Physiological importance of heme oxygenase-1 on hemopoiesis, inflammation and immunology system

• Project/Area Number: 20591275
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kanazawa University
• Principal Investigator: KOIZUMI Shoichi Kanazawa University, 子どものこころの発達研究センター, 特任教授 (50019973)
• Co-Investigator(Renkei-kenkyūsha): YACHIE Akihiro 金沢大学, 医学系, 教授 (40210281) ; WADA Tatzou 金沢大学, 医学系, 講師 (30313646) ; NISHIMURA Ryousei 金沢大学, 医学系, 講師 (50324116) ; SUGIMOTO Naotoshi 金沢大学, 医学系, 准教授 (80272954) ; OHTA Kunio 金沢大学, 医学系, 准教授 (00303280) ; NIIDA Yo 金沢大学, 子どものこころの発達研究センター, 特任准教授 (40293344) ; SAIKAWA Yutaka 金沢大学, 医学系, 教授 (60283107)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ヘムオキシゲナーゼ / 炎症 / 血管炎 / 内皮細胞 / ヘモグロビン / 骨髄移植 / 乳児白血病 / GVHD / 腎尿細管

Research Abstract

Heme oxygenase-1(HO-1) is the rate-limiting enzyme that adds an oxygen molecule to the porphyrin ring of heme, thereby catalyzing to biliverdin, free iron (finally to bilirubin and ferritin, respectively) and carbon monoxide. In 1999, the first case of human HO-1 deficiency was reported by Yachie et al. at our Department of Pediatrics, Kanazawa University Hospital The male patient suffered from generalized severe inflammation since the age of 2, and died at 6 years of age. Quite recently the 2nd case was discovered and reported. Aggressive clinical and patho-physiological studies about these two cases and some experimental investigations have shown detailed clinical findings of HO-1 deficiency and revealed that the HO-1 enzyme is crucial for development and growth of human beings on hematopoiesis, immunological system and the defense mechanism against inflammation and oxidative stresses.

Research Products

• [Journal Article] Human heme oxygenase (HO)-1 deficiency presenting with hemolysis, nephritisand asplenia. (2011)
  • Author(s): Nita Radhakrishnan, Satya Prakash Yadav, Anuppam Sachdeva, Praveen K Pruthi, Sujata Sawhney, Tarun Piplani, Taizo Wada, Akihiro Yachie
  • Journal Title: J Pediatr Hematol Oncol 33(1) Pages: 74-81
  • Peer Reviewed
• [Journal Article] Human heme oxygenase(HO)-1 deficiency presenting with hemolysis, nephritis and asplenia. (2011)
  • Author(s): Nita Radhakrishnan, S Prakash Yadav, Taizo Wada, Akihiro Yachie
  • Journal Title: J Pediatr Hematol Oncol Volume: 33 Pages: 74-81
  • Peer Reviewed
• [Journal Article] Activation of tumor suppressor protein PTEN and induction ofapoptosis are involved incAMP-mediated inhibition ofcell number in B92 glial cells. (2011)
  • Author(s): Naotoshi Sugimoto, Shinji Miwa, Takako Ohno-Shosaku, Hiroyuki Tsuchiya, Yoshiaki Hitomi, HiroyukiNakamura, Katsuro Tomita, Akihiro Yachie, Shoichi Koizumi
  • Journal Title: Neuroscience Volume: in press
  • Peer Reviewed
• [Journal Article] Dense methylation of type1 and type2 regulatory regions of the CD10 gene promoter in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene. (2010)
  • Author(s): Ikawa Y, Sugimoto N, Koizumi S, Yachie A, Saikawa Y.
  • Journal Title: J Pediatric Hematology Oncology 32(1) Pages: 4-10
  • Peer Reviewed
• [Journal Article] Long-term results of Japanese Childhood Cancer and Leukemia Study Group studies 811, 841, 874 and 911 on childhood acute lymphoblastic leukemia. (2010)
  • Author(s): Tsurusawa M, Shimomura Y, Asami K, Kikuta A, Watanabe A, Horikoshi Y, Matsushita T, Kanegane H, Ohta S, Iwai A, Mugishima H, Koizumi S.
  • Journal Title: Leukemia 24 Pages: 335-344
  • Peer Reviewed
• [Journal Article] Dense methylation of type 1 and type 2 regulatory regions of the CD10 gene promoter in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene. (2010)
  • Author(s): Ikawa Y, Sugimoto N, Koizumi S, Yachie A, Saikawa Y.
  • Journal Title: J Pediatric Hematology Oncology Volume: 32 Pages: 4-10
  • Peer Reviewed
• [Journal Article] Long-term results of Japanese Childhood Cancer and Leukemia Study Group studies 811, 841, 874and 911 on childhood acute lymphoblastic leukemia. (2010)
  • Author(s): Tsurusawa M, Shimomura Y, KikutaA, Watanabe A, Koizumi S.
  • Journal Title: Leukemia Pages: 335-344
  • Peer Reviewed
• [Journal Article] Accelerated production ofmultiple cytokines and chemokines by Epstein-Barrvirus-infected natural killer cells and T cells. (2010)
  • Author(s): Mika Inoue, Yoshihito Kasahara, Michiko Okajima, Taizo Wada, Tomoko Toma, Masaki Shimizu, Shoichi Koizumi, Akihiro Yachie
  • Journal Title: J Juzen Medical Society Volume: 119 Pages: 154-163
  • Peer Reviewed
• [Journal Article] PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts. (2009)
  • Author(s): Hikata T, Takaishi H, Takito J, Hakozaki A, Furukawa M, Uchikawa S, Kimura T, Okada Y, Matsumoto M, Yoshimura A, Nishimura R, Reddy SV, Asahara H, Toyama Y.
  • Journal Title: Blood 113(10) Pages: 2202-2212
  • Peer Reviewed
• [Journal Article] Strong Inhibition of Alloreaction by Newly Generated Tolerogenic Dendritic Cells by Psoralen Plus UVA Treatment (2009)
  • Author(s): Maeba H, Nishimura R, Kuroda R, Araki R, Mase S, Ikawa Y, Yachie A, Koizumi S.
  • Journal Title: Blood (ASH Annual Meeting Abstracts) 114 Pages: 3686-3686
  • Peer Reviewed
• [Journal Article] Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome. (2008)
  • Author(s): Wada T, Yasui M, Toma T, Nakayama Y, Nishida M, Shimizu M, Okajima M, Kasahara Y, Koizumi S, Inoue M, Kawa K, Yachie A.
  • Journal Title: Blood 112(5) Pages: 1872-1875
  • Peer Reviewed
• [Journal Article] Lead-pipe colon revisited in chronic graft-versus-host disease. (2008)
  • Author(s): Saikawa Y, Ikawa Y, Kagaya T, Koizumi S.
  • Journal Title: J Pediatr Gastroenterol Nutr 46(5) Pages: 483-483
  • Peer Reviewed
• [Journal Article] Right homonymous hemianopsia following allogenic haematopoietic stem cell transplantation. (2008)
  • Author(s): Saikawa Y, Horisawa T, Mase S, Araki R, Ikawa Y, Kuroda R, Nishimura R, Koizumi S.
  • Journal Title: Eur J Haematol. 80(6) Pages: 551-551
  • Peer Reviewed
• [Journal Article] Human heme oxygenase-1 deficiency : A lesson on serendipity in the discovery of the novel disease. (2008)
  • Author(s): Koizumi S.
  • Journal Title: Pediatrics International 49(2) Pages: 125-132
  • Peer Reviewed
• [Journal Article] In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. (2008)
  • Author(s): Nishimura R, Baker J, Beilhack A, Zeiser R, Olson JA, Sega EI, Karimi M, Negrin RS.
  • Journal Title: Blood 112(6) Pages: 2563-2574
  • Peer Reviewed
• [Journal Article] Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs. (2008)
  • Author(s): Beilhack A, Schulz S, Baker J, Beilhack GF, Nishimura R, Baker EM, Landan G, Herman EI, Butcher EC, Contag CH, Negrin RS.
  • Journal Title: Blood 111(5) Pages: 2919-2928
  • Peer Reviewed
• [Journal Article] Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome. (2008)
  • Author(s): Wada T, Yasur M, Toma T, Nakayama Y, Nishida M, Shimizu M, Okajima M, Kasahara Y, Koizumi S, Inoue M, Kawa K, Yachie A
  • Journal Title: Blood 112 Pages: 1872-1875
  • Peer Reviewed
• [Journal Article] Lead-pipe colon revisited in chronic graft-versus-host disease. (2008)
  • Author(s): Saikawa Y, Ikawa Y, Kagaya T, Koizumi S.
  • Journal Title: J Pediatr Gastroenterol Nutr 46 Pages: 463-463
  • Peer Reviewed
• [Journal Article] 腎性低尿酸血症を伴わなかった運動後急性腎不全(ALPE)の1例 (2008)
  • Author(s): 横山忠史, 清胃水正樹, 小泉晶一, 龍泰治, 古市賢吾, 和田隆志, 大田和秀, 長沖優子, 伊川泰広, 和田英男, 貝藤裕史, 野津寛大
  • Journal Title: 日本小児腎不全学会雑誌 28 Pages: 205-207
  • NAID: 10025701806
  • Peer Reviewed
• [Presentation] Expansion of Liver-Infiltrating CTL Clone In Concert with the Development of Hepatitis-Associated AA. (2010)
  • Author(s): Yasuhiro Ikawa, Ryosei Nishimura, Shintaro Mase, Rie Kuroda, Raita Araki, Hideaki Maeba, Masaki Shimizu, Taizo Wada, Tomoko Toma, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 53rd annual meeting of the American Society of Hematology.
  • Place of Presentation: San Diego Convention Center, USA
  • Year and Date: 2010-12-10
• [Presentation] Potent Strategy for Treatmet of Gvhd and Autoimmune-Diseased by Infusion of Donor-Typed or Even Third-Party Tolerogenic Dendritic Cells by Psoralen Plus UVA Treatment. (2010)
  • Author(s): Hideaki Maeba, Ryosei Nishimura, Rie Kuroda, Raita Araki, Shintaro Mase, Yasuhiro Ikawa, Akihiro Yachie, Shoichi Koizumi
  • Organizer: 53rd annual meeting of the American Society of Hematology.
  • Place of Presentation: San Diego Convention Center, USA
  • Year and Date: 2010-12-10
• [Presentation] Cytokine-Induced Killer Cells Facilitate Immune Reconstitution After Allogeneic BMT In Mice. (2010)
  • Author(s): Shintaro Mase, Ryosei Nishimura, Rie Kuroda, Hideaki Maeba, Kazuhito Naka, Raita Araki, Yasuhiro Ikawa , Shoichi Koizumi, Akihiro Yachie
  • Organizer: 53rd annual meeting of the American Society of Hematology.
  • Place of Presentation: San Diego Convention Center, USA
  • Year and Date: 2010-12-10
• [Presentation] Role of Il-17 Varies at Different Periods After Hematopoietic Stem Cell Transplantation : Protection From Acute Graft-Versus-Host Disease and Exacerbation of Chronic Graft-Versus-Host Disease. (2010)
  • Author(s): Rie Kuroda, Ryosei Nishimura, Katsuaki Sato, Hideaki Maeba, Kazuhito Naka, Shintaro Mase, Raita Araki, Yasuhiro Ikawa, Yoichiro Iwakura, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 53rd annual meeting of the American Society of Hematology.
  • Place of Presentation: San Diego Convention Center, USA
  • Year and Date: 2010-12-10
• [Presentation] Potent Strategy for Treatmet of GVHD and Autoimmune-Diseased by Infusion of Donor-Typed or Even Third-Party Tolerogenic Dendritic Cells by Psoralen Plus UVATreatment. (2010)
  • Author(s): H Maeba, R Nishimura, R Kuroda, S Koizumi
  • Organizer: 53rd annual meeting of the American Society ofHematology(ASH)
  • Place of Presentation: San Diego Convention Center(USA)
• [Presentation] Expansion of Liver-Infiltrating CTL Clone in Concert with the Development of Hepatitis-Associated Aplastic Anemia. (2010)
  • Author(s): Yasuhiro Ikawa, Ryosei Nishimura, Shintaro Mase, Rie Kuroda, RaitaAraki, Hideaki Maeba, Masaki Shimizu, Taizo Wada, Tomoko Toma, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 53rd annual meeting ofthe American Society of Hematology(ASH)
  • Place of Presentation: San Diego Convention Center(USA)
• [Presentation] Cytokine-Induced Killer Cells Facilitate Immune Reconstitution After Allogeneic BMT in Mice. (2010)
  • Author(s): Shintaro Mase, Ryosei Nishimura, Yasuhiro Ikawa, Rie Kuroda, Raita Araki, Hideaki Maeba, Masaki Shimizu, Taizo Wada, Tomoko Toma, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 53rd annual meeting ofthe American Society of Hematology(ASH)
  • Place of Presentation: San Diego Convention Center(USA)
• [Presentation] Role of I1-17 Varies at Different Periods After Hematopoietic Stem Cell Transplantation : Protection From Acute Graft-Versus-Host Disease and Exacerbation of Chronic Graft-Versus-Host Disease. (2010)
  • Author(s): Rie Kuroda, Ryosei Nishimura, Yasuhiro Ikawa, Shintaro Mase, Raita Araki, Hideaki Maeba, Masaki Shimizu, Taizo Wada, Tomoko Toma, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 53rd annual meeting ofthe American Society of Hematology(ASH)
  • Place of Presentation: San Diego Convention Center(USA)
• [Presentation] Differential expression of activation and homing molecules predict GVHD severity in affected organs. (2010)
  • Author(s): Rie Kuroda, Ryosei Nishimura, Yasuhiro Ikawa, Shintaro Mase, Raita Araki, Hideaki Maeba, Kazuhiro Naka, Yasuhiro Ikawa, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] Liver-infiltrating CTL clone expands with the development of hepatitis-associated aplastic anemia. (2010)
  • Author(s): Ryosei Nishimura, Rie Kuroda, Yasuhiro Ikawa, Shintaro Mase, Raita Araki, Hideaki Maeba, Masaki Shimizu, Yasuhiro Ikawa, Taizo Wada, Tomoko Toma, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] New treatment strategy for GVHD by infusion of donor-typed PLTVA-treatedtolerogenic dendritic cells. (2010)
  • Author(s): Hideaki Maeba, Ryosei Nishimura, Rie Kuroda, Yasuhiro Ikawa, Sliintaro Mase, Raita Araki, Yasuhiro Ikawa, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] Cytokine-induced killer.cells facilitate immune reconstitution after allogeneic BMT inmice. (2010)
  • Author(s): Shintaro Mase, Ryosei Nishimura, Hideaki Maeba, Rie Kuroda, Raita Araki, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
• [Presentation] 制御性樹状細胞を用いた新たな造血幹細胞移植療法にむけて(現状とその問題点について) (2010)
  • Author(s): 前馬秀昭, 西村良成, 黒田梨絵, 馬瀬新太郎, 荒木来太, 小泉晶一, 谷内江昭宏
  • Organizer: 第32回日本造血細胞移植学会
  • Place of Presentation: 大阪国際会議場(大阪府)
• [Presentation] 再再発鼻腔原発NKリンパ腫に対する非血縁間同種骨髄移植後に多発骨壊死を来たした小児例 (2010)
  • Author(s): 馬瀬新太郎, 西村良成, 前馬秀昭, 黒田梨絵, 荒木来太, 小泉晶一, 谷内江昭宏
  • Organizer: 第32回日本造血細胞移植学会
  • Place of Presentation: 大阪国際会議場(大阪府)
• [Presentation] I-131MIBG内照射併用自家末梢血幹細胞移植を施行したMYCN増幅Stage4の1歳神経芽細胞腫初発例 (2010)
  • Author(s): 荒木来太, 西村良成, 前馬秀昭, 黒田梨絵, 馬瀬新太郎, 小泉晶一, 谷内江昭宏
  • Organizer: 第32回日本造血細胞移植学会
  • Place of Presentation: 大阪国際会議場(大阪府)
• [Presentation] 造血幹細胞移植後早期の末梢血CD69陽性HLA-DR陰性CD8細胞増加は正着不全の指標となりうる (2010)
  • Author(s): 黒田梨絵, 西村良成, 前馬秀昭, 馬瀬新太郎, 荒木来太, 小泉晶一, 谷内江昭宏
  • Organizer: 第32回日本造血細胞移植学会
  • Place of Presentation: 大阪国際会議場(大阪府)
• [Presentation] Strong Inhibition of Alloreaction by Newly Generated Tolerogenic Dendritic Cells by Psoralen Plus UVA Treatment. (2009)
  • Author(s): Maeba H, Nishimura R, Kuroda R, Araki R, Mase S, Ikawa Y, Yachie A, Koizumi S.
  • Organizer: 52nd annual meeting of the American Society of Hematology.
  • Place of Presentation: New Orleans Convention Center, USA
  • Year and Date: 2009-12-05
• [Presentation] Strong Inhibition of Alloreaction by Newly Generated Tolerogenic Dendritic Cells by Psoralen Plus UVA Treatment (2009)
  • Author(s): Maeba H, Nishimura R, Kuroda R, Araki R, Mase S, Ikawa Y, Yachie A., Koizumi S.
  • Organizer: 51st ASH Annual Meeting (アメリカ血液学会)
  • Place of Presentation: ニューオルリンズ、アメリカ合衆国
  • Year and Date: 2009-12-05
• [Presentation] Promoter DNA methylation of CD10 in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene. (2009)
  • Author(s): Y.Ikawa, N.Sugimoto, S.Koizumi, A.Yachie, Y.Saikawa
  • Organizer: 2009 annual meeting of the American Society of Clinical Oncology
  • Place of Presentation: Orlando Convention Center, USA
  • Year and Date: 2009-05-29
• [Presentation] Dense Methylation Patterns of CD10 Promoters in CD 10-Negative Infant Acute Lymphoblastic Leukemia (ALL) with Mixed-Lineage Leukemia (MLL) Gene Rearrangements (2009)
  • Author(s): Yasuhiro Ikawa, Naotoshi Sugimoto, Shintaro Mase, Rie Kuroda, Raita Araki^1 Ryosei Nishimura, Toru Horisawa, Naoki Okada, Shoichi Koizumi, Akihiro Yachie, Yutaka Saikawa
  • Organizer: 100th annual meeting of the American Association of Cancer Research
  • Place of Presentation: Denver Convention Center, USA
  • Year and Date: 2009-04-18
• [Presentation] 免疫寛容を誘導する制御性樹状細胞の大量培養の確立とGVHD制御の応用に向けて (2009)
  • Author(s): 前馬秀明, 西村良成, 黒田理恵, 馬瀬新太郎, 谷内江昭宏, 小泉晶一
  • Organizer: 第25回日本小児がん学会、第51回日本小児血液学会
  • Place of Presentation: 東京、東京ベイホテル東急
• [Presentation] Donor Bone Marrow Derived IL-17 Expressing Cells Exacerbate Chronic Graft-Versus-Host Disease in a Murine Bone Marrow Transplantation (2008)
  • Author(s): Rie Kuroda, Ryosei Nishimura, Katsuaki Sato, Hideaki Maeba, Kazuhito Naka, Yo Niida, Raita Araki, Yoichiro Iwakura, Shoichi Koizumi, Akihiro Yachie
  • Organizer: 51st annual meeting of the American Society of Hematology.
  • Place of Presentation: San Francisco Convention Center, USA
  • Year and Date: 2008-12-05
• [Presentation] Donor bone marrow derived IL-17 expressing cells exacerbate chronic graft-versus-host disease in a murine bone marrow transplantation. (2008)
  • Author(s): Kuroda R, Nishimura R, Sato K, Maeba H, Naka K, Niida Y, Araki R, Iwakura Y, Koizumi S, Yachie A
  • Organizer: American Society of Hematology
  • Place of Presentation: San Francisco
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