1996 Fiscal Year Annual Research Report

慢性関節リウマチの病因遺伝子に関する研究

Research Project

Project/Area Number	05404028
Research Institution	St.Marianna University School of Medicine
Principal Investigator	西岡久寿樹聖マリアンナ医科大学, 難病治療研究センター, 教授 (60049070)
Co-Investigator(Kenkyū-buntansha)	住田孝之聖マリアンナ医科大学, 難病治療研究センター, 助教授 (00183054)
Keywords	アポトーシス / HTLV-1 tax遺伝子 / 単クローン性滑膜細胞 / 抗Fas抗体
Research Abstract	原因が不明で難治性疾患の代表とされている慢性関節リウマチ(RA)は、有病率も高い難治性疾患であり、我々の調査では70万人、年内発症1.5千人とされている。その成因は長い間不明であったが、我々は、世界に先駆けC型レトロウイルスの1つであるヒトT細胞白血病(HTLV-1)がRA類似の病変を招くことを臨床的、病理学的に明らかにした。さらにその後、このウイルスを構成するtax遺伝子が滑膜増殖に関与する遺伝子であることを明確にした。その後の分子医学的研究により、HTLV-1env-p40X遺伝子が世界で初めて、RAの病因遺伝子である事を突き止めた。また、研究途上、新たなフラビウイルス遺伝子の一群がリウマチの病因と密接に関連していることも明らかにしてきた。本研究はさらに、すでに我々のグループにより一般のRA患者滑膜細胞が特異的なアポトーシスをFas分子で誘導させることを明らかにした。この結果、Fas/FasLの分子間機構の解析がRAの病態形成及び治療戦略の確立上極めて重要であることを明らかにした。さらに滑膜T細胞の認識する抗原ペプチドを一部同定し、リウマチの病因究明に大きな足掛りができた。現在、peptide libraryを用いて、この解析を急いでいる。

Research Products

(24 results)

All Other

All Publications (24 results)

[Publications] K.Nishioka,T.Sumida,T.Hasunuma: "Human T Lymphotropic Virus Type 1 in Arthropathy and Autoimmune Disorders" Arthritis Rheum. 39. 1410-1418 (1996)
[Publications] K.Nishioka: "HTLV-1 in Arthropathy and Sjogren's Syndrome" Human T-cell Lymphotropic Type 1. 247-261 (1996)
[Publications] K.Fujisawa,H.Aono,T.Hasunuma K.Yamamoto,S.Mita,K.Nishioka: "Activation of Transcription Factor NF-kB in Human Synovial Cell in Response to Tumor Necrosis Factor-alpha" Arthritis Rheum. 39. 197-203 (1996)
[Publications] K.Masuko,S.Kato,M.Hagihara F.Tsuchida,Y.Takemoto,K.Izawa T.Kato,S.Yamamori,Y.Mizushima K.Nishioka,K.Tsuji,K.Yamamoto: "Stable clonal expansion of T cell induced by bone marrow transplantation" Blood. 87. 789-799 (1996)
[Publications] H.Aono,T.Hasunuma,K.Fujisawa T.Nakajima,K.Yamamoto,S.Mita K.Nishioka: "Direct Suppression of Human Synovial Cell Proliferation in Vitro by Salazosulfapyridine and Bucillamine" J. Rheumatol.22. 65-70 (1996)
[Publications] S.Motokawa,T.Hasunuma,K.Tajima A.M.Krieg.S.Ito,K.Iwasaki K.Nishioka: "High Prevalence of Arthropathy in HTLV-1 Carriers on Japanese Island" Ann. Rheum. Dis.55. 193-195 (1996)
[Publications] T.Dorner,E.Feist,A.Wagenmann T.Kato,K.Yamamoto,K.Nishioka G.R.Burmester,F.Hiepe: "Anti-52 kDa (Ro) SSA Autoantibodies in Different Autoimmune Diseases Preferentially Recognize Epitopes on the Central Region of the Antigen" J.Rheumatol.23. 462-468 (1996)
[Publications] Y.Ikeda,K.Masuko,Y.Nakai T.Kato,T.Hasunuma,S.Yoshino Y.Mizushima,K.Nishioka,K.Yamamoto: "High frequencies of identical T cell clonotypes in synovial tissues of rheumatoid arthritis patients suggest the occurrence of common antigen-driven immune responses" Arthritis Rheum. 39. 446-453 (1996)
[Publications] K.Fujisawa,H.Asahara,K.Okamoto H.Aono,T.Hasunuma,T.Kobata Y.Iwakura,S.Yonehara,T.Sumida K.Nishioka: "Therapeutic Effect of the Ant-Fas Anti-Fas Antibody on Arthritis in HTLV-1 tax Transgenic Mice" J. Clin. Invest.98. 271-278 (1996)
[Publications] I.Matsumoto,K.Tsubota,Y.Satake Y.Kita,R.Matsumura,H.Murata T.Namekawa,K.Nshioka,I.Iwamoto Y.Saitoh,T.Sumida: "Common T Cell Receptor Clonotype in Lacrimal Glands and Labial Salivary Glands from Patients with Sjogren's Syndrome" J. Clin. Invest.97. 1969-1977 (1996)
[Publications] T.T.M.Hoa,T.Hasunuma,H.Aono K.Masuko,T.Kobata,K.Yamamoto T.Sumida,K.Nishioka: "Novel Mechanisms of Selective Apoptosis in Synovial T Cells of Patients with Rheumatoid Arthritis" J. Rheumatol.23. 1332-1337 (1996)
[Publications] T.Kato,Y.Ikeda,Z.Zong H.Sasakawa,M.Kurokawa,K.Masuko R.Igarashi,Y.Mizushima,K.Nishioka K.Yamamoto: "Characterization of T cell receptor beta chains of accumulating T cells in skin allografts in mice" Transplantation. 62. 266-272 (1996)
[Publications] S.Matsumoto,U.M.Ladner,R.E.Gay K.Nishioka,S.Gay: "Ultrastrucutal Demonstration of Apoptosis, Fas and Bcl-2 Expression on Rheumatoid Synovial Fibroblasts" J. Rheumatol.23. 1345-1352 (1996)
[Publications] Y.Komagata,K.Masuko,F.Tashiro T.Kato,K.Ikuta,K.Nishioka K.Ito,J.Miyazaki,K.Yamamoto: "Clonal prevalence of T cells infiltrating into the pancreas of prediabetic NOD mice" Intern.Immunol.8. 807-814 (1996)
[Publications] K.Nishioka: "HTLV-1 Arthropathy and Sjogren Syndrome" J. Acquired Immune Deficiency Syndromes and Human Retroviorology. 13. 57-62 (1996)
[Publications] T.Hasunuma,T.T.M.Hoa,H.Aono H.Asahara,H.Yonehara,K.Yamamoto T.Sumida,S.Gay,K.Nishioka: "Induction of Fas-dependent apoptosis in synovial infiltrating cells in rheumatoid arthritis" Intern. Immunol.8. 1595-1602 (1996)
[Publications] H.Asahara,T.Hasunuma,T.Kobata H.Yagita,K.Okumura,H.Inoue S.Gay,T.Sumida,K.Nishioka: "Expression of Fas antigen and Fas ligand in the rheumatoid synovial tissue" Clin. Immun. Immunopath. 81. 27-34 (1996)
[Publications] T.Sumida,I.Matsumoto,H.Murata T.Namekawa,R.Matsuura,H.Tomioka I.Iwamoto,Y.Saito,Y.Mizushima T.Hasunuma,T.Maeda,K.Nishioka: "T cell receptor of Fas-sensitive T cells from labial salivary glands of patients with sjogren's syndrome" J. Immunol.22. 1020-1025 (1996)
[Publications] T.Sumida,T.Namekawa,T.Maeda K.Nishioka: "New T-cell epitope of Ro/SS-A 52kD protein in lablal salivary glands from patients with sjogren's syndrome" Lancet. 348. 1667 (1996)
[Publications] H.Asahara,T.Hasunuma,T.Kobata H.Inoue,U.M.Ladner,S.Gay T.Sumida,K.Nishioka: "In situ expression of protooncogenes and Fas/Fas ligand in the synovium with rheumatoid artritis" J.Rheumatol.(in press). (1996)
[Publications] T.Hasunuma,N.Kayagaki,H.Asahara S.Motokawa,T.Kobata,H.Yagita H.Aono,T.Sumida,K.Okumura K.Nshioka: "Accumulation of Soluble Fas in Inflamed Joints of Patients with Rheumatoid Arhritis" Arthritis Rheum. (in press). (1996)
[Publications] K.Okamoto,K.Fujisawa,T.Kobata T.Sumida,K.Nishioka: "Selective activation of JNK/AP-1 pathway in Fas-mediated apoptosis of rheumatoid arthritis synoviocytes" Arthritis Rheum. (in press). (1996)
[Publications] T.Sumida,T.T.M.Hoa,H.Asahara T.Hasunuma,K.Nishioka: "T cell receptor of Fas-sensitive T cells in rheumatoid synovium" J. Immunol.(in press). (1996)
[Publications] H.Asahara,K.Fujisawa,T.Kobata T.Hasunuma,T.Maeda,M.Asanuma N.Ogawa,H.Inoue,T.Sumida K.Nishioka: "Direct evidence of high DNA-binding activity of transcription factor AP-1 in the synovium with rheumatoid arthritis" Arthritis Rheum. (in press). (1996)

1996 Fiscal Year Annual Research Report

慢性関節リウマチの病因遺伝子に関する研究

Principal Investigator

西岡 久寿樹 聖マリアンナ医科大学, 難病治療研究センター, 教授 (60049070)

Research Products

[Publications] K.Nishioka,T.Sumida,T.Hasunuma: "Human T Lymphotropic Virus Type 1 in Arthropathy and Autoimmune Disorders" Arthritis Rheum. 39. 1410-1418 (1996)

[Publications] K.Nishioka: "HTLV-1 in Arthropathy and Sjogren's Syndrome" Human T-cell Lymphotropic Type 1. 247-261 (1996)

[Publications] K.Fujisawa,H.Aono,T.Hasunuma K.Yamamoto,S.Mita,K.Nishioka: "Activation of Transcription Factor NF-kB in Human Synovial Cell in Response to Tumor Necrosis Factor-alpha" Arthritis Rheum. 39. 197-203 (1996)

[Publications] K.Masuko,S.Kato,M.Hagihara F.Tsuchida,Y.Takemoto,K.Izawa T.Kato,S.Yamamori,Y.Mizushima K.Nishioka,K.Tsuji,K.Yamamoto: "Stable clonal expansion of T cell induced by bone marrow transplantation" Blood. 87. 789-799 (1996)

[Publications] H.Aono,T.Hasunuma,K.Fujisawa T.Nakajima,K.Yamamoto,S.Mita K.Nishioka: "Direct Suppression of Human Synovial Cell Proliferation in Vitro by Salazosulfapyridine and Bucillamine" J. Rheumatol.22. 65-70 (1996)

[Publications] S.Motokawa,T.Hasunuma,K.Tajima A.M.Krieg.S.Ito,K.Iwasaki K.Nishioka: "High Prevalence of Arthropathy in HTLV-1 Carriers on Japanese Island" Ann. Rheum. Dis.55. 193-195 (1996)

[Publications] T.Dorner,E.Feist,A.Wagenmann T.Kato,K.Yamamoto,K.Nishioka G.R.Burmester,F.Hiepe: "Anti-52 kDa (Ro) SSA Autoantibodies in Different Autoimmune Diseases Preferentially Recognize Epitopes on the Central Region of the Antigen" J.Rheumatol.23. 462-468 (1996)

[Publications] K.Fujisawa,H.Asahara,K.Okamoto H.Aono,T.Hasunuma,T.Kobata Y.Iwakura,S.Yonehara,T.Sumida K.Nishioka: "Therapeutic Effect of the Ant-Fas Anti-Fas Antibody on Arthritis in HTLV-1 tax Transgenic Mice" J. Clin. Invest.98. 271-278 (1996)

[Publications] I.Matsumoto,K.Tsubota,Y.Satake Y.Kita,R.Matsumura,H.Murata T.Namekawa,K.Nshioka,I.Iwamoto Y.Saitoh,T.Sumida: "Common T Cell Receptor Clonotype in Lacrimal Glands and Labial Salivary Glands from Patients with Sjogren's Syndrome" J. Clin. Invest.97. 1969-1977 (1996)

[Publications] T.T.M.Hoa,T.Hasunuma,H.Aono K.Masuko,T.Kobata,K.Yamamoto T.Sumida,K.Nishioka: "Novel Mechanisms of Selective Apoptosis in Synovial T Cells of Patients with Rheumatoid Arthritis" J. Rheumatol.23. 1332-1337 (1996)

[Publications] T.Kato,Y.Ikeda,Z.Zong H.Sasakawa,M.Kurokawa,K.Masuko R.Igarashi,Y.Mizushima,K.Nishioka K.Yamamoto: "Characterization of T cell receptor beta chains of accumulating T cells in skin allografts in mice" Transplantation. 62. 266-272 (1996)

[Publications] S.Matsumoto,U.M.Ladner,R.E.Gay K.Nishioka,S.Gay: "Ultrastrucutal Demonstration of Apoptosis, Fas and Bcl-2 Expression on Rheumatoid Synovial Fibroblasts" J. Rheumatol.23. 1345-1352 (1996)

[Publications] Y.Komagata,K.Masuko,F.Tashiro T.Kato,K.Ikuta,K.Nishioka K.Ito,J.Miyazaki,K.Yamamoto: "Clonal prevalence of T cells infiltrating into the pancreas of prediabetic NOD mice" Intern.Immunol.8. 807-814 (1996)

[Publications] K.Nishioka: "HTLV-1 Arthropathy and Sjogren Syndrome" J. Acquired Immune Deficiency Syndromes and Human Retroviorology. 13. 57-62 (1996)

[Publications] T.Hasunuma,T.T.M.Hoa,H.Aono H.Asahara,H.Yonehara,K.Yamamoto T.Sumida,S.Gay,K.Nishioka: "Induction of Fas-dependent apoptosis in synovial infiltrating cells in rheumatoid arthritis" Intern. Immunol.8. 1595-1602 (1996)

[Publications] H.Asahara,T.Hasunuma,T.Kobata H.Yagita,K.Okumura,H.Inoue S.Gay,T.Sumida,K.Nishioka: "Expression of Fas antigen and Fas ligand in the rheumatoid synovial tissue" Clin. Immun. Immunopath. 81. 27-34 (1996)

[Publications] T.Sumida,I.Matsumoto,H.Murata T.Namekawa,R.Matsuura,H.Tomioka I.Iwamoto,Y.Saito,Y.Mizushima T.Hasunuma,T.Maeda,K.Nishioka: "T cell receptor of Fas-sensitive T cells from labial salivary glands of patients with sjogren's syndrome" J. Immunol.22. 1020-1025 (1996)

[Publications] T.Sumida,T.Namekawa,T.Maeda K.Nishioka: "New T-cell epitope of Ro/SS-A 52kD protein in lablal salivary glands from patients with sjogren's syndrome" Lancet. 348. 1667 (1996)

[Publications] H.Asahara,T.Hasunuma,T.Kobata H.Inoue,U.M.Ladner,S.Gay T.Sumida,K.Nishioka: "In situ expression of protooncogenes and Fas/Fas ligand in the synovium with rheumatoid artritis" J.Rheumatol.(in press). (1996)

[Publications] T.Hasunuma,N.Kayagaki,H.Asahara S.Motokawa,T.Kobata,H.Yagita H.Aono,T.Sumida,K.Okumura K.Nshioka: "Accumulation of Soluble Fas in Inflamed Joints of Patients with Rheumatoid Arhritis" Arthritis Rheum. (in press). (1996)

[Publications] K.Okamoto,K.Fujisawa,T.Kobata T.Sumida,K.Nishioka: "Selective activation of JNK/AP-1 pathway in Fas-mediated apoptosis of rheumatoid arthritis synoviocytes" Arthritis Rheum. (in press). (1996)

[Publications] T.Sumida,T.T.M.Hoa,H.Asahara T.Hasunuma,K.Nishioka: "T cell receptor of Fas-sensitive T cells in rheumatoid synovium" J. Immunol.(in press). (1996)

[Publications] H.Asahara,K.Fujisawa,T.Kobata T.Hasunuma,T.Maeda,M.Asanuma N.Ogawa,H.Inoue,T.Sumida K.Nishioka: "Direct evidence of high DNA-binding activity of transcription factor AP-1 in the synovium with rheumatoid arthritis" Arthritis Rheum. (in press). (1996)

西岡久寿樹聖マリアンナ医科大学, 難病治療研究センター, 教授 (60049070)