共查询到20条相似文献,搜索用时 15 毫秒
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Takafumi Yamamoto Fumiko Arakawa Ken Nakamura Tarumi Senba Yoshihiro Tomita Seiyo Ikeda Masahide Kuroki 《Cancer immunology, immunotherapy : CII》1999,48(4):165-171
Mouse monoclonal antibody FU-MK-1, raised against a human gastric adenocarcinoma, recognizes a glycoprotein antigen (termed
MK-1 antigen) present on most carcinomas and seems to be valuable in immunodiagnosis and immunotherapy of various cancers.
In a recent study, we constructed a mouse/human chimeric antibody, designated Ch FU-MK-1, by fusing the FU-MK-1 VH and Vκ genes to the human Cγ1 and Cκ genes, respectively. In the present study, we tested combination immunotherapy of Ch
FU-MK-1 with human lymphokine-activated killer (LAK) cells in vitro and in mice with severe combined immunodeficiency (SCID)
bearing human MK-1-expressing tumors. In in vitro experiments, Ch FU-MK-1 effectively mediated antibody-dependent cell-mediated
cytotoxicity (ADCC) against MK-1-expressing MKN-74 cells, which was completely blocked by an anti-FcR antibody. Since the
apoptotic pathway as well as the necrotic pathway have been shown to be utilized in various cytotoxic effector mechanisms,
we investigated the role of apoptosis in ADCC mediated by LAK cells and Ch FU-MK-1 against MKN-74 cells. The implication of
the apoptosis during ADCC was demonstrated by means of both a terminal-deoxynucleotidyltransferase-mediated dUTP-biotin nick-end-labeling
assay and a propidium iodide staining method. In vivo antitumor activity of combination treatment with LAK cells and Ch FU-MK-1
was estimated using SCID mice inoculated s.c. with MKN-74 cells. The i.v. administration of LAK cells and i.p. administration
of Ch FU-MK-1 and interleukin-2 (IL-2) produced a marked growth inhibition of MKN-74 tumors in SCID mice. When the actual
tumor weights were measured 16 days after initiation of treatment, more than 70% reduction was observed in the group receiving
LAK cells plus Ch FU-MK-1 plus IL-2 as compared to the control untreated group. Together these results suggest that Ch FU-MK-1
may serve as a potentially useful immunotherapeutic reagent for human MK-1-expressing tumors.
Received: 27 November 1998 / Accepted: 23 February 1999 相似文献
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Li Qian Si-Yan Liao Zu-Liang Huang Yong Shen Kang-Cheng Zheng 《Journal of molecular modeling》2010,16(6):1139-1150
Theoretical studies on the three-dimensional (3D) quantitative structure-activity relationship (QSAR) and mechanisms of action
of a series of pyrimidine substituent derivatives as dual inhibitors of AP-1 and NF-κB were carried out using comparative
molecular field analysis (CoMFA) and docking methods. The established 3D-QSAR model exhibits a satisfying statistical quality
and prediction ability. Docking results show somewhat lower average values of the flexible and rigid energy scores in the
chosen binding sites. The docking analysis offers appropriate orientations and conformations of these compounds at the binding
sites to both AP-1 and NF-κB in good agreement with the 3D-QSAR model from CoMFA. The combined CoMFA and docking study suggests
the following substituent selections: substituent R2 should be a kind of H–N–thienyl or CH3–N–thienyl group; substituent R5 should be a kind of COO–tBu or COOEt group; and substituent R4 should be a CH2CH3 or 2-thienyl group. The docking analysis also shows that the binding sites fall just at the joint regions between AP-1 (or
NF-κB) and DNA, where these compounds can effectively prevent free AP-1 and NF-κB from binding to DNA, and this may be the
reason that derivatives with pyrimidine substituents have an inhibition function. In addition, a very interesting finding
was that the binding sites of both AP-1 and NF-κB have a common structural characteristic, thereby providing a reasonable
explanation for the dual inhibition functions of these compounds towards both AP-1 and NF-κB. These theoretical results help
to deepen our understanding of the inhibition mechanism of these pyrimidine substituent derivatives, and will aid in directing
further drug-molecular design. 相似文献
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Tumor necrosis factor alpha (TNFα) activates the nuclear factor-kappaB (NF-κB) pathway in various cell types, leading to expression
of cell survival and inflammatory proteins. One mechanism of cell survival brought about by NF-κB is the inhibition of Activator
Protein-1 (AP-1), which when activated, could lead to cell death. However, TNFα can also induce the AP-1 pathway, and the
mechanisms by which these two pathways are regulated in response to TNFα are poorly understood. We proposed that Inhibitor
of κB Kinase gamma (IKKγ) (which is also known as NF-κB essential modulator, NEMO) plays a key role in integrating and coordinating
these two pathways. Our results showed that IKKγ activates the AP-1 pathway, via a mechanism that is dependent on the first
leucine zipper (LZ) domain of IKKγ, by interacting with two proteins of the AP-1 complex, c-Jun and c-Fos, and changing the
phosphorylation status of c-Jun. Even though IKKγ is required for the activation of NF-κB, we found that it reduced the activity
of NF-κB when it was overexpressed. In summary, we demonstrated that transfected IKKγ, while inhibiting the NF-κB pathway,
directly interacts with the AP-1 proteins and activates the AP-1 pathway independent of its effects on NF-κB. Our results
indicate that IKKγ regulates TNFα signaling by coordinating cell responses mediated by the AP-1 and NF-κB pathways.
A. S. Shifera and J. M. Friedman contributed equally to this article.
Marshall S. Horwitz—Deceased: This article is dedicated to his loving memory. 相似文献
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Lee S Park HH Son HY Ha JH Lee MG Oh TY Sohn DH Jeong TC Lee SH Son JK Lee SG Jun CD Kim SH 《Cell biology and toxicology》2007,23(2):105-112
Mast cell-mediated allergic inflammation is involved in many diseases such as asthma, sinusitis, and rheumatoid arthritis.
Mast cells induce synthesis and production of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin
(IL)-1β and IL-6 with immune regulatory properties. The formulated ethanol extract of Artemisia asiatica Nakai (DA-9601) has been reported to have antioxidative and anti-inflammatory activities. In this report, we investigated
the effect of DA-9601 on the expression of pro-inflammatory cytokines by the activated human mast cell line HMC-1 and studied
its possible mechanisms of action. DA-9601 dose-dependently decreased the gene expression and production of TNF-α, IL-1β,
and IL-6 on phorbol 12-myristate 13-acetate (PMA)- and calcium ionophore A23187-stimulated HMC-1 cells. In addition, DA-9601
attenuated PMA- and A23187-induced activation of NF-κB as indicated by inhibition of degradation of IκBα, nuclear translocation
of NF-κB, NF-κB/DNA binding, and NF-κB-dependent gene reporter assay. Our in vitro studies provide evidence that DA-9601 might contribute to the treatment of mast cell-derived allergic inflammatory diseases. 相似文献
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Depleting monocytes from human peripheral blood mononuclear cells (PBMC) enhances the in vitro activation of lymphokine-activated killer (LAK) cells. To determine if monocytes also altered LAK-cell expansion, we evaluated two methods of depleting monocytes from PBMC: nylon wool adherence (NWA) and phenylalanine methyl ester (PME) treatment. Both methods of depleting monocytes enhanced interleukin-2 (IL-2) driven, LAK-cell expansion; LAK expansion, however, was significantly greater after depletion with NWA than after PME. LAK cytotoxicity after NWA and PME depletion was equivalent. The degree of monocyte depletion, determined by evaluating morphology and the number of Leu-M3 (CD14) positive cells, and the proliferation of Leu 19 (CD56), OKT-3 (CD3), Leu2 (CD8), and Leu 3a (CD4) positive cells was also equivalent. Exposure of IL-2 activated cells to PME did not alter their cytotoxic activity. However, sequential treatment of PBMC with NWA, then PME, or with PME and then NWA, resulted in reduced expansion. This reduction in expansion was similar to PBMC treated with PME alone. Exposure of PME-depleted cells to nylon wool or to supernatants obtained from cells adherent to nylon wool further decreased LAK expansion relative to cells treated with NWA alone. We conclude that even at relatively low cell density, human monocytes markedly inhibit LAK-cell expansion in IL-2 driven PBMC cultures. Further, depletion of monocytes by NWA adherence is more effective than by treatment with PME, possibly due to subtle cellular damage induced by this latter treatment. These findings have implication for the in vitro and in vivo generation of LAK-cells by IL-2. 相似文献
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M Favrot R Capdeville V Combaret D C Zhou G Clapisson J Banchereau C R Franks S Chouaib J Y Blay T Philip 《European cytokine network》1990,1(3):141-147
The effect of human IL-4, used as a single agent or in combination with low or high dose IL-2, upon LAK-cell proliferation and activation has been tested on PBMC from patients treated with alpha 2-IFN and IL-2. Four days in vitro culture with IL-4 did not induce any LAK-cell activation; IL-4 induced the proliferation of CD3+ CD4+ T-cells, but decreased the percentage of NK cells in culture samples. When combined with high dose IL-2, IL-4 improved the recovery of MN cell without modification of T-cell subsets; however, IL-4 had no major effect on IL-2-induced NK or LAK cell activity. The combination of IL-4 and low dose IL-2 still significantly improved the total MN cell recovery but did not modify the distribution of T and NK lymphocytes; IL-4 inhibited low dose IL-2-induced NK and LAK cell activity, and increased the BL-esterase activity induced by high or low dose IL-2. The combination of IL-4 and IL-2 did not induce any large variation in the percentage of IL-2R (p55) expressing cells. In all tested conditions, IL-2R (p55) was mainly expressed on CD4+ T cells; less than 2% of the cells coexpressed the NK cell marker CD56 and IL-2R (p55). The effect of IL-4 upon IL-2-induced LAK cell expansion is thus very different on PBMC pre-activated in vivo by alpha IFN + IL-2 therapy than on PBMC pre-treated in vitro with IL-2.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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