1995 年度実績報告書

サイトカインを介した造血幹細胞の増殖と分化の制御機構の解析

研究課題

研究課題/領域番号	07269212
研究機関	九州大学
研究代表者	仁保喜之九州大学, 医学部, 助教授 (60091287)
研究分担者	浅野嘉延九州大学, 医学部, 助手 (60271110) 大塚毅九州大学, 医学部, 助手 (50213773) 大塚輝久九州大学, 医学部, 講師 (20185317) 岡村精一九州大学, 医学部, 講師 (20136435)
キーワード	G-CSF / G-CSFレセプター / シグナル伝達 / 先天性好中球減少症 / 点突然変異 / 遺伝子発現 / c-kit / stem cell factor
研究概要	造血幹細胞の増殖と分化に関与するサイトカインのレセプターとしてG-CSFレセプターとstem cell factorのレセプターであるc-kitを解析した. G-CSFレセプターは造血幹細胞の指標となっているCD34陽性細胞にも出現していること,G-CSFRを経由する増殖と分化シグナルが各々の刺激伝達蛋白(Jak-STAT系やsyk,lyn,vavなど)のリン酸化を通じて伝えられることなどを発見して報告した.特に生後一月から感染症を繰り返し,G-CSF治療を受けている6歳の先天性好中球減少症の女児のG-CSFレセプターを重点的に解析した.患者の末梢血および骨髄細胞を研究材料とし,このG-CSFレセプターcDNAの解析ではG-CSFレセプターの細胞内部分の最初の3塩基(CAG)(nt2128-2130(pHQ3)が欠失していた.そこで,体細胞遺伝子の解析および遺伝子組み換え型G-CSFレセプターを細胞に発現させ、構造異常と機能を検討した.体細胞遺伝子解析で直前のイントロンの最終部分の正常塩基配列は本患者で欠失している3塩基(CAG)と同一配列であるのだが、患者ではこれがCAAと点突然変異をきたしており,これによりGT-AGルールによるスプライシングに異常が生じたと考えられた.さらに,G-CSFによる増殖・分化に異常のある白血病細胞のG-CSFレセプターの機能領域を中心にSSCP法で解析して既に異常バンドを検出している. c-kit/SCF系の検討でc-kitは骨髄性白血病に特異的に発現しており,未分化な表面形質を示すCD34陽性例やリンパ系抗原を同時に発現している症例でc-kitの陽性率が高かった.さらに,白血病細胞株HELにおいて,c-kit高発現亜株(HEL-P1)と低発現亜株(HEL-N1)に分けて検討したところ,HEL-P1は赤芽球系抗原の発現が強いのに対し,HEL-N1は巨核球系抗原の発現が強く,両亜株は培養条件によって相互に移行することが判明した.

研究成果

(24件)

すべてその他

すべて文献書誌 (24件)

[文献書誌] Shimoda S.: "HLA DRB40101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases." Journal of Experimental Mcdicine. 181. 1835-45 (1995)
[文献書誌] Shimoda K.: "High-frequency granuloid colony-forming ability of G-CSF receptor possessing CD34 antigen positive human umbilical cord blood hematopoietic progenitors." Experimental Hematology. 23. 226-228 (1995)
[文献書誌] Kanaji T.: "Megakaryocytes produce the receptor for granulocyte colony-stimulating factor." Blood. 85. 3359-3360 (1995)
[文献書誌] Kubota A.: "Analysis of c-kit expression of human erythroleukemia cell line, HEL: clonal variation and relationship with erythroid and megakaryocytic phenotype." Leukemia Research. 19. 283-290 (1995)
[文献書誌] Baba E.: "A peptide-based human T cell leukemia virus type I vaccine containing T and B cell epitopes that induces high titers of neutralizing antibodies." Journal of Immunology. 154. 399-412 (1995)
[文献書誌] Kubota A.: "High serum levels of granulocyte-macrophage colony-stimulating factor in patients with liver cirrhosis and granulocytopenia." Clinical and Laboratory Haematology. 17. 61-63 (1995)
[文献書誌] Aoki Y.: "Protective effect of granulocyte colony-stimulating factor against T-cell-meditated lethal shock trigged by superantigens." Blood. 86. 1420-1427 (1995)
[文献書誌] Miyamoto T.: "Characterization of blasts from a patient with eosinophilic blast crisis of chronic myelogenous leukaemia." British Journal of Haematology. 69. 207-210 (1995)
[文献書誌] Takamatsu Y.: "Relationship of infused CFU-GM and CFU-Mk mobilized by chemotherapy with or without G-CSF to platelet recovery after autologous blood stem cell transplantation." Experimental Hematology. 23. 8-13 (1995)
[文献書誌] Kawasaki C.: "In vitro study of deoxymethylspergualin on functions of lymphocytes and bone marrow cells from healthy volunteers." Journal of Antibiotics. 48. 243-247 (1995)
[文献書誌] Nagafuji K.: "Functional expression of Fas antigen(CD95)on hematopoietic progenitor cells." Blood. 86. 883-889 (1995)
[文献書誌] Matsuishi E.: "Allogeneic peripheral blood stem cell transplantation for treatment of induction failure in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia." International Journal of Hematology. 61. 43-47 (1995)
[文献書誌] Fujisaki T.: "Granulocyte colony-stimulating factormobilizes primitive hematopoietic stem cells in normal individuals." Bone Marrow Transplantation. 16. 57-62 (1995)
[文献書誌] Miyamoto T.: "Quantitative analysis of AML1/ETO transcripts in peripheral blood stem cell harvests from patients with t(8;21) acute myelogenous leukemia." British Journal of Haematology. 91. 132-138 (1995)
[文献書誌] Fujisaki T.: "Effects of Bestatin on hematopoiesis in long-term human bone marrow cultures." Biomedicine and Pharmacotherapy. 49. 69-74 (1995)
[文献書誌] Ikematsu W.: "Surface phenotype and immunoglobulin heavy chain gene usage in chronic B cell leukemias." New York Academy of Science.(印刷中).
[文献書誌] Miyamoto T.: "Serum concentration of soluble interleukin-2 receptor for monitoring acute graft-versus-host disease." Bone Marrow Transplantation. (印刷中).
[文献書誌] Kuroiwa M.: "Effects of granulocyte colony-stimulating factor on the hemostatic system in healthy volunteers." Intrernational Journal of Hematology. (印刷中).
[文献書誌] 仁保喜之: "G-CSFレセプターの構造と機能「造血幹細胞と造血因子-基礎から臨床まで-」(溝口秀昭編)" 医歯薬出版,東京, 4(29〜32) (1995)
[文献書誌] Niho Y.: "A randamized study of low-dose aclarbicine versus very low-dose cytosine arabinoside for myelodysplastic syndrome. Myelodysplastic Syndromes Advances in Research and Treatment, (Ed. Nomura T, Yoshida Y)." Elsevir Scuence B. V., Amsterdam, 6,(383〜388) (1995)
[文献書誌] 仁保喜之: "血液細胞の分化と成熟.「血液病学(三輪史朗他編)」" 文光堂,東京, 8,(20〜27) (1995)
[文献書誌] 岡村精一: "白血病における造血因子とそのレセプター,「造血幹細胞と造血因子-基礎から臨床まで-(溝口秀昭編)」" 医歯薬出版,東京, 4,(59〜62) (1995)
[文献書誌] Asano Y: "Analysis of G-CSF receptor in various hematological disorders. Fukuoka International Symposium on Medical Science (Niho Y. ed)." Kyushu University Press., Fukuoka(印刷中),
[文献書誌] 下田和哉: "JAK-Tykキナーゼと骨髄造血.「Annual Review血液1995」" 中外医学社,東京, 13,(20〜32) (1995)

1995 年度 実績報告書

サイトカインを介した造血幹細胞の増殖と分化の制御機構の解析

研究代表者

仁保 喜之 九州大学, 医学部, 助教授 (60091287)

研究成果

[文献書誌] Shimoda S.: "HLA DRB40101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases." Journal of Experimental Mcdicine. 181. 1835-45 (1995)

[文献書誌] Shimoda K.: "High-frequency granuloid colony-forming ability of G-CSF receptor possessing CD34 antigen positive human umbilical cord blood hematopoietic progenitors." Experimental Hematology. 23. 226-228 (1995)

[文献書誌] Kanaji T.: "Megakaryocytes produce the receptor for granulocyte colony-stimulating factor." Blood. 85. 3359-3360 (1995)

[文献書誌] Kubota A.: "Analysis of c-kit expression of human erythroleukemia cell line, HEL: clonal variation and relationship with erythroid and megakaryocytic phenotype." Leukemia Research. 19. 283-290 (1995)

[文献書誌] Baba E.: "A peptide-based human T cell leukemia virus type I vaccine containing T and B cell epitopes that induces high titers of neutralizing antibodies." Journal of Immunology. 154. 399-412 (1995)

[文献書誌] Kubota A.: "High serum levels of granulocyte-macrophage colony-stimulating factor in patients with liver cirrhosis and granulocytopenia." Clinical and Laboratory Haematology. 17. 61-63 (1995)

[文献書誌] Aoki Y.: "Protective effect of granulocyte colony-stimulating factor against T-cell-meditated lethal shock trigged by superantigens." Blood. 86. 1420-1427 (1995)

[文献書誌] Miyamoto T.: "Characterization of blasts from a patient with eosinophilic blast crisis of chronic myelogenous leukaemia." British Journal of Haematology. 69. 207-210 (1995)

[文献書誌] Takamatsu Y.: "Relationship of infused CFU-GM and CFU-Mk mobilized by chemotherapy with or without G-CSF to platelet recovery after autologous blood stem cell transplantation." Experimental Hematology. 23. 8-13 (1995)

[文献書誌] Kawasaki C.: "In vitro study of deoxymethylspergualin on functions of lymphocytes and bone marrow cells from healthy volunteers." Journal of Antibiotics. 48. 243-247 (1995)

[文献書誌] Nagafuji K.: "Functional expression of Fas antigen(CD95)on hematopoietic progenitor cells." Blood. 86. 883-889 (1995)

[文献書誌] Matsuishi E.: "Allogeneic peripheral blood stem cell transplantation for treatment of induction failure in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia." International Journal of Hematology. 61. 43-47 (1995)

[文献書誌] Fujisaki T.: "Granulocyte colony-stimulating factormobilizes primitive hematopoietic stem cells in normal individuals." Bone Marrow Transplantation. 16. 57-62 (1995)

[文献書誌] Miyamoto T.: "Quantitative analysis of AML1/ETO transcripts in peripheral blood stem cell harvests from patients with t(8;21) acute myelogenous leukemia." British Journal of Haematology. 91. 132-138 (1995)

[文献書誌] Fujisaki T.: "Effects of Bestatin on hematopoiesis in long-term human bone marrow cultures." Biomedicine and Pharmacotherapy. 49. 69-74 (1995)

[文献書誌] Ikematsu W.: "Surface phenotype and immunoglobulin heavy chain gene usage in chronic B cell leukemias." New York Academy of Science.(印刷中).

[文献書誌] Miyamoto T.: "Serum concentration of soluble interleukin-2 receptor for monitoring acute graft-versus-host disease." Bone Marrow Transplantation. (印刷中).

[文献書誌] Kuroiwa M.: "Effects of granulocyte colony-stimulating factor on the hemostatic system in healthy volunteers." Intrernational Journal of Hematology. (印刷中).

[文献書誌] 仁保喜之: "G-CSFレセプターの構造と機能「造血幹細胞と造血因子-基礎から臨床まで-」(溝口秀昭編)" 医歯薬出版,東京, 4(29〜32) (1995)

[文献書誌] Niho Y.: "A randamized study of low-dose aclarbicine versus very low-dose cytosine arabinoside for myelodysplastic syndrome. Myelodysplastic Syndromes Advances in Research and Treatment, (Ed. Nomura T, Yoshida Y)." Elsevir Scuence B. V., Amsterdam, 6,(383〜388) (1995)

[文献書誌] 仁保喜之: "血液細胞の分化と成熟.「血液病学(三輪史朗他編)」" 文光堂,東京, 8,(20〜27) (1995)

[文献書誌] 岡村精一: "白血病における造血因子とそのレセプター,「造血幹細胞と造血因子-基礎から臨床まで-(溝口秀昭編)」" 医歯薬出版,東京, 4,(59〜62) (1995)

[文献書誌] Asano Y: "Analysis of G-CSF receptor in various hematological disorders. Fukuoka International Symposium on Medical Science (Niho Y. ed)." Kyushu University Press., Fukuoka(印刷中),

[文献書誌] 下田和哉: "JAK-Tykキナーゼと骨髄造血.「Annual Review血液1995」" 中外医学社,東京, 13,(20〜32) (1995)

1995 年度実績報告書

仁保喜之九州大学, 医学部, 助教授 (60091287)