2001 Fiscal Year Annual Research Report

樹状細胞へのex vivo遺伝子導入による炎症性腸疾患の治療法開発

Research Project

Project/Area Number	13470124
Research Institution	Research Institute, International Medical Center of Japan
Principal Investigator	土肥多惠子国立国際医療センター, 研究所・消化器疾患研究部, 部長 (60250221)
Co-Investigator(Kenkyū-buntansha)	松島綱治東京大学, 大学院・医学系研究科・分子予防医学教室, 教授 (50222427) 切替照雄国立国際医療センター, 熱帯感染症研究部, 部長 (50192563)
Keywords	潰瘍性大腸炎 / 樹状細胞 / パイエル板 / サイトカイン / ケモカイン / 常在細菌叢 / リポポリサッカライド / 炎症性腸疾患
Research Abstract	1.潰瘍性大腸炎マウスモデルにおけるパイエル板の役割:Th2型腸炎(潰瘍性大腸炎型の腸炎モデル)は,可溶性リンホトキシン受容体投与により,治療可能であることが明らかになった.炎症の軽症化に先立って,パイエル板内の細胞数の顕著な減少が起こったが,特に,subepithelial domeの樹状細胞,ろ胞内活性化樹状細胞の脱落が認められた.無治療のマウス腸炎においては炎症の誘導から7日目をピークとして末梢血中に樹状細胞が増加し,パイエル板に樹状細胞の組織内への遊走・浸潤を促すケモカインの発現が見られた.よって,腸炎の遷延化には樹状細胞のリクルートメントが重要であることが明らかになった. 2.経口免疫寛容におけるパイエル板の役割:パイエル板欠損マウスを用いた実験により,低分子抗原に対する経口免疫寛容はパイエル板構造を必要としないが,蛋白抗原に対する経口免疫寛容を誘導するにはパイエル板構造が必須であることが明らかになった. 3.ヒト消化管における常在細菌に対する免疫寛容:常在菌(Bacteroides vulgatus)由来リポポリサッカライド(LPS)を精製抽出し,これに対する健常人(癌手術例の健常部)の大腸粘膜固有層より調整した単核細胞の応答を解析した所,ヒト大腸単核細胞は常在及び病原性グラム陰性桿菌由来LPSによる刺激に対し,TNFαをほとんど産生せず,IL-10を産生することが明らかになった.ヒト大腸単核細胞のかなりの部分は大腸粘膜固有層から粘膜下層にまたがって多数存在する,リンパろ胞(大腸パイエル板)に由来すると考えられる.このような大腸免疫担当細胞の特徴が,腸内常在菌に対する積極的な免疫抑制機構を担っていると考えられる.

Research Products

(15 results)

All Other

All Publications (15 results)

[Publications] Taeko Dohi: "Elimination of colonic patches with lymphotoxin B receptor-Ig prevents Th2 cell-type colitis"J.Immunol.. 167. 2781-2790 (2001)
[Publications] Kohtaro Fujihashi: "Peyer's patches are required for oral tolerance to proteins"Proc.Natl.Acad.Sci.U.S.A.. 98. 3310-3315 (2001)
[Publications] Masahito Hashimoto: "Structural elucidation of capsular polysaccharide from a clinical isolate of Bacteroides vulgatus from a patient with Crohn's disease"Eur.J.Biochem.. 268. 1-7 (2001)
[Publications] Masahito Hashimoto: "Protective effect of OK-432 on mice against endotoxemia and infection with Pseudomonas aeruginosa and Salmonellaenteritidis"Microbiol.Immunol.. 45. 425-432 (2001)
[Publications] Fukase, K: "Synthesis of [3H]-labeled bioactive lipid A analogs and their use for detection of lipid A-binding proteins on murine macrophages"Bull.Chem.Soc.Jpn.. 74. 2189-2197 (2001)
[Publications] Watando, A.: "Pulmonary Mycobacterium avium infection in an immunocompetent young adult related to use of home bath with a circulating water system"Jpn.J.Infect.Dis.. 54. 151-152 (2001)
[Publications] Matsuyama, N: "Non-standard biological activities of LPS from Helicobacter pylori"J.Med.Microbiol.. 50. 865-869 (2001)
[Publications] Kaneko, A: "Molecular heterogeneity of heat-stable toxin-producing and non-producing Escherichia coli O25 isolated in Japan"Microbial.Immunol.. 45. 433-438 (2001)
[Publications] Takai, S.: "Identification of virulence-associated antigens and plasmids in Rhodococcusequi from AIDS patients and prevalence of virulent R. equi in soil collectedfrom domestic animal farms in Chiang Mai"Am.J.Trap.Med.Hyg.. (in press). (2002)
[Publications] Nagai, S.: "Comprehensive gene expression profile of human activated T(h)1-and T(h)2-polarized cells"Int Immunol. 13. 367-376 (2001)
[Publications] Itakura, M.: "Blockade of secondary lymphoid tissue chemokine exacerbates Propionibacterium acnes-induced acute lung inflammation"J Immunol. 166. 2071-2079 (2001)
[Publications] Kawasaki, S.: "Intervention of thymus and activation-regulated chemokine attenuates the development of allergic airway inflammation and hvperresvonsiveness in mice"J Immunol. 166. 2055-2062 (2001)
[Publications] Yoneyama, H.: "Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease."J Exp Med. 193. 35-49 (2001)
[Publications] Ishikawa, S.: "Aberrant high expression of B lymphocyte chemokine (BLC/CXCL13) by C11b+CD11c+ dendritic cells in murine lupus and preferential chemotaxis of B1 cells towards BLC"J.Exp.Med. 193. 1393-1402 (2001)
[Publications] Takeko Dohi: "Trends in Gastroenterology and Hepatology : Millennium 2000, Essential roles for Th2-type responses in chronic intestinal inflammation"Springer-Verlag. 193-196 (2001)

2001 Fiscal Year Annual Research Report

樹状細胞へのex vivo遺伝子導入による炎症性腸疾患の治療法開発

Principal Investigator

土肥 多惠子 国立国際医療センター, 研究所・消化器疾患研究部, 部長 (60250221)

Research Products

[Publications] Taeko Dohi: "Elimination of colonic patches with lymphotoxin B receptor-Ig prevents Th2 cell-type colitis"J.Immunol.. 167. 2781-2790 (2001)

[Publications] Kohtaro Fujihashi: "Peyer's patches are required for oral tolerance to proteins"Proc.Natl.Acad.Sci.U.S.A.. 98. 3310-3315 (2001)

[Publications] Masahito Hashimoto: "Structural elucidation of capsular polysaccharide from a clinical isolate of Bacteroides vulgatus from a patient with Crohn's disease"Eur.J.Biochem.. 268. 1-7 (2001)

[Publications] Masahito Hashimoto: "Protective effect of OK-432 on mice against endotoxemia and infection with Pseudomonas aeruginosa and Salmonellaenteritidis"Microbiol.Immunol.. 45. 425-432 (2001)

[Publications] Fukase, K: "Synthesis of [3H]-labeled bioactive lipid A analogs and their use for detection of lipid A-binding proteins on murine macrophages"Bull.Chem.Soc.Jpn.. 74. 2189-2197 (2001)

[Publications] Watando, A.: "Pulmonary Mycobacterium avium infection in an immunocompetent young adult related to use of home bath with a circulating water system"Jpn.J.Infect.Dis.. 54. 151-152 (2001)

[Publications] Matsuyama, N: "Non-standard biological activities of LPS from Helicobacter pylori"J.Med.Microbiol.. 50. 865-869 (2001)

[Publications] Kaneko, A: "Molecular heterogeneity of heat-stable toxin-producing and non-producing Escherichia coli O25 isolated in Japan"Microbial.Immunol.. 45. 433-438 (2001)

[Publications] Takai, S.: "Identification of virulence-associated antigens and plasmids in Rhodococcusequi from AIDS patients and prevalence of virulent R. equi in soil collectedfrom domestic animal farms in Chiang Mai"Am.J.Trap.Med.Hyg.. (in press). (2002)

[Publications] Nagai, S.: "Comprehensive gene expression profile of human activated T(h)1-and T(h)2-polarized cells"Int Immunol. 13. 367-376 (2001)

[Publications] Itakura, M.: "Blockade of secondary lymphoid tissue chemokine exacerbates Propionibacterium acnes-induced acute lung inflammation"J Immunol. 166. 2071-2079 (2001)

[Publications] Kawasaki, S.: "Intervention of thymus and activation-regulated chemokine attenuates the development of allergic airway inflammation and hvperresvonsiveness in mice"J Immunol. 166. 2055-2062 (2001)

[Publications] Yoneyama, H.: "Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease."J Exp Med. 193. 35-49 (2001)

[Publications] Ishikawa, S.: "Aberrant high expression of B lymphocyte chemokine (BLC/CXCL13) by C11b+CD11c+ dendritic cells in murine lupus and preferential chemotaxis of B1 cells towards BLC"J.Exp.Med. 193. 1393-1402 (2001)

[Publications] Takeko Dohi: "Trends in Gastroenterology and Hepatology : Millennium 2000, Essential roles for Th2-type responses in chronic intestinal inflammation"Springer-Verlag. 193-196 (2001)

土肥多惠子国立国際医療センター, 研究所・消化器疾患研究部, 部長 (60250221)