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1.
H. Yanagawa Takashi Haku Keiji Hiramatsu Hiroshi Nokihara Eiji Takeuchi Seiji Yano Masaki Hanibuchi Saburo Sone 《Cancer immunology, immunotherapy : CII》1997,45(2):93-99
The effect of intrapleural instillation of recombinant human interferon γ (IFNγ) at increasing doses of (1–12) × 106 U was examined in six patients with cytologically positive pleural effusion due to lung cancer. Intrapleural instillation
was repeated up to three times. Clinically, no reaccumulation of pleural effusion was observed in one patient and disappearance
of lung cancer cells from the pleural effusion was seen in two other patients. No severe side-effects were observed. Considerable
levels of IFNγ remained in the pleural effusion as well as in patients’ serum up to 7 days after instillation of 2 × 106 U and higher doses. The total cell number showed a transient decrease on day 1 of therapy. Levels of pro-inflammatory cytokines,
such as tumor necrosis factor α, interleukin(IL)-1β and IL-6, in the pleural effusion remained almost stable after IFNγ instillation.
On the other hand, intrapleural IL-1 receptor antagonist levels were remarkably elevated by the instillation of IFNγ. IL-2-
and IL-12-inducible killer activity of pleural mononuclear cells tended to increase slightly. Despite the inability of IFNγ
to control pleural effusion in this treatment schedule, IFNγ instilled by an intrapleural route had a potential local antitumor
activity. Moreover, since IFNγ persists in pleural effusions for a long time after a single instillation, such a therapy in
combination with other fibrogenic biological response modifiers can be promising.
Received: 28 February 1997 / Accepted: 23 July 1997 相似文献
2.
W. Lasek Wojciech Feleszko Jakub Goląb Tomasz Stokłosa Maria Marczak Anna Dąbrowska Magdalena Malejczyk Marek Jakóbisiak 《Cancer immunology, immunotherapy : CII》1997,45(2):100-108
There is strong evidence that antitumor activity of interleukin-12 (IL-12) in vivo is mediated, in part, through interferon
(IFNγ) produced by IL-12-stimulated natural killer and T cells. Since IFNγ and tumor necrosis factor α (TNFα) have been reported
to synergize in antitumor effects in a number of models, we decided to examine whether the combined treatment with recombinant
mouse IL-12 and recombinant human TNFα would produce similar effects. The efficacy of the combined IL-12/TNFα immunotherapy
was evaluated in three tumor models in mice: B16F10 melanoma, Lewis lung (LL/2) carcinoma and L1 sarcoma. Intratumoral daily
injections of 1 μg IL-12 in combination with 5 μg TNFα into B16F10-melanoma-bearing mice resulted in a significant retardation
of the tumor growth as compared with that in controls and in mice treated with either cytokine alone. Similar effects were
obtained using 0.1 μg IL-12 and 5 μg TNFα in LL/2 carcinoma and L1 sarcoma models. Antitumor activity against L1 sarcoma was
still preserved when TNFα at a low dose (1 μg) was combined with 0.1 μg IL-12 and applied for a prolonged time. Potentiation
of antitumor effects, which was observed in IL-12/TNFα-based immunotherapy, could result from at least three different mechanisms,
partly related to stimulation of IFNγ and TNFα production in treated mice: (a) direct cytostatic/cytotoxic effects on tumor
cells, (b) induction of antitumor activity of macrophages, and (c) inhibition of blood vessel formation in the tumor. Our
studies demonstrate that combination tumor immunotherapy with IL-12 and TNFα may be more effective than single-cytokine treatment,
and suggest possible mechanisms by which IL-12 and TNFα may exert potentiated therapeutic effects against locally growing
tumors.
Received: 17 February 1997 / Accepted: 5 August 1997 相似文献
3.
Kimura K Nishimura H Matsuzaki T Yokokura T Nimura Y Yoshikai Y 《Cancer immunology, immunotherapy : CII》2000,49(2):71-77
Interleukin(IL)-15, which uses IL-2 receptor (R) β and γ chains for signal transduction, shares many of the biological activities
of IL-2. We examined the effects of exogenous IL-15 on protection in a murine malignant pleurisy model using BALB/c mice and
syngeneic MethA fibrosarcoma (MethA). Intrapleural administration of IL-15 significantly prolonged the survival time of mice
after an intrapleural inoculation of MethA, whereas the same dose of IL-2 did not. The in vivo antitumor effect of IL-15 was
synergistically enhanced by additive administration of IL-12. Combination therapy of IL-15 and IL-12 protected mice from death
from bloody pleural fluid. Such treatment induced marked increases in the number of CD3-IL-2Rβ+ cells corresponding to natural killer (NK) cells and the production of interferon γ (IFNγ) by T cells in the thoracic exudate
cells (TEC). Administration of anti-IFNγ mAb partly inhibited the protective effect of a combination of IL-15 and IL-12. A
tumor-neutralizing (Winn) assay revealed that the antitumor activity of effector cells in the TEC was abrogated by treatment
with anti-CD8 mAb or anti-asialoGM1 Ab plus complement. Thus, treatment with IL-15 in combination with IL-12 may enhance the
activities of NK and CD8+ T cells in the TEC, providing strong antitumor activity against the malignant pleurisy. These results suggest that IL-15
together with IL-12 may have potential for the immunotherapy of some types of malignant pleurisy.
Received: 13 July 1999 / Accepted: 3 December 1999 相似文献
4.
Toshihiro Fujimoto Michael A. O’Donnell Akos Szilvasi H. Yang R. B. Duda 《Cancer immunology, immunotherapy : CII》1996,42(5):280-284
Although immunotherapy with bacillus Calmette Guérin (BCG) is an established adjuvant treatment for malignant melanoma, the
mechanism of its role in this process is unclear. To investigate the possible contribution of tumor-inhibitory cytokines induced
by BCG, B16F10 melanoma cell growth in culture was assessed in response to purified cytokines and conditioned media of BCG-stimulated
splenocytes. Interferon-γ (IFNγ) was the most potent single agent (IC50≈50 pg/ml). Tumor necrosis factor α was substantially weaker (IC50>10 ng/ml) but provided synergy with IFNγ. None of the other
cytokines such as interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12, or granulocyte/macrophage-colony-stimulating factor had
direct antitumor activity against B16F10 melanoma cells. However, when IL-2 and/or GM-CSF were combined with BCG either by
exogenous addition or through endogenous production by novel cytokine-secreting recombinant BCG (rBCG), a substantial increase
in INFγ production by splenocytes was observed. Antitumor activity of this conditioned medium directly correlated with IFNγ
concentration and was completely blocked by neutralizing antibody to IFNγ. These results suggest that BCG may exert part of
its antitumor action on melanoma through the induction of IFNγ, which can be greatly enhanced through the concomitant addition
of IL-2 and/or GM-CSF. Furthermore, by utilizing rBCG that secrete these cytokines, it may be possible to potentiate the antitumor
effect of BCG directly at the site of BCG inoculation.
Received: 29 January 1996 / Accepted: 9 April 1996 相似文献
5.
Xue G Liu RY Li Y Cheng Y Liang ZH Wu JX Zeng MS Tian FZ Huang W 《Cancer immunology, immunotherapy : CII》2007,56(11):1831-1843
Backgroud and objective Dendritic cells play an important role in initiation and regulation of immune responses. Previous studies demonstrated that
intratumoral administration of 6Ckine-modified DCs enhanced local and systemic antitumor effects. Herein we report the investigation
of the specific CTL responses elicited by adenoviral 6Ckine/IFNγ fusion gene-modified DCs in vitro.
Methods Human monocyte-derived DCs were modified with an adenoviral vector encoding 6Ckine/IFNγ fusion protein (Ad-6Ckine/IFNγ), and
then investigated the effect of 6Ckine/IFNγ fusion protein on the maturation, cytokine and chemokine secretion of DCs, and
their activities of recruiting and activating T cells in vitro were investigated.
Results 6Ckine/IFNγ fusion protein induced DC maturation characterized with the upregulation of CD83 and CCR7. And it up-regulated
the expression of RANTES and IL-12p70, down-regulated that of IL-10 in DCs. Additionally, 6Ckine/IFNγ markedly increased DC’s
recruiting ability for naive T cells, benefiting from the enhanced expression of chemokines 6Ckine and RANTES in DCs. Fusion
gene-modified DCs significantly promoted the proliferation of autologous T cells, induced Th1 differentiation by upregulating
the expression of IL-2 and T-bet in T cells, and increased specific cytotoxicity of CTLs against specific tumor cells, HepG2
or LoVo cells, respectively.
Conclusion Combining the effects of 6Ckine and IFNγ, Ad-6Ckine/IFNγ modified DCs induced enhanced CTL responses in vitro, which indicated
that Ad-6Ckine/IFNγ modified DCs might be used as an adjuvant to trigger an effective antitumor immune response.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Gang Xue, Ran-yi Liu, Yan Li contributed equally to this work. 相似文献
6.
Akio Uemura Tetsuo Takehara Takuya Miyagi Takahiro Suzuki Tomohide Tatsumi Kazuyoshi Ohkawa Tatsuya Kanto Naoki Hiramatsu Norio Hayashi 《Cancer immunology, immunotherapy : CII》2010,59(3):453-463
Although the anti-tumor effect of IL-12 is mediated mostly by IFNγ, which cell types most efficiently produce IFNγ and therefore
initiate or promote the anti-tumor effect of IL-12 has not been clearly determined. In the present study, we demonstrated
hydrodynamic injection of the IL-12 gene led to prolonged IFNγ production, NK-cell activation and complete inhibition of liver
metastasis of CT-26 colon cancer cells in wild-type mice, but not in IFNγ knockout mice. NK cells expressed higher levels
of STAT4 and upon IL-12 administration displayed stronger STAT4 phosphorylation and IFNγ production than non-NK cells. Adoptive
transfer of wild-type NK cells into IFNγ knockout mice restored IL-12-induced IFNγ production, NK-cell activation and anti-tumor
effect, whereas transfer of the same number of wild-type non-NK cells did not. In conclusion, NK cells are predominant producers
of IFNγ that is critical for IL-12 anti-tumor therapy. 相似文献
7.
Deviation of type 1/type 2 cytokine balance to type 2 predominance may contribute to tumour progression. We investigated effect of interleukin (IL-)15 on modulation of type 1/type 2 balance in addition to non-major histo-compatibility complex (MHC)-restricted killer induction in the tumour-growing site. IL-15 induced significant killer activity in mononuclear cells (MNC) in malignant pleural effusion as well as those in peripheral blood. Pleural MNC produced more IFN-gamma (type 1 cytokine) by incubation with IL-15 or IL-2 than blood MNC. Moreover, IL-4 and IL-5 (type 2 cytokines) production by pleural MNC were observed only by incubation with IL-2, but not with IL-15. These observations suggest that IL-15 has a potent activity to restore type 1/type 2 balance in addition to killer induction in tumour-growing site. 相似文献
8.
Anja ten Brinke Gijs van Schijndel Remco Visser Tanja D. de Gruijl Jaap Jan Zwaginga S. Marieke van Ham 《Cancer immunology, immunotherapy : CII》2010,59(8):1185-1195
Dendritic cells (DCs) are promising antigen presenting cells for cancer treatment. Previously, we showed that the combination
of monophosphoryl lipid A (MPLA) with IFNγ generates mature DCs that produce IL-12 and polarize CD4+ T cells towards a Th1 phenotype. Here, we extended these observations by showing that the DCs generated with the clinical
grade maturation cocktail of MPLA/IFNγ induce superior tumour antigen-specific CD8+ CTL responses compared to the cytokine cocktail matured DCs that are currently used in the clinic. MPLA/IFNγ DCs can induce
CTL responses in healthy individuals as well as in melanoma patients. The CTL induction was mainly dependent on the IL-12
produced by the MPLA/IFNγ DCs. The high amounts of induced CTLs are functional as they produce IFNγ and lyse target cells
and this cytolytic activity is antigen specific and HLA restricted. Furthermore, the CTLs proved to kill tumour cells expressing
endogenous tumour antigen in vitro. Therefore, MPLA/IFNγ DCs are very promising for the use in future cancer immunotherapy. 相似文献
9.
Vascular endothelial growth factor in malignant pleural effusion associated with lung cancer 总被引:13,自引:0,他引:13
Hiroaki Yanagawa Eiji Takeuchi Yoshihiro Suzuki Yasukazu Ohmoto Hiroyasu Bando Saburo Sone 《Cancer immunology, immunotherapy : CII》1999,48(7):396-400
The presence of vascular endothelial growth factor (VEGF) was examined by enzyme immunoassay in 60 cytology-documented malignant
pleural effusions associated with primary lung cancer and 51 other benign and malignant pleural effusions. Exudative pleural
effusions contained significantly higher amounts of VEGF than transudative pleural effusions. Among exudative pleural effusions,
levels of VEGF in malignant pleural effusions associated with lung cancer were significantly higher than those of benign exudative
pleural effusions. There was no significant difference in pleural VEGF in patients with different histological types or clinical
stages of lung cancer. Serial measurement of pleural VEGF levels was performed in six lung cancer patients treated with intrapleural
instillation of recombinant interferon γ, and reduction of pleural effusion was associated with decreasing pleural VEGF levels.
These findings suggest that VEGF has a role in the accumulation of exudative pleural effusions, especially that of malignant
pleural effusion associated with lung cancer.
Received: 14 April 1999 / Accepted: 10 June 1999 相似文献
10.
Wilke CM Wei S Wang L Kryczek I Kao J Zou W 《Cancer immunology, immunotherapy : CII》2011,60(11):1529-1541
It is generally thought that each cytokine exerts either immune stimulatory (inflammatory) or immune inhibitory (antiinflammatory
or regulatory) biological activities. However, multiple cytokines can enact both inhibitory and stimulatory effects on the
immune system. Two of these cytokines are interleukin (IL)-10 and interferon-gamma (IFNγ). IL-10 has demonstrated antitumor
immunity even though it has been known for years as an immunoregulatory protein. Generally perceived as an immune stimulatory
cytokine, IFNγ can also induce inhibitory molecule expression including B7-H1 (PD-L1), indoleamine 2,3-dioxygenase (IDO),
and arginase on multiple cell populations (dendritic cells, tumor cells, and vascular endothelial cells). In this review,
we will summarize current knowledge of the dual roles of both of these cytokines and stress the previously underappreciated
stimulatory role of IL-10 and inhibitory role of IFNγ in the context of malignancy. Our progressive understanding of the dual
effects of these cytokines is important for dissecting cytokine-associated pathology and provides new avenues for developing
effective immune therapy against human diseases, including cancer. 相似文献
11.
Cellular characteristics of peripheral blood lymphocytes and tumour-infiltrating lymphocytes in patients with gynaecological tumours 总被引:3,自引:0,他引:3
T. Schöndorf Heike Engel Carsten Lindemann Hannelore Kolhagen Alexander A. von Rücker Peter Mallmann 《Cancer immunology, immunotherapy : CII》1997,44(2):88-96
Immunotherapy of gynaecological cancer with tumour-infiltrating lymphocytes (TIL) or peripheral blood lymphocytes (PBL) has
become a valid treatment modality with varying degrees of success in obtaining an antitumour response. TIL consist of lymphocytes,
mainly T cells and minor populations of natural killer cells or B cells. Conventional cytogenetic studies of tumour cells
from patients with breast and ovarian cancer have shown multiple chromosomal abnormalities including chromosomes 7 and 12.
This study was designed to analyse the surface further, as well as investigate the intracellular, characteristics of TIL by
multicolour flow cytometry and the cytogenetic features by fluorescence in situ hybridization. Tumour cell, peripheral blood
and TIL samples from 25 patients (15 ovarian tumours, 8 breast cancers, 1 uterine sarcoma, 1 cervical carcinoma) were analysed
for their phenotype, the expression of major cytokines [interleukin-2 (IL-2), IL-4 and interferon γ (IFNγ)], their proliferation
rate, their cytotoxic ability and for the presence of numerical aberrations of chromosomes 7 and 12. All the tumour cells
showed a high frequency of numerical aberration in chromosomes 7 and 12, especially trisomies or tetrasomies and combined
aberrations. Trisomies of both chromosomes also occured at a low percentage in TIL and PBL.
Received: 20 June 1996 / Accepted: 4 January 1997 相似文献
12.
M. Margaret Prechel Yvonne Lozano Mark A. Wright J. Ihm M. R. I. Young 《Cancer immunology, immunotherapy : CII》1996,42(4):213-220
Lewis lung carcinoma (LLC-LN7) tumors stimulate myelopoiesis and increase the presence of granulocyte/macrophage (GM) progenitor
cells having natural suppressor activity. Treatment of these tumor-bearing mice with interleukin-12 (IL-12) resulted in minimal
immune modulation. The objective of this study was to determine whether eliminating natural suppressor activity would allow
for immune stimulation by IL-12. Treatment of LLC-LN7 tumor-bearing mice with vitamin D3 eliminated natural suppressor activity. In mice that were first treated with vitamin D3 and then also with IL-12, there was stimulation of splenic T cell proliferation in response to immobilized anti-CD3 plus
IL-2. In addition, spleen and lymph node cells from vitamin-D3/IL-12-treated tumor-bearing mice became stimulated in response to autologous tumor to produce interferon γ (IFNγ), although
IL-2 production was not stimulated. A prominent effect of the combined vitamin-D3/IL-12 treatment regimen was the synergistic augmentation of autologous tumor-specific cytolytic activity within the regional
lymph nodes. The generation of these tumor-specific effector cells required the presence of the tumor mass since such activity
was not elicited in the lymph nodes of mice from which the tumors had been surgically excised. The results of this study show
that, after treatment of tumor bearers with vitamin D3 to eliminate GM-suppressor cells, IL-12 can induce select regional antitumor immune responses, particularly IFNγ production
and cytolysis by regional lymph node cells of autologous tumor.
Received: 15 December 1995 / Accepted: 22 March 1996 相似文献
13.
Synergistic antitumor effects of interleukin-12 gene transfer and systemic administration of interleukin-18 in a mouse bladder cancer model 总被引:2,自引:0,他引:2
Kazuki Yamanaka Isao Hara Hiroshi Nagai Hideaki Miyake Kazuo Gohji Mark J. Micallef Masashi Kurimoto Soichi Arakawa Sadao Kamidono 《Cancer immunology, immunotherapy : CII》1999,48(6):297-302
We introduced the interleukin-12 (IL-12) gene into the mouse bladder cancer cell line (MBT2) to establish sublines that secrete
bioactive IL-12. IL-12-secreting MBT2 (MBT2/IL-12) sublines were completely rejected when subcutaneously implanted into immunocompetent
syngeneic C3H mice. Although this antitumor effect did not change when IL-12-secreting cells were injected into immunodeficient
mice whose CD8+ T or CD4+ T cells had been depleted by the corresponding antibody, it was abrogated when natural killer cells were depleted by anti-asialoGM1
antibody. In addition, when parental MBT2 cells mixed with MBT2/IL-12 cells were subcutaneously injected into mice, admixed
MBT2/IL-12 inhibited the growth of the parental tumor. Furthermore, this antitumor effect was enhanced by systemic IL-18 administration.
This synergism was abrogated when the mice were treated with interferon-γ-neutralizing antibody in vivo. In conclusion, local
secretion of IL-12 led to effective antitumor activity that was enhanced by systemic administration of IL-18. Interferon-γ
plays an important role in the synergism of IL-12 gene transduction and systemic administration of IL-18.
Received: 7 May 1998 / Accepted: 27 May 1999 相似文献
14.
Burkhard Hennemann Gabriele Beckmann Annette Eichelmann Annegret Rehm R. Andreesen 《Cancer immunology, immunotherapy : CII》1997,45(5):250-256
Cells of the monocyte/macrophage lineage have shown antitumor activity in vitro and in murine models after activation with
interferon (IFN) γ. In vitro data suggest an additional effect on macrophage antitumor activity when IFNγ is combined with
endotoxin (lipopolysaccharides; LPS). In this study we treated nine cancer patients with a total of 62 MAK infusion cycles
with autologous macrophages given intravenously (i.v.) after in vitro activation with IFNγ and LPS. Low-grade fever (WHO I/II)
was the commonest side-effect. Chills, nausea, and headache were noted when the number of transfused macrophages exceeded
2×108. One WHO IV toxicity occurred, consisting of hypotension after transfer of 3×108 cells, defining this dose as the maximum cell number tolerated. After pretreatment with ibuprofen, however, the maximum cell
number could be increased without reaching dose-limiting toxicity. The highest number of cells reinfused was 15×108. Circulating interleukin(IL)-6 increased in a dose-dependent manner as did IL-1 receptor antagonist (IL-1RA) and IL-8. Tumor
response consisted of one case of stable disease (12 weeks) in a patient with formerly progressing colorectal cancer and progressive
diseases in eight patients. This study indicates that reinfusion of autologous LPS-activated macrophages upon pretreatment
with ibuprofen is feasible and tolerated without major side-effects.
Received: 22 May 1997 / Accepted: 2 October 1997 相似文献
15.
A. B. Geldhof Thierry VandenDriessche Ghislain Opdenakker Patrick De Baetselier 《Cancer immunology, immunotherapy : CII》1996,42(6):329-338
Interferon-γ(IFNγ)-induced up-regulation of MHC class I expression on tumor cells can induce a potent CD8-mediated antitumor
response. Consequently, many investigators have proposed IFNγ gene transfection as a means to immunogenize tumor cells and
to vaccinate against metastatic disease. In this study, we demonstrate that transfection of the IFNγ gene in a BW5147 variant
(LiDlo) with low MHC class I expression results in a selective induction of H-2Dk but unaltered H-2Kk expression. In earlier reports we demonstrated a positive correlation between H-2Dk expression and enhanced metastatic potential of BW variants. In accordance with these observations, we observed that intravenous
inoculation of LiDlo(IFNγ) variants into syngeneic AKR mice led to enhanced metastasis as compared to parental LiDlo and LiDlo(neo) control transfectants. Tumor cells, derived from local subcutaneous tumors or sporadic metastases from mice inoculated
with LiDlo tumor cells, were found to up-regulate H-2Dk selectively. Anti-asialoGM1 treatment of AKR mice allowed rapid experimental metastasis formation by the LiDlo and LiDlo(neo) variants, indicating that natural killer (NK) cells control the metastatic behavior of these tumor cells. This was corroborated
by in vitro cytotoxicity experiments, demonstrating that LiDlo and LiDlo(neo) tumor cells were NK-sensitive, while the BW IFNγ transfectants became resistant to lymphokine-activated killer cells
and poly(I)·poly(C)-induced NK cells. We thus conclude that (a) IFNγ up-regulates selectively the MHC class I antigen H-2Dk, (b) H-2Dk governs susceptibility towards NK cells, and (c) NK susceptibility determines the experimental metastatic behavior of BW
tumor cells.
Received: 2 May 1996/Accepted: 21 May 1996 相似文献
16.
Masato Okamoto Ryoji Kaji Hisashi Goda Go Ohe Hideo Yoshida Mitsunobu Sato Hirofumi Kasatani 《Cancer immunology, immunotherapy : CII》1998,47(4):233-241
It has been reported that certain chemotherapeutic agents exhibit effects that enhance the antitumor host responses in the
patients with malignant diseases. In the present study, we investigated whether cis-diamminedichloroplatinum (cisplatin) and 5-fluorouracil (5-FU) may induce cytokines and effector cells with antitumor efficacy
in vivo and in vitro. The cultivation of human peripheral blood mononuclear cells (PBMC) in the presence of cisplatin (0–1.0
μg/ml) or 5-FU (0–5.0 μg/ml) resulted in the significant augmentation of natural killer (NK) and lymphokine-activated killer
(LAK) cell activities as well as generation of interferon (IFN) γ, tumor necrosis factor (TNF) α, β, interleukin(IL)-1β, IL-6
and IL-12 in vitro. In addition, all of these activities were almost completely neutralized by addition of anti-asialoGM1
antibody and complement (P < 0.05). In an in vivo model, the administration of anti-asialoGM1 antibody significantly shortened the survival time extended
by the treatment with cisplatin or 5-FU (P < 0.05), both on nude mice bearing salivary gland tumors and on syngeneic MethA-tumor-bearing BALB/c mice. Furthermore, high
levels of NK and LAK activities and significant increases of the numbers of cells positive for asialoGM1, IFNγ, TNFα, or IL-1β
were detected in the spleen cells derived from animals given cisplatin or 5-FU as compared with those given saline (P < 0.001–0.05). These findings clearly indicate that cisplatin and 5-FU are potent inducers of several types of cytokines and
effector cells carrying antitumor activity mediated by asialoGM1-positive cells (mainly NK cells) for the most part, and that
these abilities are closely associated with the in vivo antitumor effect of these agents.
Received: 23 July 1998 / Accepted: 10 September 1998 相似文献
17.
Øystein Bruserud Laila Mentzoni Brynjar Foss Jann Bergheim Sigbjørn Berentsen Ingerid Nesthus 《Cancer immunology, immunotherapy : CII》1997,43(5):275-282
Normal peripheral blood mononuclear cells (PBMC responders) were cultured together with non-irradiated allogeneic PBMC (more
than 95% leukaemia blasts) derived from patients with acute leukaemia (referred to as leukaemic PBMC stimulators). Cytokine
secretion was determined as cytokine concentrations in supernatants. Both normal PBMC and enriched CD4+ and CD8+ T cells responded to allostimulation with interferon (IFNγ) secretion. Interleukin-1 (IL-1) receptor antagonist and IL-2-neutralizing
antibodies decreased IFNγ secretion. Exogenous IL-1β, IL-2 and IL-7 increased allostimulated IFNγ secretion, whereas decreased
levels were seen in the presence of IL-6, IL-10 and granulocyte-colony-stimulating factor (G-CSF). During allorecognition
IFNγ -neutralizing antibodies decreased acute myelogenous leukaemia (AML) blast secretion of G-CSF. We conclude that (i) both
CD4+ and CD8+ T cells show allostimulated cytokine secretion in response to allogeneic stimulator cells containing a dominating population
of native, cytokine-secreting leukaemia blasts, and (ii) IFNγ released during this response can modulate the function of allogeneic
AML blasts.
Received: 4 June 1996 / Accepted: 15 October 1996 相似文献
18.
Diverse manifestations of tumorigenicity and immunogenicity displayed by the poorly immunogenic B16-BL6 melanoma transduced with cytokine genes 总被引:4,自引:0,他引:4
Marjorie J. Arca John C. Krauss Scott E. Strome Mark J. Cameron A. E. Chang 《Cancer immunology, immunotherapy : CII》1996,42(4):237-245
We evaluated the in vivo response to the poorly immunogenic B16-BL6 (BL6) murine melanoma genetically altered to secrete
interleukin-2 (IL-2), IL-4, interferon γ (IFNγ) and granulocyte/macrophage-colony-stimulating factor (GM-CSF). Three parameters
were evaluated: (1) tumorigenicity, (2) vaccination of naive animals, and (3) assessment of antitumor reactivity of T cells
derived from tumor-draining lymph nodes (TDLN). Secretion of IL-2 abrogated the tumorigenicity of BL6, while IFNγ and IL-4
partially reduced tumorigenicity, and GM-CSF had no effect. Protective immunity to wild-type tumor challenge could not be
achieved by vaccination with irradiated cytokine-secreting tumors, although IL-2 and IL-4 secretion appeared to retard the
growth of the challenge inoculum significantly. An alternative method to evaluate the immunogenicity of the cytokine-secreting
tumors was to measure the ability of T cells obtained from TDLN to mediate regression of wild-type tumor in adoptive immunotherapy.
Neither IL-2 nor IFNγ secretion resulted in the induction of immune T cells. By contrast, GM-CSF and IL-4 secretion were found
to induce immune T cells in the TDLN with GM-CSF being superior to IL-4. The combined secretion of GM-CSF and IL-4 did not
lead to enhanced induction of immune T cells. GM-CSF secretion was found to up-regulate B7-1 expression in TDLN, consistent
with an increase in the population of antigen-presenting cells. These studies demonstrated that reduced tumorigenicity by
cytokine secretion did not correlate with increased immunogenicity. With the cytokines examined, there was limited capability
of developing protective immunity against the BL6 tumor. Nevertheless, GM-CSF and IL-4 secretion significantly enhanced T
cell immune reactivity to the poorly immunogenic BL6 tumor.
Received: 30 January 1996 / Accepted: 22 March 1996 相似文献
19.
Kircheis R Siegl P Grunt S Halanek N Loibner H Mudde GC Nechansky A 《Cancer immunology, immunotherapy : CII》2007,56(6):863-873
Tumor-associated antigens resulting from aberrant glycosylation, such as the SialylTn carbohydrate antigen, are frequently
over-expressed on cancer cells and provide potential targets for cancer vaccination. Immunization of Rhesus monkeys with SialylTn
coupled to a highly immunogenic carrier molecule and formulated on aluminum hydroxide induced a strong immune response against
the carrier protein but only a moderate IgM immune response against the SialylTn carbohydrate antigen. Co-formulation with
QS-21 adjuvant dramatically enhanced the anti-SialylTn immune response and resulted in a SialylTn-specific IgG switch. The
kinetics of the carbohydrate-specific IgG response correlated with a temporary release of cytokines such as IFNγ, IL-2, IL-1β,
TNFα and GM-CSF which was measurable in the immune serum by xMAP Multiplex technology. Furthermore, tumor cell killing by
activated natural killer cells was induced. These data demonstrate that immunization with a tumor-associated carbohydrate
antigen in a highly immunogenic formulation results in a temporary release of type 1 cytokines which may be required for the
induction of a specific IgG immune response against the carbohydrate antigen as well as for activation of effector cells against
tumor cells. 相似文献
20.
Mitsuhiro Takenoyama Kosei Yasumoto Mamoru Harada Keizo Sugimachi Kikuo Nomoto 《Cancer immunology, immunotherapy : CII》1998,47(4):213-220
Monoclonal antibodies (mAb) are promising substances for the treatment of colorectal carcinoma, but the efficiency of this
therapy still needs further improvement. We used a flow-cytometric cytotoxicity test to determine the efficacy of the cytokines
interferon α (IFNα) and γ (IFNγ), interleukin-2 (IL-2), macrophage-colony-stimulating factor (M-CSF), granulocyte/macrophage-CSF
(GM-CSF) and tumor necrosis factor α (TNFα) in enhancing the antibody-dependent cellular cytoxicity (ADCC) of the mAb 17-1A
and the mAb BR55-2 against the colorectal carcinoma cell line HT29. In experiments performed at an effector to target ratio
of 9:1, with peripheral blood mononuclear cells from five healthy volunteers as effector cells, we found that IFNα, IFNγ and
IL-2 significantly augmented the ADCC of both mAb at concentrations between 3 ng/ml and 30 ng/ml. The other three cytokines
were not effective. In further experiments we examined combinations of the three effective cytokines in different concentrations.
The combination of IFNα and IL-2 proved to be optimal in enhancing ADCC of both mAb. Thus, the examination of ADCC by flow
cytometry may reveal potentially useful combinations of cytokines and mAb for the treatment of colorectal carcinoma.
Received: 11 September 1997 / Accepted: 19 February 1998 相似文献