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The complexity of the immune system mirrors its manifold mechanisms of host-microbe interactions. A relatively simplified view was posited after the identification of host innate immune receptors that their distinct mechanisms of sensing 'microbial signatures' create unique molecular switches to trigger the immune system. Recently, more sophisticated and cooperative strategies for these receptors have been revealed during receptor-ligand interactions, trafficking and intra- and intercellular signaling, in order to deal with a diverse range of microbes. Continued mapping of the complex networks of host-microbe interactions may improve our understanding of self non-self discrimination in immunity and its intervention (Fig. 1, 2).

(Fig. 1)

(Fig. 2)

The issues of why and how these innate immune receptors including Toll-like receptors (TLRs) recognize such a diverse range of microbial ligands, which are structurally and biochemically distinct, have been enigmatic, while crystal structural analyses of the ectodomains of some TLRs have revealed their shape and how they bind to their cognate ligands. As more pieces of evidence continue to accumulate, more questions are being raised, such as why and how agonists, but not antagonists, induce conformational changes of TLRs and how the LRR motifs of each TLR confer ligand-specificity and/or flexibility. Clarification of these issues will be of considerable interest, since the LRR motifs can interact with a variety of ligands such as proteins, lipids, carbohydrates and nucleic acids (Fig.3).

(Fig. 3)

 

Successful vaccines contain a component as an adjuvant that activates innate immune system, thereby eliciting antigen specific immune responses. Many of the adjuvant appeared to be a ligand for Toll-like receptors, which are thus being a promising target to develop a novel adjuvant to elicit vaccine immunogenicity. Recent evidence, however, suggests that some adjuvants do activate innate immune system in a TLR-independent manner, possibly through the other pattern recognition receptors and signaling machinery. In particular, newly identified intracellular RIG-like receptors, NOD -like receptors, or even as yet unknown recognition machinery for the adjuvant effect may regulate TLR-independent vaccine imunogenicity. Towards the optimal vaccine development, it is critical to understand how TLR-dependent and -independent innate immune activation by various adjuvants control their consequent adaptive immune responses to vaccine (Fig. 4).

(Fig. 4)

 

Our laboratory is to conduct functional and structural analysis of innate immune receptors and their interaction with the cognate ligand, which are often utilized as vaccine adjuvants. In addition, we continue to invent novel strategies and technologies to develop better and safer vaccines and their adjuvants. Our particular focus towards this goal is on elucidating the intra- and inter-cellular signaling pathways that mediate the immunogenicity of vaccines. By doing so, we hope to gain some senses not only for developing more efficient technologies for vaccines and adjuvants, but also ensuring their safety to higher level.

Principal Investigator

Ken J. Ishii Professor

Research field: Immunology, Microbiology, Vaccinology and Regulatory science
+81-6-6879-4948 (IFReC) +81-72-641-8043(NIBIOHN)
kenishii atmark biken.osaka-u.ac.jp (IFReC) kenishii atmark nibiohn.go.jp (NIBIOHN)
Education history
04/2015-present Director, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition (NBIOHN), Osaka
04/2010-present Professor, Lab. of Vaccine Science, IFReC, Osaka University
03/2003 Ph.D., Graduate School of Medicine, Yokohama City University, Kanagawa, Japan
03/1993M.D., School of Medicine, Yokohama City University, Kanagawa, Japan
Research and career history
04/2015-presentDirector, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition (NBIOHN), Osaka
04/2010-presentProfessor, Lab. of Vaccine Science, IFReC, Osaka University
04/2010-PresentProject Leader, Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO), Osaka Japan
08/2008-PresentProgram Officer, Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government
12/2007-03/2010Associate Professor: Laboratory of Host Defense, iFREC, Osaka Univ.
12/20+81-6-03/2010Associate Professor, Department of Molecular Protozoology, RIMD, Osaka Univ.
10/2003-03/2008Group Leader, Akira Innate Immunity Project, ERATO, JST, Osaka Univ.
10/1996-09/2003 Visiting Scientist and IND reviewer, Office of Vaccine Research and Review (OVRR), Cent. for Biologics and Evaluation Res. (CBER), Food and Drug Administration (FDA), MD, USA.
04/1996-10/1996Staff, Dep. of Anesthesiology, School of Medicine, YCU, Kanagawa, Japan
05/1995-03/1996 Anesthesiologist, Yokohama City Municipal Hospital, Kanagawa, Japan
04/1993-04/1995 Resident, School of Medicine, Yokohama City University (YCU), Kanagawa, Japan

Members

Etsushi Kuroda Visiting Academic Staff
kuroetu atmark ifrec.osaka-u.ac.jp
Natsuko Kishishita Research Fellow
nkishishita atmark nibiohn.go.jp
Mariko Nakamura Research Fellow
mariko06 atmark biken.osaka-u.ac.jp
Norihumi Iijima Research Fellow
iijima atmark nibiohn.go.jp
Takato K Kusakabe Research Fellow
 
Masatoshi Momota Research Fellow
 
 
 

Publications

Temizoz B, Kuroda E, Ohata K, Jonai N, Ozasa K, Kobiyama K, Aoshi T, Ishii KJ*. TLR9 and STING agonists synergistically induce innate and adaptive type II IFN. Eur J Immunol. 2015. 45(4) 1159?1169
Onishi M, Ozasa K, Kobiyama K, Ohata K, Kitano M, Taniguchi K, Homma T, Kobayashi M, Sato A, Katakai Y, Yasutomi Y, Wijaya E, Igarashi Y, Nakatsu N, Ise W, Inoue T, Yamada H, Vandenbon A, Standley DM, Kurosaki T, Coban C, Aoshi T, Kuroda E, Ishii KJ* Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen. J Immunol. 2015 194(6):2673-82.
Koo CX, Kobiyama K, Shen YJ, LeBert N, Ahmad S, Khatoo M, Aoshi T, Gasser S, Ishii KJ*. RNA Polymerase III Regulates Cytosolic RNA:DNA Hybrids and Intracellular MicroRNA Expression. J Biol Chem. 2015. 290(12):7463-73
Onishi M, Kitano M, Taniguchi K, Homma T, Kobayashi M, Sato A, Coban C, Ishii KJ* Hemozoin is a potent adjuvant for hemagglutinin split vaccine without pyrogenicity in ferrets Vaccine 2014 32(25):3004-9.
Kobiyama K, Aoshi T, Narita H, Kuroda E, Hayashi M, Tetsutani K, Koyama S, Mochizuki S, Sakurai K, Katakai Y, Yasutomi Y, Saijo S, Iwakura Y, Akira S, Coban C, Ishii KJ*. Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist. Proc Natl Acad Sci U S A. 2014 111(8):3086-91. (Direct submission)
Kobiyama K, Kawashima A, Jounai N, Takeshita F, Ishii KJ, Ito T, Suzuki K. Role of Extrachromosomal Histone H2B on Recognition of DNA Viruses and Cell Damage. Front Genet. 2013 4:91.
Tang CK, Aoshi T, Jounai N, Ito J, Ohata K, Kobiyama K, Dessailly BH, Kuroda E, Akira S, Mizuguchi K, Coban C, Ishii KJ*. The chemotherapeutic agent DMXAA as a unique IRF3-dependent type-2 vaccine adjuvant. PLoS One. 2013;8(3):e60038.
Kuroda E, Coban C, Ishii KJ* Particulate adjuvant and innate immunity:past achievements, present findings and future prospects. Int. Rev. Immunol. 2013 2013;32(2):209-20
Jounai N, Kobiyama K, Takeshita F, Ishii KJ*. Recognition of damage-associated molecular patterns related to nucleic acids during inflammation and vaccination. Front Cell Infect Microbiol. 2012 2 (168) 1-13.
Tetsutani K, Ishii KJ*. Adjuvants in influenza vaccines. Vaccine. 2012 30(52):7658-61.
Desmet CJ, Ishii KJ*. Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat Rev Immunol. 2012 12(7):479-91.
Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, Lekeux P, Coban C, Akira S, Ishii KJ*, Bureau F*, Desmet CJ*. DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med. 2011 17(8):996-1002.
Koyama S, Aoshi T, Tanimoto T, Kumagai Y, Kobiyama K, Tougan T, Sakurai K, Coban C, Horii T, Akira S*, Ishii KJ*. Plasmacytoid dendritic cells delineate immunogenicity of influenza vaccine subtypes. Sci Transl Med. 2010 2(25):25ra24.
Koyama S, Coban C, Aoshi T, Horii T, Akira S, Ishii KJ*. “Innate immune control of nucleic acid-based vaccine immunogenicity.” Expert Rev Vaccines. 2009 8(8):1099-107.
Ishii KJ*, Akira S*. “Potential link between the immune system and metabolism of nucleic acids.” Curr Opin Immunol. 2008 20(5):524-9.
Takeshita F, Ishii KJ*. “Intracellular DNA sensors in immunity.” Curr Opin Immunol. 2008 20(4):383-8
Ishii KJ*, Koyama S, Nakagawa A, Coban C, Akira S. “Host innate immune receptors and beyond: making sense of microbial infections.” Cell Host Microbe. 2008 3(6):352-63.
Coban C, Koyama S, Takeshita F, Akira S, Ishii KJ*. “Molecular and cellular mechanisms of DNA vaccines.” Hum Vaccin. 2008 4(6).
Ishii KJ*, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T, Uematsu S, Takeuchi O, Takeshita F, Coban C, Akira S*. “TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines.” Nature. 2008 451(7179):725-9.
Ishii KJ*, Akira S. “Toll or Toll-Free Adjuvant Path Toward the Optimal Vaccine Development.” J Clin Immunol. 2007 27(4):363-71.
Ishii KJ, Uematsu S, Akira S. “’Toll' gates for future immunotherapy.” Curr Pharm Des. 2006;12(32):4135-42.
Ishii KJ, Akira S. “Innate immune recognition of, and regulation by, DNA.” Trends Immunol. 2006 27(11):525-32.
Ishii KJ, Coban C, Akira S. “Manifold Mechanisms of Toll-Like Receptor-Ligand recognition.” J Clin Immunol. 2005 25(6):511-521.
Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, Ludwig H, Sutter G, Suzuki K, Hemmi H, Sato S, Yamamoto M, Uematsu S, Kawai T, Takeuchi O, Akira S. “A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA.” Nat Immunol. 2006 7(1):40-48.
Ishii KJ, Akira S.“TLR ignores methylated RNA?” Immunity. 2005 23(2):111-3.
Ishii KJ, Akira S. “Innate immune recognition of nucleic acids: Beyond toll-like receptors.” Int J Cancer. 2005 117(4):517-23.
Ishii KJ, Ito S, Tamura T, Hemmi H, Conover J, Ozato K, Akira S, Klinman DM. “CpG-activated Thy1.2(+) dendritic cells protect against lethal Listeria monocytogenes infection.” Eur J Immunol. 2005 35(8):2397-405.
Ishii KJ, Gursel I, Gursel M and Klinman DM. “ Immunotherapeutic Utility of Stimulatory and Suppressive Oligonucleotides” Curr. Opin. Mol. Ther. 6(2):166-74, 2004.
Ishii KJ*, Kawakami K, Gursel I, Klinman DM and Puri RK. “Anti-tumor therapy with bacterial DNA and toxin: Liposomal CpG ODN plus IL-13 cytotoxin induces complete regression of established human tumor in animal models.” Clinical Cancer Research. 9(17): 6516-22, 2003.
Ishii KJ, Takeshita F, Gursel I, Gursel M, Nussenzweig A and Klinman DM. "Potential Role of PI3 Kinases, rather than DNA-PK, in CpG DNA Induced Immune Activation" J. Exp. Med. Jul 15;196(2):269-74, 2002.
Ishii KJ, Suzuki K, Itoh Y, Coban C, Takeshita F, Matoba H, Kohn LD, Klinman DM. “Genomic DNA released by dying cells induces the maturation of antigen presenting cells.” J. Immunol. 167(5): 2602-2607, 2001.
Klinman DM, Verthelyi D, Takeshita F, Ishii KJ. “Immune recognition of foreign DNA.” Immunity, Vol.11, 123 129, 1999.
Ishii KJ, Weiss WR, Ichino M, Verthelyi D, Hoffman SL, Klinman DM. “Activity and Safety of DNA Plasmids Encoding IL 4 and IFN gamma.” Gene Ther. 6: (2) 237 244, 1999.
Ishii KJ, Weiss WR, Klinman DM. “Prevention of neonatal tolerance by plasmid DNA encoding GMCSF.” Vaccine, Vol.18, 703-10, 1999.

Books

Prize

2014 32th Osaka Science Prize
2014 ‘Highly cited researcher’ in Thomson Reuters THE WORLD'S MOST INFLUENTIAL SCIENTIFIC MINDS 2014
2012 Thinking inside the box award DNA vaccines
2010 Isamu Tagaya Memorial Vaccine Research Award
2008 Japanese Society of Immunology, Young Investigator Award
2007 ‘Rising star in Immunology’(Sep 2007) Thompson Reuter’s ISI