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61.
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63.
Fas-ligand-mediated lysis of erbB-2-expressing tumour cells by redirected cytotoxic T lymphocytes 总被引:1,自引:0,他引:1
Haynes NM Smyth MJ Kershaw MH Trapani JA Darcy PK 《Cancer immunology, immunotherapy : CII》1999,47(5):278-286
A chimeric receptor, consisting of the single-chain variable (scFv) domains of an anti-erbB-2 mAb linked via a CD8 membrane-proximal
hinge to the Fc receptor γ chain, was expressed in the mouse cytotoxic T lymphocyte (CTL) hybridoma cell line, MD45. This
cell line was grafted with the additional specificity to recognise and bind erbB-2-expressing breast carcinoma target cells
T47D, MCF-7 and BT-20 in a non-MHC-restricted manner. Tumour cell lysis was antigen-specific since erbB-2-negative tumours
were insensitive to lysis by MD45-scFv-anti-erbB-2-γ clones, and lysis of erbB-2+ tumour targets was inhibited in the presence of an anti-erbB-2 mAb. Furthermore, target cell death correlated with the level
of chimeric receptor expression on the effector MD45 subclones. Redirected MD45 CTL utilised Fas ligand to induce target cell
death since soluble Fas-Fc fusion protein completely inhibited cytolysis. The sensitivity of tumour target cells to Fas ligand
was further enhanced by treating them with interferon-γ, a regulator of Fas and downstream signalling components of the Fas
pathway. Overall, this study has demonstrated the requirement for successful activation of Fas ligand function in conjunction
with cytokine treatment for effective lysis of breast carcinoma target cells mediated by redirected CTL.
Received: 23 July 1998 / Accepted: 5 October 1998 相似文献
64.
The purpose of this study was to evaluate the hypothesis that spacer devices have limited effect on the in vitro fine particle
dose emitted from solution metered dose inhalers containing different proportions of HFA134a [1,1,1,2-tetrafluoroethane] propellant.
Two solution formulations (80% and 97.5% wt/wt HFA134a) were tested across the actuator alone, actuator plus Aerochamber,
and Ace holding chamber. Particle size distributions were determined using laser diffraction (LD) and cascade impaction (CI).
Multimodal particle size distributions were identified using LD. CI analyses were characterized by a major mode located at
≈0.5 μm. The fine particle dose emitted from the inhaler spacer combinations containing 97.5% HFA134a was independent of the
device setup used. Fine particle doses were influenced by spacer setup in 80% HFA134a formulations, indicating different plume
dynamics of low vapor pressure formulations. Sampling inlet deposition was approximately O when spacer devices were used with
either formulation. When spacers were not used, sampling inlet deposition was increased significantly. However, inlet deposition
with the 97.5% HFA134a formulation was significantly less than that of the 80% HFA134a formulation (≈25% of emitted dose compared
with 69% respectively). Thus, high propellant concentration formulations appear to have more robust in vitro performance.
This is particularly important given the preponderance of poor patient compliance that is associated with spacer use. High
propellant concentrations had the advantage of fine particle doses that were independent of the device setup and significantly
lowered sampling inlet deposition when no spacer was used. 相似文献
65.
An analysis of the X-ray structure of cilastatin bound to membrane dipeptidase, together with docking studies, is presented here to reveal how a simple amide may act as a high-affinity, reversible, amidase inhibitor. Cilastatin binds as a normal substrate and is orientated in a perfect near-attack conformer for formation of a tetrahedral intermediate with the zinc-bound water/hydroxide. This intermediate is fated, however, only to revert to its starting components as scission of the amide bond is prevented by the precise fit of cilastatin within the active site. The cilastatin alkyl end groups that are tightly buttressed against amino acid residues on opposite sides of the active site, are aligned along the C-N reaction coordinate axis thereby preventing collapse of the intermediate via rupture of the C-N bond. Such a feature could have more general applicability in the explicit design of substrate variants as selective, tight-binding, and reversible inhibitors. 相似文献
66.
Okamoto O Bachy S Odenthal U Bernaud J Rigal D Lortat-Jacob H Smyth N Rousselle P 《The Journal of biological chemistry》2003,278(45):44168-44177
Basal keratinocytes of the epidermis adhere to their underlying basement membrane through a specific interaction with laminin-5, which is composed by the association of alpha3, beta3, and gamma2 chains. Laminin-5 has the ability to induce either stable cell adhesion or migration depending on specific processing of different parts of the molecule. One event results in the cleavage of the carboxyl-terminal globular domains 4 and 5 (LG4/5) of the alpha3 chain. In this study, we recombinantly expressed the human alpha3LG4/5 fragment in mammalian cells, and we show that this fragment induces adhesion of normal human keratinocytes and fibrosarcoma-derived HT1080 cells in a heparan- and chondroitin sulfate-dependent manner. Immunoprecipitation experiments with Na2 35SO4-labeled keratinocyte and HT1080 cell lysates as well as immunoblotting experiments revealed that the major proteoglycan receptor for the alpha3LG4/5 fragment is syndecan-1. Syndecan-4 from keratinocytes also bound to alpha3LG4/5. Furthermore we could show for the first time that unprocessed laminin-5 specifically binds syndecan-1, while processed laminin-5 does not. These results demonstrate that the LG4/5 modules within unprocessed laminin-5 permit its cell binding activity through heparan and chondroitin sulfate chains of syndecan-1 and reinforce previous data suggesting specific properties for the precursor molecule. 相似文献
67.
Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells 总被引:21,自引:0,他引:21
Takeda K Hayakawa Y Smyth MJ Kayagaki N Yamaguchi N Kakuta S Iwakura Y Yagita H Okumura K 《Nature medicine》2001,7(1):94-100
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells in vitro, but its physiological role in tumor surveillance remains unknown. Here, we report that TRAIL is constitutively expressed on murine natural killer (NK) cells in the liver and plays a substantial role in suppressing tumor metastasis. Freshly isolated NK cells, but not natural killer T cells or ordinary T cells, from the liver expressed cell surface TRAIL, which was responsible for spontaneous cytotoxicity against TRAIL-sensitive tumor cells in vitro along with perforin and Fas ligand (FasL). Administration of neutralizing monoclonal antibody against TRAIL significantly increased experimental liver metastases of several TRAIL-sensitive tumor cell lines. Such an anti-metastatic effect of TRAIL was not observed in NK cell-depleted mice or interferon-gamma-deficient mice, the latter of which lacked TRAIL on liver NK cells. These findings provide the first evidence for the physiological function of TRAIL as a tumor suppressor. 相似文献
68.
Perforin/granzyme-induced apoptosis is the main pathway used by cytotoxic lymphocytes to eliminate virus-infected or transformed cells. Studies in gene-disrupted mice indicate that perforin is vital for cytotoxic effector function; it has an indispensable, but undefined, role in granzyme-mediated apoptosis. Despite its vital importance, the molecular and cellular functions of perforin and the basis of perforin and granzyme synergy remain poorly understood. The purpose of this review is to evaluate critically recent findings on cytotoxic granule-mediated cell death and to assess the functional significance of postulated cell-death pathways in appropriate pathophysiological contexts, including virus infection and susceptibility to experimental or spontaneous tumorigenesis. 相似文献
69.
70.
Perforin (pfp)/Fas ligand (FasL) double-deficient mice have previously been shown to be infertile, lose weight and die prematurely due to tissue destruction caused by a significant inflammatory infiltrate of monocytes/macrophages and T cells. Herein we have compared disease progression in mice additionally deficient in the inflammatory mediator TNF. Unlike pfp/FasL double-deficient mice (TNF+/+ pfp-/- gld), mice lacking functional TNF, FasL and pfp (TNF-/- pfp-/- gld) were comparatively fertile, with the majority of mice not suffering severe pancreatitis or hysterosalphingitis in the first 5 months of life. The mean lifespan of TNF-/- pfp-/- gld mice was 217 +/- 79 days compared with 69 +/- 10 days for TNF+/+ pfp-/- gld mice and the majority of moribund TNF-/- pfp-/- gld mice appeared to die as a result of severe pancreatitis, suggesting that loss of TNF was not completely protective. At 8 weeks of age, characteristics associated with the gld phenotype, such as expansion of B220+ CD4- CD8- T cells, lymphadenopathy and hypergammaglobulinemia were comparable between TNF+/+ pfp-/- gld and TNF-/- pfp-/- gld mice, although the lymphoid organs of TNF+/+ pfp-/- gld mice contained greater numbers of B220+ CD4- CD8- T cells, macrophages and T cells. We conclude that TNF is necessary for the full manifestation of immune dysregulation caused by pfp/FasL-deficiency, in particular in the early and overwhelming tissue infiltration and destruction caused by inflammatory cells. 相似文献