免疫システム構築の情報伝達制御

• Project/Area Number: 12051103
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 烏山 一 東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (60195013)
• Co-Investigator(Kenkyū-buntansha): 徳久 剛史 千葉大学, 大学院・医学研究科, 教授 (20134364) ; 桂 義元 東京医科歯科大学, 大学院・医歯学総合研究科, 客員教授 (90027095)
• Project Period (FY): 2000 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥27,600,000 (Direct Cost: ¥27,600,000); Fiscal Year 2002: ¥7,900,000 (Direct Cost: ¥7,900,000); Fiscal Year 2001: ¥8,100,000 (Direct Cost: ¥8,100,000); Fiscal Year 2000: ¥11,600,000 (Direct Cost: ¥11,600,000)
• Keywords: B細胞分化 / T細胞分化 / リンパ球前駆細胞 / 胚中心 / 遺伝子再構成 / プレB細胞レセプター / Btk / BLNK / サイトカイン / STAT / NK細胞 / CD94

Research Abstract

「リンパ球の初期分化を誘導・制御するシグナル伝達機構」「リンパ球の系列分岐・運命分岐を決定するシグナル伝達機構」「末梢リンパ組織における免疫系再構築のシグナル伝達機構」を研究課題とする3つの計画研究を設定して、8名の計画研究班員と15名の公募研究班員によって研究を遂行した。本調整班では、研究グループ間の連絡調整・情報交換、実験条件の統一のための共通試薬等の検定・購入等をおこない、効率よい研究推進のための支援体制強化につとめた。(1)ノックアウトマウスの作製に最適なgermline transmissionに優れたES細胞を樹立選別し、未分化状態に維持に必要な至適培養条件を見いだし、最良のES細胞の供給をおこなった。(2)DNAシークエンス決定支援をおこなった。(3)細胞培養に最適な牛胎児血清を選別し、培養条件の標準化、均一化をはかった。(4)ハイブリドーマなど共有細胞株の保存管理と供給をおこなった。(5)遺伝子改変動物の樹立と系統維持、供給をおこなった。このように研究支援体制を強化継続したことにより、免疫システム構築の情報伝達制御機構に関して多くの新知見をみいだし、その成果は国際雑誌に数多く発表することができた。さらに2003年2月20-23日に、3年間の研究の総括と成果発表・討論のため、海外の一流研究者を交えて、International Symposium on Regulation of Immune Response in Heath and Diseaseを開催した。

Research Products

• [Publications] Obata, S., et al.: "Overexpression of the c-fos gene perturbs functional maturation of M1 cells into macrophages"Mol. Immunol.. 39. 585-594 (2003)
• [Publications] Sasagawa, K., et al.: "Identification of Nd1, a novel murine kelch family protein, involved in stabilization of actin filaments"J. Biol. Chem.. 277. 44140-44146 (2002)
• [Publications] Bahar, R., et al.: "Growth retardation, polyploidy and multinucleation induced by Clast3, a novel cell cycle-regulated protein"J. Biol. Chem.. 277. 40012-40019 (2002)
• [Publications] Yoshida, T., et al.: "Activation of STAT3 by the Hepatitis C virus core protein leads to cellular transformation"J. Exp. Med.. 196. 641-653 (2002)
• [Publications] Nakagawa, Y., et al.: "Downregulation of bcl-xL is relevant to UV-induced apoptosis in fibroblasts"J. Biochem. Mol. Biol.. 35. 452-458 (2002)
• [Publications] Toyama, H., et al.: "Memory B cells without somatic hypermutation are generateded from Bcl6-deficient B cells"Immunity. 17. 329-339 (2002)
• [Publications] Tada, Y., et al.: "A novel role for Fas ligand in facilitating antigen acquisition by dendritic cells"J. Immunol.. 169. 2241-2245 (2002)
• [Publications] Arima, M., et al.: "A putative silencer element in the IL-5 gene recognized by Bcl6"J. Immunol.. 169. 829-836 (2002)
• [Publications] Ichii, H., et al.: "Role for Bcl-6 in the generation and maintenance of memory CD8^+ T cells"Nature Immunol.. 3. 558-563 (2002)
• [Publications] Hikita, S., et al.: "Overexpression of TIAP/m-survivin in thymocytes enhances cell proliferation"Mol. Immunol.. 39. 289-298 (2002)
• [Publications] Oshitari, T., et al.: "Suppression of c-fos mediates inhibition of cell death and increases neurite regeneration in retinal ganglion cells"Invest. Ophtalm. Vis. Sci.. 43. 2442-2449 (2002)
• [Publications] Sakashita, C., et al.: "Cloning and characterization of the human BAZF gene, a homologue of the BCL6 oncogene"Biochem. Biophys. Res. Commun.. 291. 567-573 (2002)
• [Publications] Kojima, S., et al.: "Histological analysis of vaginal opening and spermatogenesis in Bcl6-deficient mice"Jpn. J. Fertil. Steril.. 47. 39-45 (2002)
• [Publications] Sata, M., et al.: "Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis"Nature Med.. 8. 403-409 (2002)
• [Publications] Seimiya, M., et al.: "Clast5/Stra13 is a negative regulator of B lymphocyte activation"Biochem. Biophys. Res. Commun.. 292. 121-127 (2002)
• [Publications] Murasawa, M., et al.: "GL7 defines the cycling stage of pre-B cells in murine bone marrow"Eur. J. Immunol.. 32. 291-298 (2002)
• [Publications] Hamada, H., et al.: "Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine"The Journal of Immunology. 168. 57-64 (2002)
• [Publications] Nishiyama, Y., et al.: "Homeostatic regulation of intestinal villous epithelia by B lymphocytes"The Journal of Immunology. 168. 2626-2633 (2002)
• [Publications] Onai, N., et al.: "Pivotal role of CCL25 (TECK)/CCR9 in the formation of gut cryptopatches and consequent appearance of intestinal intraepithelial T lymphocytes"International Immunology. 14. 687-694 (2002)
• [Publications] Murai, M., et al.: "Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction"Nature Immunology. 4. 154-160 (2003)
• [Publications] Lu, M., et al.: "The common myelolymphoid progenitor : A key intermediate stage in hemopoiesis generating T and B cells"J. Immunol.. 169. 3519-3525 (2002)
• [Publications] Kawamoto, H., et al.: "Extensive proliferation of T cell lineage restricted progenitors in the thymus : An essential process for clonal expression of diverse T cell receptor beta chains"Eur. J. Immunol.. 33(in press). (2003)
• [Publications] Ueno, T., et al.: "Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus"Immunity. 16. 205-218 (2002)
• [Publications] Akamatsu, Y., et al.: "Deletion of the RAG2 C-terminus leads to impaired lymphoid development in mice"Proc. Natl. Acad. Sci. USA. 100. 1209-1214 (2003)
• [Publications] Wang, Y-H., et al.: "Differential surrogate light chain expression governs B cell differentiation"Blood. 99. 2459-2467 (2002)
• [Publications] Taguchi, T., et al.: "Pre-BCR-mediated signal inhibits CD24-induced apoptosis in human pre-B cells"J. Immunol.. 170. 252-260 (2003)
• [Publications] Kubo, S., et al.: "Long-term maintenance of IgE-mediated memory in mast cells in the absence of detectable serum IgE"J. Immunol.. 170. 775-780 (2003)
• [Publications] Sato, E., et al.: "Chronic inflammation in skin can be induced in IgE transgenic mice by a single challenge of multivalent antigen"J. Allergy Clin. Immunol.. 111. 143-148 (2003)
• [Publications] Saijo, K., et al.: "Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development"Nature Immunol.. 4. 274-279 (2003)
• [Publications] Tsuchiya, K., et al.: "Molecular cloning and characterization of TPP36 and its isoform TPP32, novel substrates of Abl tyrosine kinase"FEBS lett.. 537. 203-209 (2003)
• [Publications] 烏山 一: "プレB細胞レセプターを介するB細胞分化誘導"蛋白質核酸酵素増刊号. 47. 2182-2187 (2002)
• [Publications] 烏山 一: "B細胞発生・分化の分子制御機構とその破綻"感染炎症免疫. 32. 18-27 (2002)
• [Publications] Wiltshire, C., et al.: "A new c-Jun N-terminal kinase (JNK)-interacting protein Sab(SH3BP5), associates with mitochondria"Biochem J.. 367. 577-585 (2002)
• [Publications] Agematsu, K., et al.: "Absence of memory B cells in patients with common variable immunodeficiency"Clin Immunol.. 103. 34-42 (2002)
• [Publications] Inabe, K., et al.: "Bruton's tyrosine kinase regulates B cell antigen receptor-mediated JNK1 response through Rac1 and phospholipase C-gamma2 activation"FEBS Lett.. 514. 260-262 (2002)
• [Publications] Lee, H.-C., et al.: "Seeding of dendritic epidermal T cells in the neonatal skin is reduced in 129 strain of mice"Immunol. Lett.. 81. 211-216 (2002)
• [Publications] Han, H., et al.: "Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision"Int. Immunol.. 14. 637-645 (2002)
• [Publications] Watanabe, N., et al.: "Activation and differentiation of autoreactive B-1 cells by interleukin-10 induce autoimmune hemolytic anemia in Fas-deficient anti-erythrocyte immunoglobulin transgenic mice"J. Exp. Med.. 196. 141-146 (2002)
• [Publications] Lahn, M., et al.: "MHC class I-dependent Vγ4^+ pulmonary T cells regulate αβ T cell-independent airway responsiveness"Proc. Natl. Acad. Sci. USA.. 99. 8850-8855 (2002)
• [Publications] Wang, J.W., et al.: "Influence of SHIP on the NK repertoire and allogeneic bone marrow transplantation"Science. 15. 2094-2097 (2002)
• [Publications] 反町典子: "NK細胞の系統発生-missing self認識の起源を求めて 動物界における免疫系の進化 別冊医学のあゆみ"医歯薬出版株式会社. 5 (2002)
• [Publications] 反町典子: "抑制性レセプターによる細胞接着制御 蛋白質核酸酵素増刊号 免疫研究の最前線"共立出版. 5 (2002)
• [Publications] 反町典子: "NKレセプターファミリー分,CD94とLy49Qの機能 Molecular Medicine増刊号 免疫2002"中山書店. 9 (2002)
• [Publications] 南野昌信, 石川博通: "粘膜免疫学の最前線 粘膜リンパ球の発達分化"医薬ジャーナル社. 11 (2002)
• [Publications] 南野昌信, 石川博通: "胸腺外T細胞の発達・分化 標準免疫学 第2版"医学書院. 8 (2002)
• [Publications] Katsura, Y., Kawamoto, H.: "A new clonal assay system for lymphoid and myeloid lineages"Margaret H. Baron (Humana Press) (In Press). (2003)
• [Publications] Ueno, T., et al.: "Basic Cell Culture Protocols"Humana Press, NJ, USA (in press). (2003)
• [Publications] 烏山 一: "「B細胞の初期分化」標準免疫学第2版(谷口克、宮坂昌之編)"医学書院. 9 (2002)
• [Publications] Kojima, S., et al.: "Disruption of the Bcl6 gene increases testicular germ cell apoptosis in mice"Development. 128. 57-65 (2001)
• [Publications] Zhang, H., et al.: "A novel functional domain of Bc16 family that recruits histone deacethylases"Biochim.Biophys.Acta. 1543. 188-200 (2001)
• [Publications] Bannai, M. et al.: "Abundance of unconventional CD8(+) natural killer T cells in the large intestine"Eur.J.Immunol.. 31. 3361-3369 (2001)
• [Publications] Mizushima, N., et al.: "Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells"J.Cell Biol.. 152. 657-668 (2001)
• [Publications] Hamada, H. et al.: "Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine"J.Immunol.. 168. 57-64 (2002)
• [Publications] Murasawa, M., et al.: "GL7 defines the cycling stage of pre-B cells in murine bone marrow"Eur.J.Immunol.. 32. 291-298 (2002)
• [Publications] Ikawa, T., et al.: "Commitment to natural killer cells requires the helix-loop-helix inhibitor Id2"Proc.Natl.Acad.Sci.USA. 98. 5164-5169 (2001)
• [Publications] Ohmura, K., et al.: "Immature multipotent hematopoietic progenitors lacking long-term bone marrow-reconstituting activity in the aorta-gonad-mesonephros region of murine day 10 fetuses"J.Immunol.. 166. 3290-3296 (2001)
• [Publications] Shimizu, C., et al.: "Progression of T cell lineage restriction in the earliest subpopulation of murine adult thymus visualized by the expression of lck proximal promoter activity"Int.Immunol.. 13. 105-117 (2001)
• [Publications] Egawa, T., et al.: "The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor"Immunity. 15. 1-20 (2001)
• [Publications] Yoshida, H., et al.: "Expression of a4b7 intergrn defines a distinct pathway of lymphoid progenitors committed to T cells, fetal intestinal lymphotoxin producer, NK, and dendritic cells"J.Immunol.. 167. 2511-2521 (2001)
• [Publications] Itoi, M., et al.: "Two distinct steps of immigration of hematopoietic progenitors into the early thymus anlage"Int.Immunol.. 13. 1203-1211 (2001)
• [Publications] Katsura, Y.: "Stepwise lineage restriction of progenitors in lympho-myelopoiesis"Int.Rev.Immunol.. 20. 1-20 (2001)
• [Publications] Katsura, Y., et al.: "Redefinition of lymphoid progenitors"Nature Rev.Immunol.. 2. 127-132 (2002)
• [Publications] Ueno, T., et al.: "Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus"Immunity. (in press). (2002)
• [Publications] Yoh, K., et al.: "Transgenic overexpression of MafK suppresses T cell proliferation and function in vivo"Genes to Cells. 6. 1055-1066 (2001)
• [Publications] Tada M., et al.: "Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells"Current Biology. 11. 1553-1558 (2001)
• [Publications] Sano, S., et al.: "Stat3 in thymic epithelial cells is essential for postnatal maintenance of thymic architecture and thymocyte survival"Immunity. 15. 261-273 (2001)
• [Publications] Masuyama, N., et al.: "Akt inhibits the orphan nuclear receptor Nur77 and T cell apoptosis"J.Biol.Chem.. 276. 32799-32805 (2001)
• [Publications] Takahama, Y.: "Genetic modulation of immature T lymphocytesand its application"J.Med.Invest.. 48. 25-30 (2001)
• [Publications] Toyama-Sorimachi, N., et al.: "Mouse CD94 participates in Qa-1-mediated self recognition by NK cells and delivers inhibitory signals independent of Ly-49"J.Immunol.. 166. 3771-3779 (2001)
• [Publications] Kouro, T., et al.: "Bruton's tyrosine kinase (Btk) is required for signaling the CD79b-mediated pro-B to pre-B cell transition"Int.Immunol.. 13. 485-493 (2001)
• [Publications] Agematsu, K., et al.: "Complete arrest from pro-to pre-B cells in a case of B cell-negative severe combined immunodeficiency (SCID) without recombinase activating gene (RAG) mutations"Clin.Exp.Immunol.. 124. 461-464 (2001)
• [Publications] Kinoshita, T., et al.: "Oncostatin M suppresses generation of lymphoid progenitors in fetal liver by inhibiting the hepatic microenvironment"Exp.Hematol.. 299. 1091-1097 (2001)
• [Publications] Kubo, S., et al.: "Drastic up-regulation of high affinity IgE receptor on mast cells is induced by IgE binding through stabilization and accumulation of the receptor on the cell surface"J.Immunol.. 167. 3427-3434 (2001)
• [Publications] Stephan, R.P.: "Analysis of VpreB expression during B lineage differentiation in lambda5-deficient mice"J Immunol. 167. 3734-3739 (2001)
• [Publications] Wang, Y-H., et al.: "Differential surrogate light chain expression governs B cell differentiation"Blood. (in press). (2002)
• [Publications] Honda, K., et al.: "Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis"J.Exp.Med.. 193. 621-630 (2001)
• [Publications] Agata, Y., et al.: "Histone acetylation determines the developmentally regulated accessibility for T cell receptor-γ gene recombination"J.Exp.Med.. 193. 873-879 (2001)
• [Publications] Lee, H.-C., et al.: "Induction of germline transcription in the human T cell receptor γ locus by STAT5"J.Immunol. 167. 320-326 (2001)
• [Publications] Ohba, Y., et al.: "Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis"EMBO J. 20. 3333-3341 (2001)
• [Publications] Ye, S.-K., et al.: "Differential roles of cytokine receptors in the development of epidermal γ δ T Cells"J.Immunol.. 167. 1929-1934 (2001)
• [Publications] Fagarasan, S., et al.: "In situ class switching and differentiation to IgA-producing cells in the gut lamina propria"Nature. 413. 639-643 (2001)
• [Publications] Ye, S.-K., et al.: "The IL-7 receptor controls the accessibility of the TCR γ locus by Stat5 and histone acetylation"Immunity. 15. 813-823 (2001)
• [Publications] Lee, H.-C., et al.: "Seeding of dendritic epidermal T cells in the neonatal skin is reduced in 129 strain of mice"Immunol.Lett.. (In press). (2002)
• [Publications] Sakamoto, M., et al.: "Maternal germline mosaicism of X-linked agammaglobulinemia"Am.J.Med.Genet.. 99. 234-237 (2001)
• [Publications] Baba, Y. et al.: "BLNK mediates Syk-dependent Btk activation"Proc.Natl.Acad.Sci.USA.. 98. 2582-2586 (2001)
• [Publications] Usui, K., et al.: "Reccurent pneumonia with mild hypogammaglobulinemia diagnosed as X-linked agammaglobulinemia in adults"Respir.Res.. 2. 188-192 (2001)
• [Publications] Joe, EK., et al.: "Characterization of mutations, including a novel regulatory defect in the first intron, in Bruton's tyrosine kinase (Btk) gene from seven Korean X-linked agammaglobulinemia families"J.Immunol.. 167. 4038-4045 (2001)
• [Publications] Tsukada, S., et al.: "Btk and BLNK in B cell development"Adv.Immunol.. 77. 123-162 (2001)
• [Publications] Kanegane, H., et al.: "Clinical and genetic characteristics of hypogammaglobulinemic males with Btk mutations detected by flow cytometric assay combined with genetic analysis"J.Allergy.Clin.Immunol.. 108. 1012-1020 (2001)
• [Publications] Futatani, T., et al.: "Bruton's tyrosine kinase is present in normal platelets and its absence identifies patients with X-linked agammaglobulinemia and carrier females"Br.J.Haematol.. 114. 141-149 (2001)
• [Publications] Wang, Y., et al.: "Bruton's tyrosine kinase gene mutations in Turkish patients wuth presumed X-linked agammaglobulinemia"Hum.Mutat.. 18. 356 (2001)
• [Publications] Watanabe, D., et al.: "Four tyrosine residues in phospholipase C-gamma2, identified as Btk-dependent phodphorylation sites, are required for B cell antigen receptor-coupled calcium signaling"J.Biol.Chem.. 276. 38595-38601 (2001)
• [Publications] Wang, J.-W., et al.: "SHIP influences the NK repertoire and allogeneic marrow transplantation"Science. (in press). (2002)
• [Publications] Toyama-Sorimachi, N., et al.: "Activating and inhibitory immunoglobulin-like receptors"Springer-Verlag(分担分). 5 (2001)
• [Publications] Maki, K., et al.: "Activating and inhibitory immunoglobulin-like receptors"Springer-Verlag(分担分). 6 (2001)
• [Publications] Maki,K., et al.: "Immunoglobulin β signaling regulates locus accessibility for ordered Ig gene rearrangements."J.Exp.Med.. 191. 1333-1340 (2000)
• [Publications] Nomura,K., et al.: "Genetic defect in human X-linked agammaglobulinemia impedes a maturational evolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway."Blood. 96. 610-617 (2000)
• [Publications] Kurosaki,T.and Tsukada,S.: "Connecting Syk and Btk to calcium signals."Immunity. 12. 1-5 (2000)
• [Publications] Baba,Y., et al.: "BLNK mediates Syk-dependent Btk activation."Proc.Natl.Acad.Sci.USA.. (In press).
• [Publications] Agata,Y., et al.: "Histone acetylation determines the developmentally regulated accessibility for T cell receptor-γ gene recombination."J.Exp.Med.. (In press).
• [Publications] Toyama-Sorimachi,N., et al.: "Mouse CD94 participates in Qa-1-mediated self recognition by NK cells and delivers inhibitory signals independent of Ly-49."J.Immunol.. (In press).