-and inter-cellular signaling pathways, which are indispensable for the ensuing vaccine immunogenicity, such as antigen-specific T-and B-cell responses.A variety of vaccine compositions for H1N1 influenza A virus infections are available ; however, the key innate immune … More mechanisms controlling their immunogenicity remain unclear. Here we identified that plasmacytoid dendritic cells(pDC) and their type-I IFN-mediated intra-and inter-cellular signalling were essential for the induction of virus specific CD4 T and B cells following killed virion vaccination. While Toll-like receptor(TLR) 7, but not RIG-I-like-or NOD-like-receptors, mediated immunogenicity of both live and killed virion vaccines, a commonly used split vaccine failed to activate TLR7, resulting in no efficacy in naive mice. PDC-activating adjuvant restored split vaccine immunogenicity in mice, but split vaccine alone was sufficient to recall memory responses in humans, underscoring the importance of the pDC-TLR7/9-type-I axis for priming, but not secondary immunization.Aluminum-based adjuvants(alum) are widely used in human vaccination, although little is understood of their mechanisms of action. Here, we report that, in mice, alum causes the release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we show that host DNA signaling differentially regulates IgE and IgG1 production upon alum immunization. Indeed, we show support that host DNA induces primary B cell responses, including IgG1 production, through IRF-3 independent mechanisms, and inflammatory'canonical' type 2 T cell responses associated with IgE isotype switching and effector tissue responses through IRF-3 dependent mechanisms. The finding that host cell DNA is a damage-associated molecular pattern relaying alum adjuvant activity may thus help in the comprehension of the mechanisms of action of current vaccines and in the design of novel adjuvants.1.Aoshi T et al. Innate and adaptive immune responses to viral infection and vaccination. Curr Opin Virol. 2011, 1(4): 226-232.2.Marichal T et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat. Med. 2011 17(8): 996-10023.Koyama S, et al. Plasmacytoid dendritic cells delineate immunogenicity of influenza vaccine subtypes. Sci Transl Med. 2010 2(25): 25ra24. Less

最佳的疫苗效力不仅需要保护性抗原，还需要强免疫激活剂作为佐剂。大多数病毒疫苗，如流感疫苗和非病毒基因疫苗（e。例如，在一个实施例中，DNA疫苗）含有核酸，其似乎充当必需的“内置”佐剂。特异性受体包括Toll样受体（TLR）、视黄酸诱导蛋白I（RIG-I）样受体（RLR）和核苷酸结合寡聚化结构域（NOD）样受体（NLR），它们可以检测特定的核酸模式，如序列、结构和修饰，这些模式也受到免疫组织、细胞类型和细胞内定位的影响。所产生的免疫激活由细胞内和细胞间信号传导途径独特地调节，所述信号传导途径对于随后的疫苗免疫原性（例如抗原特异性T细胞和B细胞应答）是不可或缺的。 ...更多信息 控制其免疫原性的机制仍不清楚。在这里，我们确定了浆细胞样树突状细胞（pDC）和它们的I型IFN介导的细胞内和细胞间信号传导是诱导病毒特异性CD 4 T和B细胞后杀死的病毒粒子接种所必需的。虽然Toll样受体（TLR）7而不是RIG-I样或NOD样受体介导活病毒体疫苗和灭活病毒体疫苗的免疫原性，但常用的裂解疫苗未能激活TLR 7，导致在幼稚小鼠中没有功效。PDC活化佐剂恢复裂解疫苗在小鼠中的免疫原性，但裂解疫苗本身足以回忆起人类的记忆反应，强调了pDC-TLR 7/9-I型轴对于引发的重要性，但不是二次免疫。在这里，我们报告说，在小鼠中，明矾引起宿主细胞DNA的释放，这作为一个强大的内源性免疫刺激信号介导明矾佐剂活性。此外，我们表明，宿主DNA信号差异调节IgE和IgG 1生产明矾免疫。事实上，我们表明支持宿主DNA诱导主要B细胞反应，包括IgG 1的生产，通过IRF-3的独立机制，和炎症“典型”2型T细胞反应与IgE同种型转换和效应组织反应通过IRF-3依赖性机制。宿主细胞DNA是一种损伤相关的分子模式，传递明矾佐剂活性，这一发现可能有助于理解当前疫苗的作用机制和设计新型佐剂。病毒学Curr Opin 2011，1（4）：226-232.2.Marichal T等人，DNA released from dying host cells mediates aluminum adjuvant activity. 2011 17（8）：996-10023.Koyama S等人，Plasmacytoid dendritic cells delineate immunoglobulin of influenza vaccine subtypes. Sci Transl Med.2010 2（25）：25ra24.少

项目成果

Plasmacytoid dendritic cells in influenza vaccine response

流感疫苗反应中的浆细胞样树突状细胞

• 发表时间: 2010
• 作者: Tomiyama K;Maeda R;Urakawa I;Yamazaki Y;Tanaka T;Ito S;Nabeshima Y;Tomita T;Odori S;Hosoda K;Nakao K;Imura A;Nabeshima Y;Masahi Hashimoto;國弘暁子;市來孝志・石川正弘・小山内康人・中野伸彦・足立達朗・木村純一・仙田量子;伊藤詔子;高村ゆかり;羽柴寛文・前田健一・刈田圭一・牛渡裕二・川瀬良司;西部忠;木津久美子,廣瀬潤子,本庄勉,成田宏史;Ken J.Ishii
• 通讯作者: Ken J.Ishii

Extracellular nucleic acids : Immune recognition of nucleic acids and their metabolites

细胞外核酸：核酸及其代谢物的免疫识别

• 发表时间: 2010
• 作者: Koyama S;Akira S;Ishii KJ
• 通讯作者: Ishii KJ

DNA released from dying host cells mediates aluminum adjuvant activity

• DOI: 10.1038/nm.2403
• 发表时间: 2011-08-01
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Marichal, Thomas;Ohata, Keiichi;Desmet, Christophe J.
• 通讯作者: Desmet, Christophe J.

Innate Immune Mechanisms of Vaccines

疫苗的先天免疫机制

• 发表时间: 2010
• 作者: Asai O;Nakatani K;Tanaka T;Sakan H;Imura A;Yoshimoto S;Samejima K;Yamaguchi Y;Matsui M;Akai Y;Konishi N;Iwano M;Nabeshima Y;Saito Y;Ken J.Ishii
• 通讯作者: Ken J.Ishii

Endo-and Exogenous Adjuvant for Influenza Vaccination

流感疫苗的内源性和外源性佐剂

• 发表时间: 2011
• 作者: Fuse;T. and Kobayashi;Y.;Ishii KJ
• 通讯作者: Ishii KJ