Analysis of pathomechanisms of bullous pemphigoid and development of novel therapy by using humanized active mouse model

2011 Fiscal Year Final Research Report

• Project/Area Number: 21249063
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Hokkaido University
• Principal Investigator: SHIMIZU Hiroshi 北海道大学, 大学院・医学研究科, 教授 (00146672)
• Co-Investigator(Kenkyū-buntansha): SHIBAKI Akihiko 北海道大学, 北海道大学病院, 講師 (40291231) ; AKIYAMA Masashi 名古屋大学, 大学院・医学研究科, 教授 (60222551) ; ABE Riichiro 北海道大学, 大学院・医学研究科, 准教授 (60344511) ; NISHIMURA Emi 東京医科歯科大学, 難治疾患研究所, 教授 (70396331) ; NISHIE Wataru 北海道大学, 北海道大学病院, 講師 (20443955)
• Project Period (FY): 2009 – 2011
• Keywords: 自己免疫疾患 / 水疱性類天疱瘡 / 17型コラーゲン / ヒト化マウス / 疾患モデル動物 / CHO細胞 / NOD-Scid

Research Abstract

Bullous pemphigoid (BP) is the most common autoimmune blistering disorder that preferentially occurs in elderly people. To analyze the precise pathomechanisms of BP and to develop a novel therapeutic strategy for BP, we tried to develop a novel active disease model for BP of which lymphocytes, autoantibodies and autoantigens have been humanized. First, we generated COL17-humanized/Nod-Scid mice by crossing COL17-humanized mice with immunodeficient NOD-Scid mice. Next, we developed CHO cells which persistently produce anti-human COL17 IgG4 antibodies using circulating lymphocytes from a BP patient, and injected them into COL17-humanized/Nod-Scid mice. Injected CHO cells could survive in the recipient mice for a long period and continuously produce anti-human COL17 IgG4 in vivo.

Research Products

• [Journal Article] Antibodies to pathogenic epitopes on type XVII collagen cause skin fragility in a complement-dependent and independent manner (2012)
  • Author(s): Natsuga K, Nishie W, Shinkuma S, UjiieH, Nishimura M, Sawamura D, Shimizu H
  • Journal Title: J Immunol Volume: 188 Pages: 5792-5799
  • Peer Reviewed
• [Journal Article] Noncollagenous 16A domain of type XVII collagen-reactive CD4+ T cells play a pivotal role in the development of active disease in experimental bullous pemphigoid model (2012)
  • Author(s): Ujiie H, Shibaki A, Nishie W, ShinkumaS, Moriuchi R, Qiao H, Shimizu H
  • Journal Title: Clin Immunol Volume: 142 Pages: 167-175
  • Peer Reviewed
• [Journal Article] Possible modifier effects of keratin 17 gene mutation onkeratitis-ichthyosis-deafness syndrome (2012)
  • Author(s): Natsuga K, Shinkuma S, Kanda M, SuzukiY, Chosa N, Narita Y, Setoyama M, Nishie W, Akiyama M, Shimizu H
  • Journal Title: Br J Dermatol Volume: 166 Pages: 903-905
  • Peer Reviewed
• [Journal Article] New insight into genotype/phenotype correlations in ABCA12 mutations in harlequin ichthyosis (2011)
  • Author(s): Umemoto H, Akiyama M, Yanagi T, SakaiK, Aoyama Y, Oizumi A, Suga Y, KitagawaY, Shimizu H
  • Journal Title: J Dermatol Sci Volume: 61 Pages: 136-138
  • Peer Reviewed
• [Journal Article] Hair follicle stem cells provide a functional niche for melanocyte stem cells (2011)
  • Author(s): Tanimura S, Tadokoro Y, Inomata K, Binh NT, Nishie W, Yamazaki S, NakauchiH, Tanaka Y, McMillan JR, Sawamura D, Yancey K, Shimizu H, Nishimura EK
  • Journal Title: Cell Stem Cell Volume: 8 Pages: 177-187
  • Peer Reviewed
• [Journal Article] Extremely severe palmoplantar hyperkeratosis in a generalized epidermolytic hyperkeratosis patient with a keratin 1 gene mutation (2011)
  • Author(s): Osawa R, Akiyama M, Izumi K, Ujiie H, Sakai K, Nemoto-Hasebe I, Yanagi T, Koizumi H, Shimizu H
  • Journal Title: J Am Acad Dermatol Volume: 64 Pages: 991-993
  • Peer Reviewed
• [Journal Article] Expression of exon-8-skipped kindlin-1does not compensate for defects of Kindler syndrome (2011)
  • Author(s): Natsuga K, Nishie W, Shinkuma S, Nakamura H, Matsushima Y, Tatsuta A, Komine M, Shimizu H
  • Journal Title: J Dermatol Sci Volume: 61 Pages: 38-44
  • Peer Reviewed
• [Journal Article] A founder effect of c.1938delC in ITGB4 underlies junctional epidermolysis bullosa and its application for prenatal testing (2011)
  • Author(s): Natsuga K, Nishie W, Shinkuma S, Nakamura H, Arita K, Yoneda K, Kusaka T, Yanagihara T, Kosaki R, Sago H, Akiyama M, Shimizu H
  • Journal Title: Exp Dermatol Volume: 20 Pages: 74-76
  • Peer Reviewed
• [Journal Article] Malignant skin tumours in patients with inherited ichthyosis (2011)
  • Author(s): Natsuga K, Akiyama M, Shimizu H
  • Journal Title: Br J Dermatol Volume: 165 Pages: 263-268
  • Peer Reviewed
• [Journal Article] Definitions and outcome measures for bullous pemphigoid : Recommendations by an international panel of experts (2011)
  • Author(s): Murrell DF, Daniel BS, Joly P, Borradori L, Amagai M, Hashimoto T, Caux, Marinovic B, Sinha AA, Hertl M, Bernard P, Sirois D, Cianchini G, Fairley JA, Jonkman MF, Pandya AG, Rubenstein D, Zillikens D, Payne AS, Woodley D, Zambruno G, Aoki V, Pincelli C, Diaz L, Hall RP, Meurer M, Mascaro JM, Jr., Schmidt E, Shimizu H, Zone J, Swerlick R, Mimouni D, Culton D, Lipozencic J, Bince B, Bystryn JC, Werth VP
  • Journal Title: J AmAcad Dermatol
  • Peer Reviewed
• [Journal Article] Childhood subepidermal blistering disease with autoantibodies to type VII collagen and laminin-332 (2011)
  • Author(s): Lin HY, Yanagi T, Akiyama M, IitaniMM, Moriuchi R, Natsuga K, Shinkuma S, Yamane N, Inokuma D, Arita K, Shimizu H
  • Journal Title: Br J Dermatol Volume: 164 Pages: 452-454
  • Peer Reviewed
• [Journal Article] Type XVII collagen ELISA indices significantly decreased after Bullous pemphigoid remission (2011)
  • Author(s): Kusajima E, Akiyama M, Sato M, Natsuga K, Shimizu H
  • Journal Title: Int J Dermatol Volume: 50 Pages: 238-240
  • Peer Reviewed
• [Journal Article] Subepidermal blistering disease with 3 distinct autoantibodies : Anti-BP230, anti-laminin gamma-1, and anti-laminin-332 (2011)
  • Author(s): Kikuchi K, Natsuga K, Shinkuma S, Nishie W, Kajita S, Sato H, Shimizu H
  • Journal Title: J Am Acad Dermatol Volume: 65 Pages: 878-880
  • Peer Reviewed
• [Journal Article] Rapid immunochromatographic test for serum granulysin is useful for the prediction of Stevens-Johnson syndrome and toxic epidermal necrolysis (2011)
  • Author(s): Fujita Y, Yoshioka N, Abe R, MurataJ, Hoshina D, Mae H, Shimizu H
  • Journal Title: J AmAcad Dermatol Volume: 65 Pages: 65-68
  • Peer Reviewed
• [Journal Article] Human IgG1 monoclonal antibody against human collagen 17 noncollagenous 16A domain induces blisters via complement activation in experimental bullous pemphigoid model (2011)
  • Author(s): Li Q, Ujiie H, Shibaki A, Wang G, Moriuchi R, Qiao HJ, Morioka H, ShinkumaS, Natsuga K, Long HA, Nishie W, ShimizuH
  • Journal Title: J Immunol Volume: 185 Pages: 7746-7755
  • Peer Reviewed
• [Journal Article] A novel active mouse model for Bullous pemphigoid targeting humanized pathogenic antigen (2010)
  • Author(s): Ujiie H, Shibaki A, Nishie W, Sawamura D, Wang G, Tateishi Y, Li Q, Moriuchi R, Qiao H, Nakamura H, AkiyamaM, Shimizu H
  • Journal Title: J Immunol Volume: 184 Pages: 2166-6174
  • Peer Reviewed
• [Presentation] Therapeutic Strategies For TargetingAutoreactive T Cells In Autoimmune Bullous Diseases (2011)
  • Author(s): Ujiie H, Shibaki A, Moriuchi R, Shimizu H
  • Organizer: 22nd World Congress of Dermatology
  • Place of Presentation: Soul, Korea
  • Year and Date: 20110524-29
• [Presentation] Novel Mouse Models of Human Skin Diseases (2011)
  • Author(s): Ujiie H, Nishie W, Fujita Y, ShibakiA, Shimizu H
  • Organizer: 22nd World Congress of Dermatology
  • Place of Presentation: Soul, Korea
  • Year and Date: 20110524-29
• [Presentation] Active Mouse Model for BullousPemphigoid (2010)
  • Author(s): Shimizu H
  • Organizer: The 7^<th> Annual Scientific Meeting Australasian Society for Dermatology Research
  • Place of Presentation: Australia
  • Year and Date: 20100619-20