Fas and its ligand in a general mechanism of T-cell-mediated cytotoxicity.

Hanabuchi, Shino; Koyanagi, Makoto; Kawasaki, Akemi; Shinohara, Nobukata; Matsubara, Akio; Nishimura, Yoshiko; Kobayashi, Yuko; Yonehara, Shin; Yagita, Hideo; Okumura, Ko

doi:10.1073/pnas.91.11.4930

Cited by 260 publications

(120 citation statements)

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“…hFasL cDNA was prepared by reverse transcriptase-polymerase chain reaction (RT-PCR) from total RNA of activated human T cell clone (4HM1), transferred into the BCMGSneo expression vector, 19 and introduced into a murine T lymphoma cell line (L5178Y) which does not express Fas. 10,17,20 At the same time, we used control mock transfectants (mock/L5178Y), prepared by transferring empty vector alone into L5178Y. 17 Flow cytometry analysis showed that hFasL transfectants expressed a high level of hFasL.…”

Section: Resultsmentioning

confidence: 99%

“…9 This molecule is expressed on activated T cells and natural killer (NK) cells and induces apoptotic cell death in target cells expressing functional Fas antigen. [10][11][12] We previously established mice carrying human T cell leukemia virus type 1 (HTLV-1) representing one of the most suitable animal models of human RA. 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.…”

Section: Introductionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 1998

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“…Fas is expressed on a variety of different cell types (8), though the physiological role of its wide constitutive expression has not yet been clarified. In contrast, FasL is more restricted in its expression and is inducibly expressed on T, B, and NK cells during activation of the immune system (9,10). Sequentially, Fas/FasL interaction down-regulates the immune response by inducing apoptosis, as activated lymphocytes express both Fas and FasL (11,12).…”

mentioning

confidence: 99%

“…Sequentially, Fas/FasL interaction down-regulates the immune response by inducing apoptosis, as activated lymphocytes express both Fas and FasL (11,12). The fact that dysregulation of the Fas system leads to uncontrolled lymphoproliferation and severe autoimmune disorders (13,14) means that the Fas system plays a role in the control of immune reactions in several organs in physiological and pathological conditions (9,15,16).…”

mentioning

confidence: 99%

TNF-α and IFN-γ Regulate Expression and Function of the Fas System in the Seminiferous Epithelium

Riccioli

Starace

D’Alessio

et al. 2000

The Journal of Immunology

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Sertoli cells have long been considered to be involved in the regulation of the immune response in the testis. More recently, the Fas system has been implicated in the maintenance of the immune privilege in the testis as well as in the regulation of germ cell apoptosis. However, the control of Fas and Fas ligand (FasL) expression in the testis remains unknown. In the present study, we demonstrate that cultured mouse Sertoli cells constitutively express a low level of membrane-bound Fas protein, but not a soluble form of Fas. Sertoli cells stimulated with TNF-α and IFN-γ markedly increase the expression of both soluble and membrane-bound Fas in a dose-dependent manner. The up-regulated membrane-bound Fas protein is functionally active because it induces a significant level of Sertoli cell death in the presence of Neuro-2a FasL+ effector cells. Interestingly, the soluble form of Fas, which is induced by the same cytokines but has an antiapoptotic effect, is also functional. In fact, conditioned media from TNF-α-stimulated Sertoli cell cultures inhibit Neuro-2a FasL+-induced cell death. Taken together, our data suggest a possible regulatory role of TNF-α and IFN-γ on Fas-mediated apoptosis in the testis through disruption of the balance between different forms of Fas.

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“…One possibility is a soluble chimeric Fas-Ig fusion. 141 Indeed, data from a study where Fas-mediated cytotoxic activity by a T cell clone against sensitized recipient target cells could be prevented by addition of the Fas-Ig fusion protein, suggest that a local, high level transfer of the Fas-Ig cDNA to allografts may be feasible in preventing FasL-dependent destruction. Alternatively, signaling-defective, dominantnegative variants of Fas, mutant downstream effectors such as FADD (Fas-associated death domain protein)-a docking protein involved in linking the intracytoplasmic domain of Fas to the death effector molecules, 142,143 inhibitors of the proapoptotic cascade like crmA protein encoded by cowpox, 144 and bcl-2 family members [145][146][147][148][149][150] may all be useful in suppressing Fas-triggered apoptosis induction (Table 3).…”

Section: Inhibition Of Apoptosismentioning

confidence: 99%