Development of therapy for allergy and immunological disorders using newly found interleukin-18 inhibitors

• Project/Area Number: 22591156
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Gifu University
• Principal Investigator: KATO Zenichiro 岐阜大学, 医学部附属病院, 准教授 (90303502)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 立体構造 / IL-18 / 創薬 / HLA / 構造生物学 / サイトカイン / IL18 / 低分子 / 薬剤

Research Abstract

Structural determination of the complex between interleukin-18 ligand and the receptor was successfully performed. The structural basis of the receptor activation was analyzed and the screening system using a virtual ligand screening method with the determined structure was established. Using the newly found inhibitors, analyses of cellular functions, protein-protein interactions, and immunological cell reactions were performed and the molecular mechanism was determined. The obtained candidate molecules were assayed by high-through-put system for interaction analysis.

Research Products

• [Journal Article] In Vitro Analysis of the Functional Effects of an NLRP3 G809S Variant with the co-Existence of MEFV Haplotype Variants in Atypical Autoinflammatory (2013)
  • Author(s): Kubota K, Ohnishi H, Teramoto T, Matsui E, Murase K, Kanoh H, Kato Z, Kaneko H, Seishima M, Kondo N
  • Journal Title: Syndrome J Clin Immunol Volume: 33 Pages: 325-34
  • Peer Reviewed
• [Journal Article] In Vitro Analysis of the Functional Effects of an NLRP3 G809S Variant with the co-Existence of MEFV Haplotype Variants in Atypical Autoinflammatory Syndrome (2013)
  • Author(s): Kubota K, Ohnishi H, Teramoto T, Matsui E, Murase K, Kanoh H, Kato Z, Kaneko H, Seishima M, Kondo N
  • Journal Title: J Clin Immunol Volume: 33 Issue: 2 Pages: 325-34
  • DOI: 10.1007/s10875-012-9805-x
  • Peer Reviewed
• [Journal Article] Molecular analysis of the binding mode of Toll/interleukin-1 receptor (TIR) domain proteins during TLR2 signaling (2012)
  • Author(s): Nada M, Ohnishi H, Tochio H, Kato Z, Kimura T, Kubota K, Yamamoto T, Kamatari YO, Tsutsumi N, Shirakawa M, Kondo N
  • Journal Title: Mol Immunol Volume: 52 Pages: 108-116
  • Peer Reviewed
• [Journal Article] Characterization of NLRP3 variants in Japanese cryopyrin-associated periodic syndrome patients (2012)
  • Author(s): Ohnishi H, Teramoto T, Iwata H, Kato ZKimura T, Kubota K, Nishikomori R, Kaneko H, Seishima M, Kondo N
  • Journal Title: J Clin Immunol Volume: 32 Pages: 221-229
  • Peer Reviewed
• [Journal Article] TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88 (2012)
  • Author(s): Ohnishi H, Tochio H, Kato Z, Kawamoto N, Kimura T, Kubota K, Yamamoto T, Funasaka T, Nakano H, Wong RW, Shirakawa M, Kondo N
  • Journal Title: PLoS One Volume: 7
  • NAID: 120005540726
  • Peer Reviewed
• [Journal Article] A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome. (2012)
  • Author(s): Ohnishi H, Miyata R, Suzuki T, Nose T, Kubota K, Kato Z, Kaneko H, Kondo N
  • Journal Title: J Allergy Clin Immunol Volume: 129 Pages: 578-80
  • Peer Reviewed
• [Journal Article] Sweet's syndrome in a neonate having non-B54 types of HLA (2012)
  • Author(s): Omoya K, Naiki Y, Kato Z, Yoshioka S, Uchida Y, Taga T, Aoki Y, Deguchi H, Kondo N
  • Journal Title: World J Pediatr Volume: 8 Pages: 181-184
  • Peer Reviewed
• [Journal Article] Characterization of NLRP3 variants in Japanese cryopyrin-associated periodic syndrome patients (2012)
  • Author(s): Ohnishi, H., T. Teramoto, H. Iwata, Z. Kato, T. Kimura, K. Kubota, R. Nishikomori, H. Kaneko, M. Seishima, and N. Kondo
  • Journal Title: J Clin Immunol Volume: 32 Issue: 2 Pages: 221-9
  • DOI: 10.1007/s10875-011-9629-0
  • Peer Reviewed
• [Journal Article] TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88. (2012)
  • Author(s): Ohnishi H, Tochio H, Kato Z, Kawamoto N, Kimura T, Kubota K, Yamamoto T, Funasaka T, Nakano H, Wong RW, Shirakawa M, Kondo N.
  • Journal Title: PLoS One. Volume: 7 Issue: 6 Pages: e38423-e38423
  • DOI: 10.1371/journal.pone.0038423
  • NAID: 120005540726
  • Peer Reviewed
• [Journal Article] Structural property of soybean protein P34 and specific IgE response to recombinant P34 in patients with soybean allergy (2012)
  • Author(s): Morita H, Kaneko H, Ohnishi H, Kato Z, Kubota K, Yamamoto T, Matsui E, Teramoto T, Fukao T, Kasahara K, Kondo N
  • Journal Title: Int J Mol Med Volume: 29 Pages: 153-8
  • DOI: 10.3892/ijmm.2011.841
  • Peer Reviewed
• [Journal Article] A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome (2012)
  • Author(s): Ohnishi H, Miyata R, Suzuki T, Nose T, Kubota K, Kato Z, Kaneko H, Kondo N
  • Journal Title: J Allergy Clin Immunol Volume: 129 Pages: 578-80
  • Peer Reviewed
• [Journal Article] Refractory Chronic Pleurisy Caused by Helicobacter equorum-like bacterium in a Patient with X-linked Agammaglobulinemia (2011)
  • Author(s): Funato M, Kaneko H, Ohkusu K, Sasai H, Kubota K, Ohnishi H, Kato Z, Fukao T, Kondo N
  • Journal Title: J Clin Microbiol Volume: 49 Pages: 3432-3435
  • Peer Reviewed
• [Journal Article] ADA-SCID with 'WAZA-ARI' mutations that synergistically abolished ADA protein stability (2011)
  • Author(s): Okura Y, Yamada M, Kobayashi I, Santisteban I, Arredondo-Santisteban G, Kato Z, Iguchi A, Yoshida M, Ohara O, Nakagawa N, Imai K, Hershfield MS, Ariga T
  • Journal Title: Brit J Haematol Volume: 153 Pages: 675-676
  • Peer Reviewed
• [Journal Article] Antigen-specific immune response to endotoxin-free recombinant P34 (2011)
  • Author(s): Morita H, Kaneko H, Ohnishi H, Kato Z, Kondo N
  • Journal Title: Allergy Volume: 66 Pages: 985-986
  • Peer Reviewed
• [Journal Article] Genetic variations in MyD88 adaptor-like are associated with atopic dermatitis (2011)
  • Author(s): An Y, Ohnishi H, Matsui E, Funato M, Kato Z, Teramoto T, Kaneko H, Kimura T, Kubota K, Kasahara K,Kondo N
  • Journal Title: Int J Mol Med Volume: 27 Pages: 795-801
  • NAID: 120006341946
  • Peer Reviewed
• [Journal Article] Adenovirus infection mimics the cerebellitis caused by rotavirus infection (2011)
  • Author(s): Kato Z, Manabe T, Teramoto T, Kondo N
  • Journal Title: Eur J Pediatr Volume: 170 Pages: 405-406
  • Peer Reviewed
• [Journal Article] ADA-SCID with 'WAZA-ARI' mutations that synergistically abolished ADA protein stability (2011)
  • Author(s): Okura Y, Yamada M, Kobayashi I, Santisteban I, Arredondo-Santisteban G, Kato Z, Iguchi A, Yoshida M, Ohara O, Nakagawa N, Imai K, Hershfield MS, Ariga T
  • Journal Title: Br J Haematol Volume: 153(5) Issue: 5 Pages: 675-6
  • DOI: 10.1111/j.1365-2141.2011.08640.x
  • Peer Reviewed
• [Journal Article] Clinical and radiological features of rotavirus cerebellitis (2010)
  • Author(s): Takanashi J, Miyamoto T, Ando N, Kubota T, Oka M, Kato Z, Hamano S, Hirabayashi S, Kikuchi M, Barkovich AJ
  • Journal Title: AJNR Am J Neuroradiol Volume: 31 Pages: 1591-1595
  • Peer Reviewed
• [Journal Article] Shirakawa M. 1H, 13C, and 15N resonance assignment of the TIR domain of human MyD88 (2010)
  • Author(s): OhnishiH, Tochio H, Kato Z, Kimura T, Hiroaki H, Kondo N
  • Journal Title: Biomol NMR Assign Volume: 4 Pages: 123-128
  • Peer Reviewed
• [Journal Article] Promoting tolerance to proteolipid protein-induced experimental autoimmune encephalomyelitis through targeting dendritic cells. (2010)
  • Author(s): Stern JN, Keskin DB, Kato Z, Waldner H, Schallenberg S, Anderson A, von BoehmerH, Kretschmer K, Strominger JL
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Pages: 17280-17285
  • Peer Reviewed
• [Journal Article] The autoimmune TCR-Ob. 2F3 can bind to MBP85-99/HLA-DR2 having an unconventional mode as in TCR-Ob.1A12 (2010)
  • Author(s): Kato Z, Stern JN, Nakamura HK, Miyashita N, Kuwata K, Kondo N
  • Journal Title: Mol Immunol Volume: 48 Pages: 314-320
  • Peer Reviewed
• [Journal Article] The autoimmune TCR-Ob.2F3 can bind to MBP85-99/HLA-DR2 having an unconventional mode as in TCR-Ob.1A12. (2010)
  • Author(s): Kato Z, Stern JN, Nakamura HK, Miyashita N, Kuwata K, Kondo N, Strominger JL.
  • Journal Title: Mol Immunol. Volume: 48 Pages: 314-320
  • Peer Reviewed
• [Journal Article] Promoting tolerance to proteolipid protein-induced experimental autoimmune encephalomyelitis through targeting dendritic cells. (2010)
  • Author(s): Stern JN, Keskin DB, Kato Z, Waldner H, Schallenberg S, Anderson A, von Boehmer H, Kretschmer K, Strominger JL.
  • Journal Title: Proc Natl Acad Sci USA. Volume: 107 Pages: 17280-17285
  • Peer Reviewed
• [Journal Article] 1H, 13C, and 15N resonance assignment of the TIR domain of human MyD88 (2010)
  • Author(s): Ohnishi H, Tochio H, Kato Z, Kimura T, Hiroaki H, Kondo N, Shirakawa M.
  • Journal Title: Biomol NMR Assign. Volume: 4 Pages: 123-125
  • NAID: 120002709551
  • Peer Reviewed
• [Presentation] 大豆主要アレルゲンRecombinant P34を用いた免疫学的手法の臨床応用 (2011)
  • Author(s): 森田秀行, 金子英雄, 大西秀典, 加藤善一郎, 近藤直実
  • Organizer: 日本アレルギー学会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-10
• [Presentation] Proteomics analysis for genetic polymorphisms associated with allergy.Joint Congress of Asia Pacific Association of Pediatric Allergy (2011)
  • Author(s): Kato Z
  • Organizer: Respirology and Immunology 2011 and 48th Annual Meeting of Japanese Society of Pediatric Allergy and Clinical Immunology
  • Place of Presentation: Fukuoka, Japan
• [Presentation] Symposium:Prevention for onset and exacerbation of bronchial asthma on the basis of tailor-made prediction. (2011)
  • Author(s): Matsui E, Kimata K, Ohnishi H, Kato Z, Teramoto T, Kaneko H, Fukao T, Kondo N
  • Organizer: The 21th congress of Interasma Japan/North Asia
  • Place of Presentation: Gifu,Japan
• [Presentation] Development of enzymatically digested peptides for immunomodulation therapy in patients with cow's milk allergy (2011)
  • Author(s): Kaneko H,Ohnishi H,Morita H,Yamamoto T,Kubota K,Teramoto T,Kato Z,Matsui E,Kato H,Nakano T,Kondo N
  • Organizer: Joint Congress of Asia Pacific Association of Pediatric Allergy,Respirology and Immunology 2011 and 48th Annual Meeting of Japanese Society of Pediatric Allergy and Clinical Immunology.
  • Place of Presentation: Fukuoka, Japan
• [Presentation] In vitro analysis of a case of chronic mucocutaneous candidiasis combined with atrophic thyroiditis and autoimmune hepatitis.Joint Congress of Asia Pacific Association of Pediatric Allergy (2011)
  • Author(s): Hori T,Ohnishi H,Tsubouchi K,Kubota K,Teramoto T,Kato Z,Hirose Y,Kaneko H,Fukao T,Ohara O,Seishima M,Kondo N
  • Organizer: Respirology and Immunology 2011 and 48th Annual Meeting of Japanese Society of Pediatric Allergy and Clinical Immunology.
  • Place of Presentation: Fukuoka, Japan
• [Presentation] A case report of an infant with Haemophilus influenzae meningitis with severe eczema,high serum IgE,and hypoproteinemia.Joint Congress of Asia Pacific Association of Pediatric Allergy (2011)
  • Author(s): Yamamoto T,Teramoto T,Ohnishi H,Kuwabara H,Usui S,Morita H,Kato Z,Kaneko H,Ohara O,Kondo N
  • Organizer: Respirology and Immunology 2011 and 48th Annual Meeting of Japanese Society of Pediatric Allergy and Clinical Immunology
  • Place of Presentation: Fukuoka, Japan
• [Presentation] Gene-environment illteractionの解明はどこまで進展したかGene-Environment interactionの分子基盤 (2010)
  • Author(s): 加藤善一郎, 大西秀典, 木村豪, 久保田一生, 安陽, 松井永子, 近藤直実
  • Organizer: 第60回日本アレルギー学会
  • Place of Presentation: 東京
  • Year and Date: 2010-11-25
• [Presentation] Symposium: Structural basis for the innate immune deficiency syndrome (2010)
  • Author(s): Ohnishi H, Tochio H, Kato Z, Kimura T, Nada M, Kubota K, Shirakawa M, Kondo N
  • Organizer: The 8th Asia Pacific Congress of Allergy, Asthma and Clinical Immunology.
  • Place of Presentation: Singapore
• [Presentation] Expression and purification of recombinant soybean protein P34 and its clinical application (2010)
  • Author(s): Kaneko H, Morita H, Ohnishi H, Kato Z, Matsui E, Kondo N
  • Organizer: The 8th Asia Pacific Congress of Allergy, Asthma and Clinical Immunology
  • Place of Presentation: Singapore
• [Presentation] The gene polymorphisms of MyD88 adaptor like protein (Mal) are associated with susceptibility to allergic diseases in Japanese children (2010)
  • Author(s): Ohnishi H,An Y,Matsui E,Kato Z,Kaneko H,Kondo N
  • Organizer: The 20th congress of Interasma Japan/North Asia
  • Place of Presentation: Tokyo, Japan
• [Presentation] Structural basis for the interactions of the MyD88 TIR domain in TLR4 signaling (2010)
  • Author(s): Ohnishi H, Tochio H, Kato Z, Kimura T, Kondo N, Shirakawa M
  • Organizer: World wide magnetic resonance conference
  • Place of Presentation: Firenze, Italy
• [Presentation] A conserved interaction mode between MyD88 and distinct membranesorting adaptors in TLR4 and IL-18 signaling (2010)
  • Author(s): Ohnishi H, Tochio H, Kato Z, Kimura T, Funasaka T, Wong R.W, Shirakawa M, Kondo N
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] Expression, purification and structural analysis of human IL-18 binding protein: A potent therapeutic molecule for allergy (2010)
  • Author(s): Kimura T, Kato Z, Ohnishi H, ,Tochio H, Shirakawa M, Kondo N
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] The LPS induced enhancement of IL-1 βand IL-18 production is a useful tool for diagnosis of familial cold inflammatory syndrome (FCAS) (2010)
  • Author(s): Ohnishi H, Teramoto T, Kato Z, Kaneko H, Nishikomori R, Kondo N
  • Organizer: Autoinflammation. Amsterdam
  • Place of Presentation: Netherlands
• [Presentation] A case report of atypical mild chronic infantile neurological cutanenus and articular syndrome showing the phenotype of mixed connective tissue disease (2010)
  • Author(s): Teramoto T, Ohnishi H, Kawamoto N, Kato Z, Kaneko H, Kondo N
  • Organizer: Autoinflammation.
  • Place of Presentation: Amsterdam, Netherlands
• [Book] アレルギー疾患の免疫療法と分子標的療法 分子標的治療とその機序 (2012)
  • Author(s): 加藤善一郎,大西秀典,近藤直実
  • Publisher: 診断と治療社
• [Book] 自己炎症性疾患・自然免疫不全症とその近縁疾患 自己炎症性疾患 総論 (2012)
  • Author(s): 加藤善一郎,大西秀典,近藤直実
  • Publisher: 診断と治療社
• [Book] 自己炎症性疾患・自然免疫不全症とその近縁疾患 ヒトパピローマウイルス易感染症 (2012)
  • Author(s): 加藤善一郎,大西秀典,近藤直実
  • Publisher: 診断と治療社
• [Book] 自己炎症性疾患・自然免疫不全症とその近縁疾患 自己炎症性疾患 総論 (2012)
  • Author(s): 加藤善一郎，大西秀典，近藤直実
  • Publisher: 診断と治療社
• [Book] 自己炎症性疾患・自然免疫不全症とその近縁疾患 ヒトパピローマウイルス易感染症 (2012)
  • Author(s): 加藤善一郎，大西秀典，近藤直実
  • Publisher: 診断と治療社
• [Book] アレルギー疾患の免疫療法と分子標的療法 分子標的治療とその機序 (2012)
  • Author(s): 加藤善一郎、近藤直実
  • Publisher: 診断と治療社
• [Patent(Industrial Property Rights)] IL-18阻害薬剤 (2010)
  • Inventor(s): 加藤善一郎, ほか
  • Industrial Property Rights Holder: 岐阜大学
  • Filing Date: 2010-05-25