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1995 Fiscal Year Final Research Report Summary

Analysis of the mechanism of abnormal B cell activation characteristic of various autoimmune diseases

Research Project

Project/Area Number 06670500
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field 内科学一般
Research InstitutionTeikyo University

Principal Investigator

HIROHATA Shunsei  Teikyo University, School of Medicine, Lecturer, 医学部, 講師 (90189895)

Co-Investigator(Kenkyū-buntansha) YANAGIDA Tamiko  Teikyo University, School of Medicine, Assistant, 医学部, 助手 (80082204)
HIRAOKA Hitomi  Teikyo University, School of Medicine, Assistant, 医学部, 助手 (60228632)
HASHIMOTO Takashi  Teikyo University, Faculty of Economy, Professor, 経済学部(医学部兼担), 教授 (30082142)
Project Period (FY) 1994 – 1995
KeywordsB cells / cell cycle / IL-2 / IL-10 / cyclin A / mRNA / apoptosis / mizoribine
Research Abstract

The current studies were undertaken to explore the mechanisms of abnormal B cell activation in autoimmune disease. For this purpose, special attention was paid to the regulation of cell cycle progression of human B cells and the influences of cytokines, including IL-10 and IL-2. First, we examined in detail the regulation of the survival of human peripheral blood B cells by IL-10 and its relevance to the Ig production. Highly purified B cells from healthy adult individuals were cultured with Staphylococcus aureus Cowan I (SA) in the presence or absense of IL-10. When IL-10 was present during the initial activation of B cells with SA,IL-10 faciliated the apoptosis of SA activated B cells, thus resulting in the very modest IgM production. IL-2 prevented the IL-10-mediated progression of the apoptosis of SA activated B cells during the initial activation, and thus restored the further differentiation of these B cells into Ig secreting cells. By contrast, IL-10 rather rescued SA activated … More B cells from apoptosis and thus supported the differentiation of these B cells without any influences of IL-2, when it was added after 72h of cultures. These results indicate that the effects of IL-10 are different depending on the state of activation of B cells after ligation of antigen receptors.
Recent clinical trials have demonstrated the efficacy of mizoribine in rheumatoid arthritis and lupus nephritis, in which abnormalities of B cell functions are also involved. We therefore examined the effects of mizoribine on the in vitro function of human B cells. IgM production was induced from highly purified B cells obtained from healthy donors by stimulation with Staphylococcus aureus Cown I (SA) plus IL-2. Mizoribine suppressed the production of IgM at its pharmacologically attainable concentrations (0.3-3mug/ml) in a dose-dependent manner. Time kinetics study revealed that mizoribine was requied to be present within the first 120 hr after the initiation of cultures to exert its suppressive effects on B cell responses. Cell cycle analysis by staining with propidium iodide disclosed that mizoribine suppressed the G1-S transition of activated B cells. The suppressive effects of mizoribine on the IgM production was not reversed by repletion of GTP with supplementation of GMP.Althogh mizoribine did not suppress the expression of CD25 and cdc2 kinase in B cells, mizoribine markedly suppressed the expression of cyclin A in SA activated B cells at the mRNA levels. These results indicate that mizoribine suppresses the production of IgM by directly inhibiting B clls with out interfering with the initial phase of activation. Moreover, the data demonstrate that mizoribine inhibits the G1-S transition of activated B cells in the cell cycle by suppressing the expression of cyclin A by a mechanism distinct from guanine ribonucleotide depletion. Less

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Hirohata S.,et al.: "Association of anti-Sm antibodies with organic brain syndrome secondary to systemic lupus erythematosus." Lancet. 343. 796 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Itoh K.,et al.: "The interplay of interleukin-10 (IL-10) and interleukin-2 (IL-2) in humoral immune responses : IL-10 synergizes with IL-2 to enhance responses of human B lymphocytes in a mechanism which is different from upregulation of CD25 expression." Cell Immunol. 157. 478-488 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirohata S.,et al.: "Interactions between lymphocytes and type A synoviocytes in rheumatoid synovium." Lancet. 344. 1158 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirohata S.,et al.: "Selective induction of IgM rheumatoid factors by CD14+ monocyte-lineage cells generated from bone marrow of patients with rheumatoid arthritis." Arthritis Rheum. 38. 384-388 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Itoh K.,et al.: "The role of IL-10 in human B cell activation,proliferation,and differentiation." J Immunol. 154. 4341-4350 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirohata S.,et al.: "Inhibition of expression of cyclin A in human B cells by an immunosuppressant mizoribine." J Immunol. 155. 5175-5183 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hirihata S,et al.: "Polymorphonuclear neutrophilis enhance suppressive activities of anti-CD3-induced CD4+ suppressor T cells." Cell Immunol. Vol.160. 270-277 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirihata S,et al.: "Selective induction of IgM rheumatoid factors by CD14+ monocyte-lineage cells generated from bone marrow of patients with rheumatoid arthritis." rthritis Rheum. Vol.38. 384-388 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Itoh K,et al.: "The role of IL-10 in human B cell activation, proliferation, and differentiation." J Immunol. Vol.154. 4341-4350 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oguchi H,et al.: "Familial systemic lupus erythematosus : analysis of extended haplotypes of major histocompatibility complex antigens." Lupus. Vol.4. 243-244 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kawasaki T,et al.: "T cell lymphoma masquerading as adult onset Still's disease." Clin Exp Rheumatol. Vol.13. 410-411 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hirihata S,et al.: "Inhibition of expression of cyclin A in human B cells by an immunosuppressant mizoribine." J Immunol. Vol.155. 5175-5183 (1995)

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

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Published: 1997-03-04  

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