• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to project page

2003 Fiscal Year Final Research Report Summary

Experimental study on the interaction between brain and immune system and its age-related changes.

Research Project

Project/Area Number 12307006
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

HIROKAWA Katsuiku  Tokyo Medical and Dental University, Graduate School, Professor, 大学院・医歯学総合研究科, 教授 (00014093)

Co-Investigator(Kenkyū-buntansha) KITAGAWA Masanobu  Tokyo Medical and Dental University, Graduate School, Associate Professor, 大学院・医歯学総合研究科, 助教授 (10177834)
IKEDA Toru  Tokyo Medical and Dental University, Graduate School, Lecturer, 大学院・医歯学総合研究科, 講師 (00211029)
UTSUYAMA Masanori  Tokyo Medical and Dental University, Graduate School, Assistant, 大学院・医歯学総合研究科, 助手 (70167287)
Project Period (FY) 2000 – 2003
KeywordsBrain / Immune system / Cytokine / Cytokine receptors / Infection / Thymus / GMF / Immunological restoration.
Research Abstract

Immune system works as major defense corps against infection and at the same time collaborates with neuro-endocrine systems to play a pivotal role in the maintenance of internal environment. The neuro-endocrine system mainly influences the immunological functions through various hormones and autonomic nerves and the immune system mainly affects the neuro-endocrine functions through various cytokines. The present, study reports 8 results, as followings, mainly focusing on the neuro-endocrine-immune interaction with aging.
1. HypothaLamus is not only a center for endocrine system but also controls thymic functions. The early decline of thymic function is partly under the control of hypothalamic function.
2. LPS injection was employed as an infection model, causing cytokine production and expression of cytokine receptors in the immune system. The study revealed that various cytokine receptors were expressed in the brain after LPS injection and the pattern of expression was different by the … More type of cytokines and age of mice. The results partly explain the difference in clinical signs between young and elderly people at the time of infection.
3.'The lvels of various monoamines in the brain were depressed in rats under chronic stress. An immunosuppressive drug, cyclosporine A enhanced the levels of monoamines and acted like anti-depressant.
4. Glia factor β (GMFβ) is known to play a role in the maturation of glia in the brain. The present study reyealed that GMFβ was also produced by thymic epithelial cells and played an important role in CD4 T cell differentiation. GMFβ is another common factor between the brain and the immune system.
5. Diethylstilbestrol, a synthetic estrogen, influences the immune system at a very low dose, but the effect is different by age and sex of mice, and dose of hormone. The results again suggest the endocrine-immune interaction is not monotonous and changes by age and sex.
6. Immunological restoration can be observed by administration or feeding of Japanese herbal medicine and the effect is especially prominent in aged mice.
7. Methods of immunological restoration in the elderly animals are composed of two types. One is stimulation of pre-existent immune cells by various stimulants. The other is implantation of young or active cells/tissues. Several methods were introduced considering human application.
8. Japanese herbal medicines are effective in the restoration of immune functions of aged animals. The study revealed, that one of them is also effective in the improvement of monoamine levels in the brain of aged mice (unpublished data). Less

  • Research Products

    (62 results)

All Other

All Publications (62 results)

  • [Publications] Tamura T, Utsuyama M, Hirokawa K et al.: "Molecular mechanism of the impairment in activation signal transaction in CD4+ T cells from old mice."International Immunology. 12. 1205-1215 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sawabe M, Hirokawa K. et al.: "Fuliminat hepatic failure in the elderly : A clinicopathological sutdy of autopsy cases aged over 65 years."Pathology International. 50. 98-105 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ogawa T, Kitagaw M, Hirokawa K.: "Age-related changes of human bone marrow ; an immunohistological estimation of T cells, B cells, amcrophagesd, proliferative cells"Mechanism of Ageing Development. 117. 58-67 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Warabi M, Kitagawa M, Hirokawa K.: "Immunohistological analysis on the relation of MHC class II expression to the grade of tumor differentiation, tumor infiltrating T cells and metastasis"Pathology Research Practice. 196. 807-815 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Warabi M, NemotoM T, Ohashi K, Kitagawa M, Hirokawa K: "Expression of protein tyrosine phosphatase and its significance in esophageal cancer."Experimental Molecular Pathology. 68. 187-195 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Wang C-R, Hino A, Hirokawa K, et al.: "Impaired delayed-type hypersensitivity response in mutant mice secreting soluble CD4 without expression of membrane-bound CD4"Immunology. 100. 309-316 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nasu K, Kohsaka H, Hirokawa K, et al.: "Adenoviral transfer of cyclin-dependent kinase inhibitor genes suppresses collagen-induced arthritis in mice."J Immunol.. 166. 7246-7252 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fukui Y, Oono T, Cananiols J-P, Nakao K, Hirokawa et al.: "Diversity of T cell repertoire by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor-contact."Proceeding of National Academy of Science. 97. 13760-13765 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakai D, Yuasa S, Takao T, Suzuki Y, Hirokawa K, et al.: "Mouse homologue of Coq7/Clk-1, logevity gene in C.Elegans, is essential for coenzyme Q synthesis."Biochemical and Biophysical Research Communications. 289. 463-471 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakajima T, Akiyama Hirokawa K, Yuasa Y et al.: "Age-related hypermethylation of the hMLH1 promotor in gastric cancers."International J Cancer. 94. 208-211 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Pawelec G, Tamas F, Hirokawa K.: "Altered T cell signalling in ageing. Aging Resaerch Review"Mechanism of Ageing and Development. 122. 1613-1637 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fujino T, Yamazaki Y, Copeland NG, Hirokawa K, et al.: "Inhibition of myeloid differentiation by Hoxa9, Hoxb8, and Meis homeobox genes."Experimental Hematology. 29. 856-863 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sghiraishi J, Utusyama M, Sunamor M, Kitagawa M, Hirokawa M: "Immunohistological analysis of thymoma by molecules differentially expressed in the thymic cortex and medulla, and its application in the differential diagnosis of thymoma."Pathology Research Practice. 197. 611-619 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamaguchi S, Kitagawa M, Utsuyama M, Hirokawa K et al.: "Role of lymphoid cells in age-related change of susceptibility to Friend leukemia virus-induced leukemia."Mechanism of Ageing and Development. 122. 219-232 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Utsuyama M, Seidlar H, Kitagawa S, Horikawa K: "Immunological restoration and anti-tumor effect by Japanese herbal medicine in aged mice."Mechanism of Ageing and Development. 122. 341-352 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ikeda T, Utsuyama M, Hirokawa K: "Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus."Endocrinology. 142. 1419-1426 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] ASanuma H, Hirokawa K, Utsuyama M, Suzuki Y, Tamura S: "Immune response and protection in different strains of aged mice immunized intranasally with an adjuvant-combined influenza vaccine"Vaccine. 19. 3981-3989 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirokawa K, Utusyama M, Kobayashi S: "Hypothalamic control of thymic function."Cellular Molecular Biology. 47. 97-102 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ikeda T, Utsuyama M, Hirokawa K: "Expression of profiles of RANKL, RANK and OPGmRNA in aged and ovariectomized rat bones."J.Bone and Mineral Research. 16. 1416-1425 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirokawa K, Goto S: "Research on biomedical genetology in Japan."Experimental Gerontology. 36. 1581-1597 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Utusyama M, Hirokawa K: "Differential expression of various cytokine receptors in the brain after stimulation with LPS in young and old mice."Experimental Gerontology. 37. 411-420 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kitagawa M, Aizawa S, Sado T, Yamaguchi S, Hirokawa K.: "A gene therapy model for retrovirus-induced disease with a viral env gene : expression-dependent resistance in immunosuppressed hosts."Leukemia. 15. 1779-1784 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Utusyama M, Kanno J, Inoue T, Hirokawa K.: "Age/sex dependent and non-monotonous dose response effect of Diethylstilbestrl (DES) on the immune function in mice."Toxciology Letters. 135. 145-153 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kitagawa M, Yamaguchi S, Hasegawa M, Hirokawa K et al.: "Friend leukemia virus function enhances DNA damage-induced apoptosis of hematopoietic cells, causing lethal anemia in C3H hosts."J.Virology. 76. 7790-7798 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirokawa K, Utsuyama M.: "Animal models and possible human application of immunological restoration in the elderly."Mechanism of Ageing and Development. 123. 1055-1063 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fujisaki C, Utsuyama M, Hirokawa K. et al.: "An immunosuppressive drug, cyclosporine-A, acts like as and anti-depressant for rats under unpredictable chronic stress."J.Medical and Dental Sciences. 50. 93-100 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Utusyama M, Shiraishi J, Hirokawa K. et al.: "Glia maturation factor produced by thymic epithelial cells plays a role in T cell differentiation in the thymic microenvironment."International Immunol.. 15. 557-564 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Utusyama M, Hirokawa K: "Radiation-induced-thymic lymphoma ocurs in young, but not in old mice: induction of thymic lymphoma is reversely related with age-related changes of thymic microenvironment, bone marrow and host environment."Experimental Molecular Pathology. 74. 319-325 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shiraishi J, Utsuyama M, Hirokawa K. et al.: "Essential microenvironment for thymopoiesis is preserved in human adult and aged thymus."Clinical and Developmental Immunol.. 10. 53-59 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagaoka S, Shiraishi J, Utsuyama M, Hirokawa K. et al.: "Poor prognosis of colorectal cancer in patients over 80 years old is associated with down-regulation of tumor suppressor genes."J.Clinical Gastroenterology. 37. 48-54 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuroyama H, Ikeda T, Utsuyama M, Saito T, Hirokawa K. et al.: "A novel form of ZAP-70 kinase expressed in pre-T cell-receptor-thymocytes, and regulates stability but not polization of microtubele-organizing center in T lymphocytes."Biochemical, Biophysical Research Communications. 315. 935-941 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tamura T, Kunimatsu T, Yee, S-T, Igarashi O, Utsuyama M, Tanaka S, Miyazaki S, Hirokawa K, Nariuchi H.: "Molecular mechanism of the impairment in activation signal transduction in CD4+ T cells from old mice."Int.Immunol.. 12. 1205-1215 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sawabe M, Araib T, Esaki Y, Fukazawa T, Takubo K, Hirokawa K.: "Fulminant hepatic failure in the elderly: A clinicopathological study of autopsy cases aged over 65 years."Pathol Int.. 50. 98-105 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ogawa T, Kitagawa M, Hirokawa K.: "Age-related changes of human bone marrow; an immunohistological estimation of T cells, B cells, macrophages, proliferative cells and apoptotic cells."Mech Ageing Dev.. 117. 58-67 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Warabi M, Kitagawa M, Hirokawa K.: "Immunosistological analysis on the relation of MHC class II expression to the grade of tumor differentiation, tumor infiltrating T cells and metastasis to the lymph nodes in colorectal cancer."Pathol.Res.Prac.. 196. 807-815 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Warabi M, Nemoto M T, Ohashi K, Kitagawa M, Hirokawa K: "Expression of protein tyrosine phosphatase and its significance in esophageal cancer."Exp.Mol.Pathol.. 68. 187-195 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Wang C-R, Hino A, Yoshimoto T, Nagase H, Kato T, Hirokawa K, Matsuzawa A, Nariuchi H.: "Impaired delayed-type hypersensitivity response in mutant mice secreting soluble CD4 without expression of membrane-bound CD4"Immunol.. 100. 309-316 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nasu K, Kohsaka H, Nonomura Y, Terada Y, Ito H, Hirokawa K, Miyasaka N.: "Adenoviral transfer of cyclin-dependent kinase inhibitor genes suppresses collagen-induced arthritis in mice."J Immunol.. 165. 7246-7252 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fukui Y, Oono T, Cananiols J-P, Nakao K, Hirokawa K, Inayoshi A, Sanui T, Kanellopoulos J, Iwata, E, Noda M, Katsuiki M, Kourilsky P, Sasazuki M.: "Diversity of T cell repertoire by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor-contact."PNAS. 97. 13760-13765 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakai D, Yuasa S, Takahashi M, Shimizu T, Asaumi S, Isono K, Takao T, Suzuki Y, Kuroyanagi H, Hirokawa K, Koseki H, Shirasawa T.: "Mouse homologue of Coq7/Clk-1, logevity gene in C.Elegans, is -essential for coenzyme Q sysnthesis, maintenance of mitochondrial integrity and neurogenesis."BBRC. 289. 463-471 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakajima T, Akiyania Y, Shiraishi J, Arai T, Yanagisawa Y, Ma M, Fukuda Y, Sawabe M, Saitoh K, Kamiyama R, Hirokawa K, Yuasa Y.: "Age-related hypermethylation of the hMLH1 promotor in gastric cancers."Lnt.J.Cancer. 94. 208-211 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Pawelec G, Tarnas F, Hirokawa K.: "Altered T cell signalling in ageing."Aging Research Review Mech.Ageing.Dev.. 122. 1613-1637 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fujino T, Yamazaki Y, Largaespada DA, Jenkins NA, Copleland NG, Hirokawa K, Nakamura K.: "Inhibition of myeloid differentiation by Hoxa9, Hoxb8, and Meis homeobox genes."Exp.Hematol.. 29. 856-863 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shiraishi J, Utsuyama M Akashi T, Nemoto T, Ohashi K, Akamatsu H, Sunamori M, Kitagawa M, Hirokawa K.: "Immunohistological analysis of thymoma by molecules differentially expressed in thymic cortex and medulla, and its application for differential diagnosis of thymoma from esophageal and lung cancer."Pathol.Res.Prac.. 197. 611-619 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamaguchi S, Kitagawa M, Inoue M, Tejima Y, Kimura M, Aizawa S, Utsuyama M, Hirokawa K.: "Role of lymphoid cells in age-related change of susceptibility to Friend leukemia virus-induced leukemia."Mech Ageing Dev.. 122. 219-232 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Utsuyama M, Seidler H, Kitagawa M, Hirokawa K.: "Immunological restoration and anti-tumor effect by Japanese herbal medicine in aged mice."Mech.Ageing Dev.. 122. 341-352 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ikeda T, Kasai M, Utsuyama M, Hirokawa K.: "Determination of 3 isoforms of RANKL and their differential expression in bone and thymus."Endocrinol.. 122. 341-352 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Asanuma H, Hirokawa K, Utsuyama M, Suzuki Y, Aizawa C, Kurata T, Sata T, Tamura S.: "Immune responses and protection in different strains of aged mice immunized intranasally with an adjuvant-combined influenza vaccine."Vaccine. 19. 3981-3989 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirokawa K, Utsuyama M, Kobayashi S.: "Hypothalamic control of thyinic function."Cell.Molec.Biol.. 47. 97-102 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ikeda T, Utsuyama M, Hirokawa K.: "Expression profiles of RANKL, RANK and OPGmRNA in aged and ovariectomized rat bones."J.Bone Miner.Res.. 16. 1416-1425 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Utsuyama, M., Seidler, H., Kitagawa, M., Hirokawa, K.: "Immunological restoration and anti-tumor effect by Japanese herbal medicine in aged mice."Mech.Ageing Dev.. 122. 341-345 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirokawa K, Goto S.: "Biomedical Gerontology in Japan."Exp.Gerontol.. 36. 11581-11597 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Utsuyama M, Hirokawa K.: "Differential experssion of various cytokine receptors in the brain after stimulation with LPS in young and old mice."Exp.Gerontol.. 37. 411-420 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Utsuyama M, Kanno J, Inoue T, Hirokawa K.: "Age/sex dependent and non-monotonous dose response effect of Diethylstilbestrl (DES) on the immune function in mice."Toxciology Letters. 135. 145-153 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kitagawa M, Yamaguchi S, Hasegawa M, Tanaka K, Sado T, Hirokawa K, Aizawa S.: "Friend leukemia virus infection enhances DNA damage-induced apoptosis of hematopoietic cells, causing lethal anemia in C3H hosts."J.Virol.. 76. 7790-7798 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirokawa K, Utsuyama M.: "Animal models and possible human application of immunological restoration in the elderly."Mech.Ageing.Develop.. 123. 1055-1063 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fujisaki C, Utsuyama M, Kuroda Y, Watanabe A, Seidler H, Watanabe S, Kitagawa M, Hirokawa K.: "An immunosuppressive drug, cyclosporine-A, acts like as an anti-depressant for rats under unpredictable chronic stress."J.Med.Dent.Sci.. 50. 93-100 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Utsuyama M, Shiraishi J, Takahashi H, Kasai M, Hirokawa K.: "Glia maturation factor produced by thymic epithelial cells plays a role in T cell differentiation in the thymic microenvironment."Int.Immunol.. 15. 557-564 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Utsuyama M, Hirokawa K.: "Radiation-induced-thyrnic lymphoma occurs in young, but not in old mice: induction of thymic lymphoma is reversely related with age-related changes of thymic microenvironment, bone marrow and host environment."Exp.Mol.Pathol.. 74. 319-325 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shiraishi J, Utsuyama M, Seki S, Akamatsu H, Sunamori M, Kasai M, Hirokawa K: "Essential microenvironment for thymopoiesis is preserved in human adult and aged thymus."Clin.Develop.Immunol.. 10. 53-59 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagaoka S, Shiraishi J, Utsuyama M, Seki S, Takemura T, Kitagawa M, Sawabe M, Takubo K, Hirokawa K.: "Poor prognosis of colorectal cancer in patients over 80 years old is associated with down-regulation of tumor suppressor genes."J.Clinical.Gastroenterol.. 37. 48-54 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuroyama H, Ikeda T, Kasai M, Yamasaki S, Tatsumi M, Utsuyama M, Saito T, Hirokawa K.A: "novel form of ZAP-70 kinase expressed in pre-T cell-receptor-thymocytes, and regulates stability but not polization of microtubule-organizing center in T lymphocytes."BBRC. 315. 835-841 (2004)

    • Description
      「研究成果報告書概要(欧文)」より

URL: 

Published: 2005-04-19  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi