2002 Fiscal Year Annual Research Report

慢性関節リウマチの臨床応用を目的としたアポトーシス誘導療法―ヒトモノクロナール抗体療法を用いたRA患者組織移植SCID-HuRAgマウスの解析―

Research Project

Project/Area Number	11470306
Research Institution	TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
Principal Investigator	松野博明富山医科薬科大学, 医学部, 助教授 (00219461)
Co-Investigator(Kenkyū-buntansha)	米原伸京都大学, ウイルス研究所, 教授 (00124503) 木村友厚富山医科薬科大学, 医学部, 教授 (80167379) 遊道和雄富山医科薬科大学, 医学部, 助手 (60272928)
Keywords	アポトーシス / SCID-HuRAgマウス / 滑膜 / 軟骨 / 関節リウマチ / モノクロナール抗体 / ヒト化抗体 / マトリックスメタロプロテアーゼ
Research Abstract	関節リウマチ(RA)の新しい治療を確立するためヒト型抗Fas抗体(hHFE7A)を用いた治療実験をSCIDマウスの背部にヒトRA組織を移植したSCID-HuRAgマウスを利用して行った。研究を開始するにあたりSCID-HuRAgマウスのRAモデルとしての妥当性も多方面から検討したが、このマウスではヒトRAに見られる組織所見が観察されるばかりでなく、血清のグロブリンやIL-6に加えリウマチ因子も産生されていることが明らかとなった。すなわち本モデルはヒトRAの研究を施行するにあたり極めて有意義なモデルであることが確認された。またこのモデルを用いた抗Fas抗体の治療実験の結果、ヒトの関節組織にアポトーシスを誘導することは、確かに炎症滑膜に対する抑制効果を持つが、その一方で正常軟骨にも障害を与えることが確認された。そこで抗体をそれまでのIgM型から2次抗体の必要なIgG型に変更したところRA組織の炎症細胞のみに選択的にアポトーシスを誘導出来ることが判明した。またこの理由として生体内では2次抗体の代わりにFcα陽性細胞が働いていることが分かった。以上よりIgG化したヒト型抗Fas抗体はRAの炎症細胞のみにアポトーシスを誘導する、新しい抗RA剤としての可能性があることが示された。

Research Products
(25 results)

All Other

All Publications (25 results)

[Publications] Yudoh K., Matsuno H., et al.: "1α-25-dihydroxyvitamin D3 inhibits the in vivo invasiveness through the extracellular matrix and in vivo pulmonary metastasis of B16 mouse melanoma"J Lab Glin Med. 133・2. 120-128 (1999)
[Publications] Matsuno H., Yudoh K., et al.: "Biochemical effect of intraarticular injections of high molecular weight hyaluronate in rheumatoid arthritis patients"Inflam Res. 48・3. 154-159 (1999)
[Publications] Yudoh K., Matsuno H., et al.: "Different mechanisms of synovial hyperplasia in RA and pigmented villonodular synovitis.-the role of telomerase activity in synovial proliferation-"Arthritis Rheum. 42・4. 669-677 (1999)
[Publications] Yudoh K., Matsuno H., et al.: "Plasma adrenomedullin in rheumatoid arthritis compared with other rheumatic diseases"Arthritis Rheum. 42・6. 1297-1298 (1999)
[Publications] Koizumi F., Matsuno H., et al.: "Synovitis in rheumatoid arthritis : scoring of characteristic histopathological features"Pathol International. 49・4. 298-304 (1999)
[Publications] Mima T., Ohshima S., Matsuno H., et al.: "Dominant and shared T Cell receptor (dhain variable regions of T cells inducing sunovial hyperplasia in rheumatoid arthritis"Biochem Biophy Res Com. 263. 172-180 (1999)
[Publications] Watanabe Y., Yarnaguchi R., Matsuno H., et al.: "Activation of progelatinase B in synovial fluids of patients with rheumatoid arthritis, with reference to stromelysin-1 and tissue inhibitor of matrix metalloproteinase-1"Clin Exp Rheumatol. 17・4. 401-406 (1999)
[Publications] Yudoh K., Matsuno H., et al.: "Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis"Arthritis Rheum. 43・3. 617-627 (2000)
[Publications] Matsuno H., Yasuda T., et al.: "Total hip arthroplasty using a cementless cup supporter for treatment of protrusio acetabuli in patients with rheumatoloid arthritis"Int Orthop. 24. 15-18 (2000)
[Publications] Yudoh K., Matsuno H., et al.: "Decreased cellular activity and replicative capacity of osteoblastic cells isolated from the replicarticular bone of rheumatoid arthritis patients compared with osteoarthritis patients"Arthritis Rheum. 43・10. 2178-2188 (2000)
[Publications] Matsuno H., Yudoh K., et al.: "Stromelysin-1 (MMP-3) in synovial fluid of patients with rheumatoid arthritis has potential to cleave membrane bound Fas ligand"J Rheumatol. 28・1. 22-28 (2001)
[Publications] Iwanaga-Egawa S., Watanabe Y., Matsuno H.: "Correlation between matrix metaroproteinase-9 and adenosine deaminase isozymes in synovial fluid from patients with rheumatoid arthritis"J Rheumatol. 28・3. 485-489 (2001)
[Publications] Yudoh K., Matsuno H., et al.: "Reconstituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblast"J Bone Miner Res. 16・8. 1453-1464 (2001)
[Publications] Goto M., Matsuno H., et al.: "Intra-articular injection of hyaluronate (SI-6601D) improves joint pain and synovial fluid prostaglandin E2 levels in rheumatoid arthritis : a multicenter clinical trial"Clin Exp Rheumatol. 19・4. 377-383 (2001)
[Publications] Nakazawa F., Matsuno H., et al.: "Methotrexate inhibits rheumatoid synovitis by inducing apoptosis"J Rheumatol. 28・8. 1800-1808 (2001)
[Publications] Watanabe Y., Matsuno H., et al.: "Induction of a novel gelatinolytic activity in synovial tissue of patients with rheumatoid arthritis"Res Commun Mol Pathol Pharmacol. 107. 239-251 (2001)
[Publications] Matsuno H., Yudoh K., et al.: "The role of TNF-α in the pathogenesis of inflammation and joint destruction in RA : A study using a human RA/SCID mice chimera"Rheumatology. 41. 329-337 (2002)
[Publications] Matsuno H., Yudoh K., et al.: "Treatment with Angiogenesis Inhibitor Endostatin Represents a Novel Therapeutic Approach in Patients with Rheumatoid Arthritis"J Rheumatol. 29. 890-895 (2002)
[Publications] Matsuno H., Yudoh K., et al.: "Antirheumatic effects of humanized anti-Fas monoclonal antibody in human Rheumatoid Arthritis/SCID mice Chimera"J Rheumatol. 29. 1609-1614 (2002)
[Publications] Ohshima S., Matsuno H., et al.: "Enhanced local production of osteopontin in rheumatoid arthritis"J Rheumatol. 29. 2061-2067 (2002)
[Publications] Matsuno H., Yudoh K., et al.: "Relationship between histological findings and clinical findings in rheumatoid arthritis"Pathol International. 52・8. 527-533 (2002)
[Publications] Nakazawa F., Matsuno H., et al.: "Corticosteroid treatment induces chondrocyte apoptosis in an experimental arthritis model and in chondrocyte cultures"Clin Exp Rheumatol. 20・6. 773-781 (2002)
[Publications] Kawaguchi Y., Matsuno H., et al.: "Radiologic findings of the lumbar spine in patients with rheumatoid arthritis, and review of pathologic mechanisms"J Spinal Disord Tech. 16・1. 38-43 (2002)
[Publications] Matsuno H., Yudoh K., Uzuki M., Kimura T.: "The SCID-HuRAg mouse as a model for rheumatoid arthritis"Mod Rheumatol. 11. 6-9 (2001)
[Publications] Yudoh K., Matsuno H.: "The role of telomerase in joint deterioration in rheumatoid arhritis"Drug Today. 9. 53-62 (2001)

2002 Fiscal Year Annual Research Report

慢性関節リウマチの臨床応用を目的としたアポトーシス誘導療法―ヒトモノクロナール抗体療法を用いたRA患者組織移植SCID-HuRAgマウスの解析―

Principal Investigator

松野 博明 富山医科薬科大学, 医学部, 助教授 (00219461)

Research Products

[Publications] Yudoh K., Matsuno H., et al.: "1α-25-dihydroxyvitamin D3 inhibits the in vivo invasiveness through the extracellular matrix and in vivo pulmonary metastasis of B16 mouse melanoma"J Lab Glin Med. 133・2. 120-128 (1999)

[Publications] Matsuno H., Yudoh K., et al.: "Biochemical effect of intraarticular injections of high molecular weight hyaluronate in rheumatoid arthritis patients"Inflam Res. 48・3. 154-159 (1999)

[Publications] Yudoh K., Matsuno H., et al.: "Different mechanisms of synovial hyperplasia in RA and pigmented villonodular synovitis.-the role of telomerase activity in synovial proliferation-"Arthritis Rheum. 42・4. 669-677 (1999)

[Publications] Yudoh K., Matsuno H., et al.: "Plasma adrenomedullin in rheumatoid arthritis compared with other rheumatic diseases"Arthritis Rheum. 42・6. 1297-1298 (1999)

[Publications] Koizumi F., Matsuno H., et al.: "Synovitis in rheumatoid arthritis : scoring of characteristic histopathological features"Pathol International. 49・4. 298-304 (1999)

[Publications] Mima T., Ohshima S., Matsuno H., et al.: "Dominant and shared T Cell receptor (dhain variable regions of T cells inducing sunovial hyperplasia in rheumatoid arthritis"Biochem Biophy Res Com. 263. 172-180 (1999)

[Publications] Watanabe Y., Yarnaguchi R., Matsuno H., et al.: "Activation of progelatinase B in synovial fluids of patients with rheumatoid arthritis, with reference to stromelysin-1 and tissue inhibitor of matrix metalloproteinase-1"Clin Exp Rheumatol. 17・4. 401-406 (1999)

[Publications] Yudoh K., Matsuno H., et al.: "Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis"Arthritis Rheum. 43・3. 617-627 (2000)

[Publications] Matsuno H., Yasuda T., et al.: "Total hip arthroplasty using a cementless cup supporter for treatment of protrusio acetabuli in patients with rheumatoloid arthritis"Int Orthop. 24. 15-18 (2000)

[Publications] Yudoh K., Matsuno H., et al.: "Decreased cellular activity and replicative capacity of osteoblastic cells isolated from the replicarticular bone of rheumatoid arthritis patients compared with osteoarthritis patients"Arthritis Rheum. 43・10. 2178-2188 (2000)

[Publications] Matsuno H., Yudoh K., et al.: "Stromelysin-1 (MMP-3) in synovial fluid of patients with rheumatoid arthritis has potential to cleave membrane bound Fas ligand"J Rheumatol. 28・1. 22-28 (2001)

[Publications] Iwanaga-Egawa S., Watanabe Y., Matsuno H.: "Correlation between matrix metaroproteinase-9 and adenosine deaminase isozymes in synovial fluid from patients with rheumatoid arthritis"J Rheumatol. 28・3. 485-489 (2001)

[Publications] Yudoh K., Matsuno H., et al.: "Reconstituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblast"J Bone Miner Res. 16・8. 1453-1464 (2001)

[Publications] Goto M., Matsuno H., et al.: "Intra-articular injection of hyaluronate (SI-6601D) improves joint pain and synovial fluid prostaglandin E2 levels in rheumatoid arthritis : a multicenter clinical trial"Clin Exp Rheumatol. 19・4. 377-383 (2001)

[Publications] Nakazawa F., Matsuno H., et al.: "Methotrexate inhibits rheumatoid synovitis by inducing apoptosis"J Rheumatol. 28・8. 1800-1808 (2001)

[Publications] Watanabe Y., Matsuno H., et al.: "Induction of a novel gelatinolytic activity in synovial tissue of patients with rheumatoid arthritis"Res Commun Mol Pathol Pharmacol. 107. 239-251 (2001)

[Publications] Matsuno H., Yudoh K., et al.: "The role of TNF-α in the pathogenesis of inflammation and joint destruction in RA : A study using a human RA/SCID mice chimera"Rheumatology. 41. 329-337 (2002)

[Publications] Matsuno H., Yudoh K., et al.: "Treatment with Angiogenesis Inhibitor Endostatin Represents a Novel Therapeutic Approach in Patients with Rheumatoid Arthritis"J Rheumatol. 29. 890-895 (2002)

[Publications] Matsuno H., Yudoh K., et al.: "Antirheumatic effects of humanized anti-Fas monoclonal antibody in human Rheumatoid Arthritis/SCID mice Chimera"J Rheumatol. 29. 1609-1614 (2002)

[Publications] Ohshima S., Matsuno H., et al.: "Enhanced local production of osteopontin in rheumatoid arthritis"J Rheumatol. 29. 2061-2067 (2002)

[Publications] Matsuno H., Yudoh K., et al.: "Relationship between histological findings and clinical findings in rheumatoid arthritis"Pathol International. 52・8. 527-533 (2002)

[Publications] Nakazawa F., Matsuno H., et al.: "Corticosteroid treatment induces chondrocyte apoptosis in an experimental arthritis model and in chondrocyte cultures"Clin Exp Rheumatol. 20・6. 773-781 (2002)

[Publications] Kawaguchi Y., Matsuno H., et al.: "Radiologic findings of the lumbar spine in patients with rheumatoid arthritis, and review of pathologic mechanisms"J Spinal Disord Tech. 16・1. 38-43 (2002)

[Publications] Matsuno H., Yudoh K., Uzuki M., Kimura T.: "The SCID-HuRAg mouse as a model for rheumatoid arthritis"Mod Rheumatol. 11. 6-9 (2001)

[Publications] Yudoh K., Matsuno H.: "The role of telomerase in joint deterioration in rheumatoid arhritis"Drug Today. 9. 53-62 (2001)

松野博明富山医科薬科大学, 医学部, 助教授 (00219461)