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1996 Fiscal Year Final Research Report Summary

Responsible proteins and genes for the development of intractable vasculitis

Research Project

Project/Area Number 07457583
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionThe Cancer Institute, Japanese Foundatiion for Cancer Research

Principal Investigator

KATO Mitsuyasu  The Cancer Inst., Jpn.Found.Cancer Res., Biochem, The Cancer Institute, Japanese Foundation for Cancer Research, Res.Fellow, 癌研究所生化学部, 研究員 (20194855)

Co-Investigator(Kenkyū-buntansha) NOSE Masato  Ehime Univ., Sch., Med., Pathol., Prof., 医学部, 教授 (70030913)
Project Period (FY) 1995 – 1996
Keywordsvasculitis / cytokine / Eta-1 / autoantibody / Fas / linkage analysis / IRF-1 / E-selectin
Research Abstract

Systemic vasculitis is a major complication of autoimmune diseases such as SLE and RA.However, it is still unclear whether this complication is a manifestation of advanced disease or represents distinct entities possibly restricted by genetic factors. An MRL/lpr strain of mice is one of the few animal models for systemic vasculitis, conicidentally developing lupus-like nephritis and artheritis. Using this strain, we clarified several responsible proteins and genes for the development and progression of systemic vasculitis as follows. 1. Taking advantage that the hybrid mice with non-vasculitis-prone C3H/lpr mice, (MRL/lprx C3H/lpr) xMRL/lpr, develop vasculitis at random, resulted from the rearrangement of the genetic background of MRL/lpr mice, we clarified that macrophage-relating cytokines have a limited pathogenic role in vasculitis. Moreover, one of these cytokines, Eta-1, had an allelic difference in the nucleotide sequence of the gene transcript between these two strains. 2. A ne … More wly established strain of mice, McH5/lpr, from the hybrid mice, developed severe vasculitis, but not glomerulonephritis and arthritis, indicating that vasculitis is under the control of genes different from those of other autoimmune diseases. Moreover, vasculitis in this strain was not associated with increased anti-DNA antibodies and pANCA.3. We established a novel vasculitis-prone mice with a deficit in the functional Fas ligand, MRL/gld, and succeeded in ameliorating vasculitis by the treatment with anti-Fas antibodies and, moreover, in transfer of vasculitis to normal mice. 4. By using MRL/lprx (MRL/lprx C3H/lpr) F1 mice, we performed the linkage analysis of vasculitis with microsatellite makers to find out vasculitis-susceptible gene loci. 5. Transfer of the interferon regulatory factor-1 gene, IRF-1, to MRL/lpr mice induced the suppression of vasculitis in these mice, indicating that vasculitis is under the control of the background genes regulatable by IRF-1.6. A transgenic mouse strain aberrantly expressing soluble E-selectin was newly established, in which the development of experimental lupusnephritis induced by the monoclonal antibodies derived from MRL/lpr mice was remarkably inhibited. This indicates that E-selectin is a critical molecule inducing microvascular injury in MRL/lpr mice. Less

  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Nose,M.,et al: "Arteritis in a novel congenic strain of mice derived from-HRL/lpr lupus mice" Am.J.Pathol. 149. 1763-1769 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nose,M.,et al: "Vascular lesicns in mice with a deficit in Fas-mediated apoptosis and their transfer" Int.J.Cardial.54(Suppl.). 35-44 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nose,M.,et al: "Nephritogenic antibodies and thrir development in autoimmune chsease mice with a doficit in Fas-mediated apoptosis" Acta Histochemica et Cytochemica. 29(Suppl.). 249-250 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Taniguchi,Y.,et al: "Role of macrophages in the development of arteritis in MRL strains of mice with a deficit in Fas-mediated apoptosis" Clin.Exp.Immunol.106. 26-34 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ito,R.M.,et al: "Rheamatic diseases in an MRL strain of mice with a deficit in functional Fas ligand" Arthritis Rheum.,in press.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nose,M.,et al: "Intractable Vasculitis Syndrome(分担)" Research Committee of Intractable Vasculitis syndrome of the Ministry of Health and Welfare of Japan, 104 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kato, M., et al.: "A human keratinocyte cell line produces two autocrine growth inhibitors, transforming growth factor-b and insulin-like growth factor binding protein-6, in a calcium-and cell density-dependent manner." J.Biol.Chem. 270. 12373-12379 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ono, M., et al.: "Allelic difference in the nucleotide sequence of the Eta-1/Op gene transcript." Mol.Immunol. 32. 447-448 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ono, M., et al.: "Sequence analysis of the germline VH gene corresponding to a nephritogenic antibody in MRL/lpr mice." Clin.Exp.Immunol.100. 284-290 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ono, M., et al.: "A novel germline VH gene encoding a murine nephritogenic autoantibody." Imunogenetics. 42. 426-427 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nose, M., et al.: "Vascular lesions in mice with a deficit in Fas-mediated apoptosis and their transfer." Int.J.Cardiol.54 (Suppl.). 35-44 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nose, M., et al.: "Ingestion of antibodies by endothelial cells : A novel mechanism for the development of glomerular injury." J.Vasc.Res.33 (Suppl.). 74 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Taniguchi, Y., et al.: "Role of macrophages in the development of arteritis in MRL strains of mice with a deficit in Fas-mediated apoptosis." Clin.Exp.Immunol.106. 26-34 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hosaka, N., et al.: "Thymus transplantation, a critical factor for correction of autoimmune disease in aging MRL/+mice." Proc.Natl.Acad.Sci.USA. 93. 8558-8562 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nose, M., et al.: "Arteritis in a novel congenic strain of mice derived from MRL/lpr lupus mice : Genetic dissociation from glomerulonephritis and limitted autoantibody production." Am.J.Pathol.149. 1763-1769 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nose, M., et al.: "Nephritogenic antibodies and their development in autoimmune disease mice with a deficit in Fas-mediated apoptosis." Acta Histochemica et Cytochemica. 29 (Suppl.). 249-250 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nose, M., et al.: Transfer of vascular lesions in lupus mice bearing Fas or Fas ligand mutant gene. In Intractable Vasculitis Syndromes (T.Nagasawa, ed.). Research Committee of Intractable Vasculitis Syndromes of the Ministry of Health and Welfare of Japan, 21-33 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ito, R.M., et al.: Rheumatic diseases in an MRL strain of mice with a deficit in functional Fas ligand.Arthritis Rheum., (in press.),

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

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Published: 1999-03-09  

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