Identification of novel immune adjuvants and their acting mechanism on dendritic cell function

新型免疫佐剂的鉴定及其对树突状细胞功能的作用机制

• 批准号: 16590403
• 负责人: KAISHO Tsuneyasu
• 金额: $ 2.3万
• 依托单位: RIKEN
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590403/
• 关键词: Dendritic cell; immune adjuvant; Toll-like receptor; gene targeting mice; type I interferon; IκB kinase; 樹状細胞サブセット; IκBキナ

Dendritic cells (DCs) are critically involved in host defense by recognizing a variety of microorganism-derived molecular components, i.e. immune adjuvants, and producing various cytokines. A group of transmembrane proteins, Toll-like receptors (TLRs), are critical for these processes. I have clarified some of these mechanisms by utilizing several gene targeting mice. I have already identified antiviral reagents, imidazoquinoline derivatives, as TLR7 ligands and also revealed that virus-derived single stranded RNAs can also function as TLR7 ligands. TLR3 and TLR4 can recognize double stranded RNAs and lipopolysaccarides (LPS), respectively, and their signaling can induce type I interferons (IFNs). IκB kinase (IKK) family members, IKKε/ι and TBK1, were found to be critical for TLR3/4-induced type I IFN production. These IKKs were also involved in virus-induced type I IFN production. A DC subset, plasmacytoid DC, expresses TLR7 and TLR9 exclusively among TLRs. Because TLR9 is involved in recognizing CpG DNA, it can be assumed that PDC can be regarded as nucleic acid-recognizing DC. Notably, PDC is unique in producing type I IFN, especially IFN-α, in response to TLR7/9 signaling. Another IKK family member, IKKα, was found to be critical for TLR7/9-induced type I IFN production from PDC. Furthermore, by utilizing a variety of DCs, IL-12-inducing activity was detected in helminth extracts. The activity was dependent on a cytoplasmic TLR adapter, MyD88, indicating that the extracts include some TLR ligands. These findings should contribute to the establishment of novel drugs for immune regulation.

树突状细胞(DC)通过识别多种微生物来源的分子成分，即免疫佐剂，并产生各种细胞因子，在宿主防御中发挥重要作用。一组跨膜蛋白，Toll样受体(TLRs)，对这些过程至关重要。我已经利用几只基因打靶的小鼠阐明了其中的一些机制。我已经确定了抗病毒试剂，咪唑喹啉衍生物，作为TLR7配体，并揭示了病毒来源的单链RNA也可以作为TLR7配体。TLR3和TLR4分别识别双链RNA和脂多糖，它们的信号转导可以诱导型干扰素(IFN)。IκB激酶(IKK)家族成员IKKε/ι和TbK1在TLR3/4诱导的I型干扰素产生中起关键作用。这些IKK还参与了病毒诱导的I型干扰素的产生。树突状细胞亚群，浆细胞样树突状细胞，在TLRs中唯一表达TLR7和TLR9。由于TLR9参与识别CpG DNA，因此可以认为PDC是一种核酸识别树突状细胞。值得注意的是，pDC在产生I型干扰素，特别是干扰素-α方面是独一无二的，以响应TLR7/9信号。另一个IKK家族成员IKKα在TLR7/9诱导的pDC产生I型干扰素过程中起关键作用。此外，通过利用多种DC，在蠕虫提取物中检测到了IL-12的诱导活性。其活性依赖于细胞质TLR接头MyD88，这表明提取物中含有一些TLR配体。这些发现应该有助于建立新的免疫调节药物。

项目成果

CXCL13 is an arrest chemokine for B cells in high endothelial venules

• DOI: 10.1182/blood-2005-01-0133
• 发表时间: 2005-10-15
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Kanemitsu, N;Ebisuno, Y;Miyasaka, M
• 通讯作者: Miyasaka, M

インターフェロンーα制御剤

干扰素-α调节剂

• 发表时间: 2005

Complement C1q regulates LPS‐induced cytokine production in bone marrow‐derived dendritic cells

• DOI: 10.1002/eji.200324026
• 发表时间: 2004-01
• 期刊: European Journal of Immunology
• 影响因子: 5.4
• 作者: Masahide Yamada;K. Oritani;T. Kaisho;J. Ishikawa;H. Yoshida;Isao Takahashi;Shin-ichiro Kawamoto;N. Ishida;H. Ujiie;H. Masaie;M. Botto;Y. Tomiyama;Y. Matsuzawa

Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA

• DOI: 10.1126/science.1093616
• 发表时间: 2004-03-05
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Diebold, SS;Kaisho, T;Sousa, CRE
• 通讯作者: Sousa, CRE

CpG RNA: Identification of Novel Single-Stranded RNA That Stimulates Human CD14+CD11c+ Monocytes

• DOI: 10.4049/jimmunol.174.4.2273
• 发表时间: 2005-02
• 期刊: The Journal of Immunology
• 作者: T. Sugiyama;M. Gursel;F. Takeshita;C. Coban;J. Conover;T. Kaisho;S. Akira;D. Klinman;K. Ishii