1996 Fiscal Year Annual Research Report

慢性関節リウマチの病因遺伝子の構造と機能の解析

Research Project

Project/Area Number	06044208
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)	STEFFEN Gay チューリッヒ大学, リウマチ科, 教授
Keywords	アポトーシス / HTLV-l 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。そお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-1tax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。更に滑膜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。

Research Products

(23 results)

All Other

All Publications (23 results)

[Publications] Y.Ikeda K.Masuko Y.Nakai T.Kato T.Hasunuma S.Yoshino Y.Mizushima K.Nishioka K.Yamamoto: "High frequencles of identlcal T cell clonolypes in synovlal llssues of rheumalold arthritls patlents suggest the occurrence of common antlgen-driven lmmune responses" Arthritls 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 Antl-Fas Antlbody on Arihritls 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.Nishioka I.Iwamoto Y.Saitoh T.Sumida: "Common T Cell Receptor Clonotype in Lacrimat Glands and Labial Sallvary Glands from Patlenls with Sjigren'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 Synovlat 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: "Characterlzation of T cell receptor beta chains of accumulating T cells in skin allogratts in mice" Transplantation. 62. 266-272 (1996)
[Publications] S.Matsumoto U.M.Ladner R.E.Gay K.Nishioka S.Gay: "Ultrastructual Demonstration of Apoptosis,Fas and Bcl-2 Expression of Rheumatold Synovial Fibroblasts" J.Rheumatol.23. 1345-1352 (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 Transcriptlon Factor NF-kB in Human Synovial Cells in Response to Tumor Necrosis Factor-alpha" Arthritis Rheum. 39. 197-203 (1996)
[Publications] K.Masuko S.Kato M.Hagihawa F.Tsuchida Y.Takemoto K.Izawa T.Kato S.Yamamori Y.Mizushima K.Nishioka K.Tsuji K.Yamamoto: "Stable clonal expansion of T cells induced by bone marrow transptantation" Btood. 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 Satazosuifapyridine and Buclllamine" J.Rheumatot.22. 65-70 (1996)
[Publications] S.Motokawa T.Hasunuma K.Tajima A.M.Krieg S.Ito K.Iwasaki K.Nishioka: "High Prevatence of Arthropathy in HTLV-1 Carriers on Japanese lstand" 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: "Antl-52 kDa (Ro) SSA Autoanttbodles in Different Autoimmune Diseases Preterenttally Recognize Epitopes on the Central Region of the Antigen" J.Rheumatol.23. 462-468 (1996)
[Publications] K.Nishioka T.Sumida T.Hasunuma: "Human T Lymphotropic Virus Type 1 in Arthropathy and Autolmmune Disorders" Arthritis Rheum. 39. 1410-1418 (1996)
[Publications] K.Nishioka: "HTLV-1 Arthropathy and Sjogren Syndrome" J.Acqutred Immune Deticiency 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 rheumatold arthritls" 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.Immunol.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-sensltive T cells from labiat salivary glands of pattents 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 labial sailvary glands from patlents 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 synovium with rheumatoid arthritis" J.Rheumatol.(IN PRESS).
[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 synovlocytes" Arthritis Rheum. (IN PRESS).
[Publications] T.Hasunuma N.Kayagaki H.Asahara S.Motokawa T.Kobata H.Yagita H.Aono T.Sumida K.Okumura K.Nishioka: "Accumutation of Sotuble Fas in inftamed Joints of Patients with Rheumatold Arthritis" Arthritis Rheum. (IN PRESS).
[Publications] T.Sumida T.T.M.Hoa H.Asahara T.Hasunuma K.Nishioka: "T cell receptor of Fas-sensitive T cells in rheumatold" J.Immunot.(IN PRESS).
[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 Fiscal Year Annual Research Report

慢性関節リウマチの病因遺伝子の構造と機能の解析

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.Fujisawa H.Asahara K.Okamoto H.Aono T.Hasunuma T.Kobata Y.Iwakura S.Yonehara T.Sumida K.Nishioka: "Therapeutic Effect of the Antl-Fas Antlbody on Arihritls 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.Nishioka I.Iwamoto Y.Saitoh T.Sumida: "Common T Cell Receptor Clonotype in Lacrimat Glands and Labial Sallvary Glands from Patlenls with Sjigren'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 Synovlat 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: "Characterlzation of T cell receptor beta chains of accumulating T cells in skin allogratts in mice" Transplantation. 62. 266-272 (1996)

[Publications] S.Matsumoto U.M.Ladner R.E.Gay K.Nishioka S.Gay: "Ultrastructual Demonstration of Apoptosis,Fas and Bcl-2 Expression of Rheumatold Synovial Fibroblasts" J.Rheumatol.23. 1345-1352 (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 Transcriptlon Factor NF-kB in Human Synovial Cells in Response to Tumor Necrosis Factor-alpha" Arthritis Rheum. 39. 197-203 (1996)

[Publications] K.Masuko S.Kato M.Hagihawa F.Tsuchida Y.Takemoto K.Izawa T.Kato S.Yamamori Y.Mizushima K.Nishioka K.Tsuji K.Yamamoto: "Stable clonal expansion of T cells induced by bone marrow transptantation" Btood. 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 Satazosuifapyridine and Buclllamine" J.Rheumatot.22. 65-70 (1996)

[Publications] S.Motokawa T.Hasunuma K.Tajima A.M.Krieg S.Ito K.Iwasaki K.Nishioka: "High Prevatence of Arthropathy in HTLV-1 Carriers on Japanese lstand" 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: "Antl-52 kDa (Ro) SSA Autoanttbodles in Different Autoimmune Diseases Preterenttally Recognize Epitopes on the Central Region of the Antigen" J.Rheumatol.23. 462-468 (1996)

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

[Publications] K.Nishioka: "HTLV-1 Arthropathy and Sjogren Syndrome" J.Acqutred Immune Deticiency 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 rheumatold arthritls" 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.Immunol.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-sensltive T cells from labiat salivary glands of pattents 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 labial sailvary glands from patlents 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 synovium with rheumatoid arthritis" J.Rheumatol.(IN PRESS).

[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 synovlocytes" Arthritis Rheum. (IN PRESS).

[Publications] T.Hasunuma N.Kayagaki H.Asahara S.Motokawa T.Kobata H.Yagita H.Aono T.Sumida K.Okumura K.Nishioka: "Accumutation of Sotuble Fas in inftamed Joints of Patients with Rheumatold Arthritis" Arthritis Rheum. (IN PRESS).

[Publications] T.Sumida T.T.M.Hoa H.Asahara T.Hasunuma K.Nishioka: "T cell receptor of Fas-sensitive T cells in rheumatold" J.Immunot.(IN PRESS).

[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).

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)