Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice.

Fujisawa, Kotaro; Asahara, Hiroshi; Okamoto, Kazuyoshi; Aono, Hiroyuki; Hasunuma, Tomoko; Kobata, Tetsuji; Iwakura, Yoichiro; Yonehara, Shin; Sumida, Takayuki; Nishioka, Kusuki

doi:10.1172/jci118789

Cited by 119 publications

(70 citation statements)

References 30 publications

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“…Based on these findings, we postulated that active induction of apoptosis in proliferative rheumatoid synovium may be useful as a new mode of therapy for RA. 14 In support of our hypothesis, we have recently demonstrated that intra-articular administration of anti-Fas mAb in the human T cell leukemia virus type 1 (HTLV-1) carrying mice, which was established by our group as a suitable model of human RA, improved the paw swelling and histologic features of arthritis by inducing apoptosis of synoviocytes and mononuclear cells in the inflamed synovium. 14 In contrast, administration of antiFas mAb or soluble FasL in mice was cytotoxic to other Fas-bearing tissues such as the liver, and induced fulminant hepatitis.…”

Section: Discussionsupporting

confidence: 57%

“…14 In support of our hypothesis, we have recently demonstrated that intra-articular administration of anti-Fas mAb in the human T cell leukemia virus type 1 (HTLV-1) carrying mice, which was established by our group as a suitable model of human RA, improved the paw swelling and histologic features of arthritis by inducing apoptosis of synoviocytes and mononuclear cells in the inflamed synovium. 14 In contrast, administration of antiFas mAb or soluble FasL in mice was cytotoxic to other Fas-bearing tissues such as the liver, and induced fulminant hepatitis. 15,16 While the above results provide strong support for a potential therapeutic use of RA synoviocyte apoptosis-inducing agents, they also indicate that further …”

Section: Discussionsupporting

confidence: 57%

“…13 Using this model, we have recently demonstrated that intra-articular administration of anti-Fas MAb improved the paw swelling and histological features of arthritis by induction of apoptosis of both synoviocytes and mononuclear cells in the inflamed synovium. 14 These findings clearly suggest that apoptosis via the Fas/FasL system may be an important factor for regression of proliferative rheumatoid synovium and administration of anti-Fas MAb could be a novel therapeutic strategy for RA.…”

Section: Introductionmentioning

confidence: 77%

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Induction of apoptosis in the rheumatoid synovium by Fas ligand gene transfer

et al. 1998

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We have recently reported that local administration of antiactivity against RA synoviocytes via the Fas/FasL system Fas monoclonal antibody (MAb) in human T cell leukemia in vitro. Histopathological and immunohistochemical studvirus type 1 (HTLV-1) carrying mice improved arthritis due ies showed that local injection of irradiated-hFasL transfecto the induction of apoptosis. This finding strongly indicated tants eliminated synoviocytes and mononuclear cells in the beneficial therapeutic effect of Fas-mediated apoptosis engrafted human rheumatoid synovium of SCID-RA mice. in rheumatoid arthritis (RA). To establish further the theraFurthermore, in situ nick end labeling analysis confirmed peutic effect of Fas-mediated apoptosis on RA taking into that the cells in engrafted synovium frequently underwent consideration safety and practicality, we investigated the apoptosis by irradiated-hFasL transfectants. Our results effect of cells transfected with human Fas ligand (hFasL) clearly demonstrated that hFasL transfectants induced gene on proliferating human rheumatoid synovium apoptosis by cell-to-cell interaction via the Fas/FasL sysengrafted in severe combined immunodeficiency (SCIDtem. Thus, ex vivo gene transfer of FasL may represent a RA) mice. The hFasL transfectants exhibited cytotoxic novel therapeutic strategy for RA.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 77%

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Induction of apoptosis in the rheumatoid synovium by Fas ligand gene transfer

et al. 1998

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“…Thus, growth of an intraperitoneal lymphoma can be controlled by intraperitoneal CD95 ligand applied locally (Rensing-Ehl et al, 1995), and intra-articular application of CD95 antibodies can control arthritis (Fujisawa et al, 1996), both in the absence of systemic toxicity. Further, circulation of CD95 ligand is not inevitably lethal (Sato et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Taxol-mediated augmentation of CD95 ligand-induced apoptosis of human malignant glioma cells: association with bcl-2 phosphorylation but neither activation of p53 nor G2/M cell cycle arrest

Roth

Wagenknecht²,

Grimmel³

et al. 1998

Br J Cancer

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Summary The anti-tumour alkaloid taxol shows strong cytotoxic and antiproliferative activity in two human malignant glioma cell lines, T98G and LN-229. CD95 (Fas/APO-1) ligand is a novel cytotoxic cytokine of the tumour necrosis factor (TNF) family that exerts prominent antiglioma activity. At clinically relevant taxol concentrations of 5-100 nM, taxol and CD95 ligand showed significant synergistic cytotoxicity and growth inhibition. High concentrations of taxol induced G/M cell cycle arrest in both cell lines. The synergy of taxol and CD95 ligand was independent of cell cycle effects of taxol as synergy was achieved at much lower taxol concentrations than G/M arrest and as cell cycle effects of taxol were unaffected by co-exposure to CD95 ligand. Similarly, high concentrations of taxol were required to induce p53 activity in the p53 wild-type cell line LN-229. This effect was not modulated by CD95 ligand, suggesting that synergy is also independent of p53 activation. However, taxol induced a mobility shift of the bcl-2 protein on immunoblot analysis, indicative of bcl-2 phosphorylation. Bcl-2 phosphorylation on serine was confirmed by immunoprecipitation and phosphoserine immunoblot analysis. Considering (1) that phosphorylation of bcl-2 interferes with its heterodimerization with bax and (2) the inhibition of CD95-mediated apoptosis by bcl-2, we propose that taxol sensitizes malignant glioma cells to CD95 ligand by increasing the functional bax/bcl-2 rheostat in favour of bax and thus cell death.

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“…A high amount of tax mRNA was amplified in synovial cclls from these HTLV-I tax-transgenic mice, and sensitivity to anti-Fas antibody was acquired in vivo (27). Moreover, Yoshiki and colleagues recently established the HTLV-I env-pX-transgenic rat and demonstrated not only dcstructive arthropathy, but also SS, vasculitis syndrome, and polymyositis with immune dysregulation in these animals (Yoshiki T: personal communication).…”

Section: Pathogenesis Of Htlv-i Arthropathymentioning

confidence: 99%