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Molecular mechanisms of immune diseases.

Research Project

Project/Area Number 05272105
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionJuntendo University

Principal Investigator

OKUMURA Ko  School of Medicine, Juntendo University, Professor, 医学部, 教授 (50009700)

Co-Investigator(Kenkyū-buntansha) WATANABE Takeshi  Medical Institute of Bioregulation, Kyushu University, Professor, 生体防御医学研究所, 教授 (40028684)
NISHIMURA Yasuharu  Kumamoto University Graduate School of Medicine Sciences, Professor, 大学院・医学研究科, 教授 (10156119)
YODOI Junji  Institute for Virus Research, Kyoto University, Professor, ウィルス研究所, 教授 (80108993)
TAKATSU Kiyoshi  The Institute of Medical Science, The University of Tokyo, Professor, 医科学研究所, 教授 (10107055)
SHIRAI Toshikazu  School of Medicine, Juntendo University, Professor, 医学部, 教授 (30115860)
Project Period (FY) 1993 – 1995
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥199,600,000 (Direct Cost: ¥199,600,000)
Fiscal Year 1995: ¥64,600,000 (Direct Cost: ¥64,600,000)
Fiscal Year 1994: ¥63,000,000 (Direct Cost: ¥63,000,000)
Fiscal Year 1993: ¥72,000,000 (Direct Cost: ¥72,000,000)
Keywordsgene / signal transduction / autoantibody / B cell / MHC / transplantation / HIV / アポトーシス / FasL / IL-5リセプター / ADF / Lyn / SLE / 抗原ペプチド / TcR / DR / HSI / B70 / NZB / 移植拒絶 / IL-5 / I-E
Research Abstract

All members of this group are involved in the analysis of the relationships between immune dysfunction and disease on a genetic level. From antibodies and thymocytes to signal transduction mechanisms, this group study a wide range of subjects related to pathological causation. 1.) This group discovered the existence of linkage between an unusual MHC haplotype and the abnormal increase in B1 cells, which are important autoimmune antibody secreting B cells. They also reported that the novel gene, which was dubbed Imh-1, is closely linked to the TNF receptor family located on the end of the 4th chromosome. In addition, the group found that the Mott-1 gene, expressed in Mott cells, which are terminally differentiated from B1 lineage cells and present in patients with immune diseases and BCLL,is linked to the Imh-1 locus on the 4th chromosome. 2.) This group reported that B Cell specific bluton kinase (Brk) and JAK2 kinase can be activated via stimulation with IL5. The group also reported t … More hat irregularities in the IL-5R signal transduction pathway are responsible for the weak response of B cells to IL-5 stimulation in XID mice. 3.) This group was successful in cloning the gene which encodes CD86, a molecule which functions as a costimulatory molecule for T cell activation. By decreasing CD28/CD80 and CD86 signal expression, specific tolerance can be induced. In animal models of SLE,rheumatoid arthritis and atopic dermatitis which already show abnormal immune reactivity, they observed a significant suppression of the abnormal immune reactivity by decreasing CD28/CD80 and CD86 signal expression. 4.) In its continued investigation of the role of intracellular signaling in the activation of lymphocytes, this group, by developing Lyn kinase and HS1 deficient mice, analyzed the effects of dysregulation of these molecules on a molecular level. The group also determined the structure of tyrosine phosphory lated HS1 protein. 5.) This group showed that substitution of amino acids in sntigenic peptides altered the immune response to the antigenic peptides. 6.) This group demonstrated that HIV env protein gp 160 can bind to CaM,producing a dimmer that causes apoptosis due to intracellular accumulation of Ca2+. Furthermore, this group observed that binding of the env protein gp 120 to CD4 cells causes FasL production and an induction of apoptosis in CD4 and CD8 cells. Less

Report

(4 results)
  • 1996 Final Research Report Summary
  • 1995 Annual Research Report
  • 1994 Annual Research Report
  • 1993 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Seino K.: "Anti-tumor effect of locally produced Fas ligand." Nature Medicine. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kaneko Y.: "CD40-mediated stimulation of B1 and B2 cells:implication in autoantibody production in murine lupus." Eur.J.Immunol.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kato K.: "Local production of IL-12 p40 suppresses Th1-mediated immune responses and prevents allogeneic myoblast rejection." Proc.Natl.Acad.Sci,USA. 93. 9085-9089 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yoshida T.: "Defective B-1 cell development and impaired immunity against angiostronglylus cantonensis in IL-5R deficient mice." Immunity. 4. 483-494 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kayagaki N.: "Metalloproteinase-mediated release of human Fas ligand." J.Exp.Med.182. 1777-1783 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kikuchi Y.: "CD38 ligation induces Btk activation and enhanced expression of IL-5 receptor a chain." Proc.Natl.Acad.Sci.USA. 92. 10879-10883 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Fukuda T.: "Restoration of surface IgM-mediated apoptosis in an anti-IgM resistant variant of WEHI-231 lymphoma cells by HS1,a protein tyrosine kinase substrate." Proc.Natl.Acad.Sci.USA. 92. 7302-7306 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nishizumi H.: "Impaired proliferation of peripheral B cells and indication of autoimmune disease in lym-deficient mice." Immunity. 3. 549-560 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Matsushita S.: "Allele specificity of structural requirement for peptides bound to HLA-DRB1^*040 and-DRB1^*0406 complexes:Implication for the HLA-associated susceptibility to methimazole-induced insulin autoimmune syndrome." J.Exp.Med.180. 873-883 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Seino K., et al.: "Anti-tumor effect of locally produced Fas ligand." Nature Medicine. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kaneko Y., et al.: "CD40-mediated stimulation of B1 and B2 cells : implication in autoantibody production in murine lupus" Eur.J.Immunol.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kato K., et al.: "Local production of IL-12 p40 suppresses Th1-mediated immune responses and prevents allogeneic myoblast rejection." Proc.Natl.Acad.Sci, USA. 93. 9085-9089 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yoshida T., et al.: "Defective B-1 cell development and impaired immunity against angiostronglylus cantonensis in IL-5R deficient mice." Immunity. 4. 483-494 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kayagaki N., et al.: "Metalloproteinase-mediated release of human Fas ligand." J.Exp.Med.182. 1777-1783 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] KiKuchi Y., et al.: "Cd38 ligation induced Btk activation and enhanced expression of IL-5 receptor a chain." Proc.Natl.Acad.Sci.USA. 92. 10879-10883 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Fukuda T., et al.: "Restoration of surface IgM-mediated apoptosis in an anti-IgM resistant variant of WEHI-231 lymphoma cells by HS1, a protein tyrosine kinase substrate." Proc.Natl.Acad.Sci.USA. 92. 7302-7306 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nishizumi H., et al.: "Impaired proliferation of peripheral B cells and indication of autoimmune disease in lym-deficient mice." Immunity. 3. 549-560 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Matsushita S., et al.: "Allele specificity of structural requirement for peptides bound to HLA-DRB1^<**>040 and -DRB1^<**>0406 complexes : Implication for the HLA-associated susceptibility to methimazole-induced-insulin autoimmune syndrome." J.Exp.Med.180. 873-883 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kayagaki,N.,: "Metalloproteinase-mediated release of human Fas ligand." J. Exp. Med.182. 1777-1783 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nagai,H.: "Increase in respiratory resistance sfter exercise in conscious guinea pigs as a model for exercise-induced asthma." Biol. Pharm. Bull.18. 37-41 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Sato,N.: "Thiol-mediated redox regulation of apoptosis: Possible roles of cellular thiols other than glutathinoe in T cell apoptosis." J. Immunol.154. 3194-3203 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hirose,S.: "Mapping of a gene for hypergammaglobulinemia to the distal region on chromosome 4 in NZB mice and its contribution to systemic lupus erythematosus in (NZB x NZW) F1 mice." Int. Immunol.6. 1857-1864 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kamoshita,K.: "Calcium requirement and inhibitor spectrum for intracellular HIV type 1 gp160 processing in cultured HeLa cells and CD4^+ lymphocytes: similarity to those of viral envelope glycoprotein maturase." J. Biochem.117. 1244-1253 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ikagawa,S.: "Single amino acid substitutions on a Japanese cedar pollen allergen (Cryj I)-derived peptide induced alterations in human T cell responses and T cell receptor antagonism:" J. Allergy Clin. Immunol.(in Press). (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nakamura,H.: "Adult T cell leukemia-derived factor/human thioredoxin protects endothelial F-2 cell injury caused by activated neutrophils or hydrogen peroxide" Immunology Letters. 42. 75-80 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hirose,S.: "Mapping of a gene for hypergammaglobulinemia to the distal region on chromosome 4 in NZB mice and its contribution to systemic lupus erythematosus in (NZB xNZW)F1 mice." Int.Immunol.6. 1857-1864 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Matsushita,S.: "Allele specificity of structural requirement for peptides bound to HLA-DRB1^*0405 and DRB1^*0406 complexes: Implication for the HLA-associated susceptibility to methimazole-induced insulin autoimmune syndorome." J.Exp.Med.180. 873-883 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Takaki,S.: "Critical cytoplasmic domain of the IL-5R α chain and its function in IL-5-mediated growth signal transduction." Mol.Cell.Biol.12. 7404-7413 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hara,H.: "Detection of human T lymphotropic Virus Type (HTLV-I) proviral DNA and analysis of T cell receptor Vβ CDR3 sequenccs in spinal cord lesions of HTLV-I associated myelopathy/Tropical spastic paraparesis." J.Experimental Medicine. 180. 831-839 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hanabuchi,S.: "Fas and its ligand in a general mechanism of T cell-mediated cytotoxity." Proc.Natl.Acad.Sci.,USA,. 91. 4930-4934 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Azuma,M.: "B70 antigen is a second ligand for CTLA-4 and CD28." Nature. 366. 76-79 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] S.Takai: "Reconatitution of the functional receptors for murine and human interelukin 5." J.Exp.Med.177. 1523-1529 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Nakamura,K.: "Redox regulation of a src family protein tyrosine kinase p56lck in T cells." Oncogene. 8. 3133-3139 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hirose,S.: "Somatic diversification and affinity maturation of IgM and IgG anti-DNA antibodies in murine lupus." Eur.J.Immunol.23. 2813-2810 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Yoshizumi,H.: "Generation of a movel CD8+ cytotoxic T lymphocyte that requires soluble factor to lyse autologous antigen-presenting cells." Eur.J.Immunol.23. 3173-3180 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Yamanashi,Y.: "Identification of HS1 protein as a major substrates of protein-throsine kinase(S) upon B cell antigen receptor-mediated signaling." Proc.Natl.Acd.Sci.USA.90. 3631-3535 (1993)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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