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1.
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
2.
Marion-Gabriele Ott Daniela N. Männel Harald Gallati Matthias Goerig Ulrich Raeth 《Cancer immunology, immunotherapy : CII》1996,42(1):31-37
Tumor necrosis factor α (TNFα) and interferon γ (IFNγ) are important immunomodulators. They are capable of acting in a synergistic
manner on tumor cells in vitro and in vivo. In a clinical phase I study 13 patients with malignant ascites due to abdominal
spread of different primary tumors received intraperitoneally (i. p.) TNFα and IFNγ once weekly over 3 – 8 weeks in order
to evaluate the effect of locoregionally administered TNFα/IFNγ on ascites formation. Therefore some peripheral and local
immunological functional parameters of peripheral blood and malignant ascites were investigated. Mononuclear lymphocytes and
natural killer (NK) cell activity of peripheral blood and ascites, TNF-inhibitory activity, soluble p55 and p75 TNF receptors,
and prostaglandin E2 values in ascites were measured immediately before and 24 h after each TNFα/IFNγ infusion. Peripheral mononuclear lymphocytes
and NK activity decreased significantly 24 h after i. p. TNFα/IFNγ application. However, over the entire treatment schedule,
peripheral NK activity in all responders showed a continuous increase, when compared to pre TNFα/IFNγ treatment levels. In
contrast, NK activity in non-responders constantly decreased. In contrast to non-responders, TNF-inhibitory activity and soluble
p55 TNF receptor levels, determined in ascites, decreased in responders. Taken together, our findings suggest, that successful
locoregional i. p. TNFα/IFNγ therapy induces systemic immunological reactions possibly after saturation of soluble p55 TNF
receptors in ascites, which leads to an increase of peripheral NK activity.
Received: 28 September 1995 / Accepted: 16 November 1995 相似文献
3.
E. C. De Boer W. H. De Jong P. A. Steerenberg L. A. Aarden E. Tetteroo E. R. De Groot A. P. M. Van der Meijden P. D. J. Vegt F. M. J. Debruyne E. J. Ruitenberg 《Cancer immunology, immunotherapy : CII》1992,34(5):306-312
Summary To study the local immunological effects of intravesical bacillus Calmette-Guérin (BCG) therapy in superficial bladder cancer patients, the production of interleukin-1 (IL-1), IL-2, IL-6, tumour necrosis factor (TNF), and interferon (IFN) was investigated in the urine. Urine specimens were collected during the six weekly BCG instillations, before instillation, and 2, 4, 6, 8, and 24 h thereafter. Results were standardized to urine creatinine. In general, the concentration of IL-1 increased markedly during the first three BCG instillations, reaching a plateau from instillations 3 to 6. IL-2 was not detected after the first BCG instillation, but from the second instillation onwards the mean IL-2 concentration increased rapidly. With respect to IL-6, patients had relatively high levels in the urine after the first BCG instillation. A relatively moderate increase of the IL-6 concentration was observed during the following weeks. Like IL-2, TNF was only detected after repeated BCG instillations. Generally the highest TNF levels were found after BCG instillation 5. The presence of IFN could not be demonstrated. With respect to the occurrence of the cytokines during the first 24 h after the BCG instillation, TNF, IL-2, and IL-6 were detectable 2 h after the instillation. In contrast, IL-1 seemed to appear later, i.e. from 4 h onwards. TNF decreased most rapidly; it was nearly absent in 6-h samples. Generally IL-2 was not detectable in the 8-h samples, whereas IL-1 and IL-6 were present up to 8 h after instillation of BCG. The presence of TNF was found less frequently than the presence of IL-1, IL-2, and IL-6. Neutralization experiments indicated that most of the IL-1 present in the urine after BCG treatment was IL-1. In conclusion, activation of BCG-specific T cells was indicated by the detection of IL-2. The presence of IL-1, IL-6, and TNF might suggest activation of macrophages by intravesically administered BCG, although production by other cell types cannot be excluded. It is suggested that these cytokines, in combination with the leucocytes that are known to be recruited to the bladder in reaction to the BCG treatment, may play an important role in the antitumour activity of BCG against bladder cancer. For monitoring purposes, collection of urine might be performed during the first 6 h after BCG instillations 4–6. A correlation between the presence of cytokines in the urine and the clinical response has yet to be evaluated. 相似文献
4.
Schiött A Johansson AC Widegren B Sjögren HO Lindvall M 《Cancer immunology, immunotherapy : CII》2000,48(10):579-587
The cytokine transforming growth factor β-1 (TGFβ1), was transfected into a TGFβ1-negative rat colon carcinoma. The growth
of isografts of TGFβ1-expressing tumors was compared to that of vector control transfectants. The TGFβ1 transfectant grew
significantly more slowly after intrahepatic isografting than did vector control and wild-type tumors. The TGFβ1-transfected
tumor tissue had significantly greater infiltration of both CD4+ and CD8+ T lymphocytes than did the vector control tumor. The tumor-infiltrating leukocytes (TIL) from TGFβ1-transfected tumor secreted
significantly more of the cytokines interleukin-10 (IL-10) and tumor necrosis factor α (TNFα) than did TIL from the vector
control tumor. The TGFβ1 transfectant also demonstrated a significantly slower outgrowth in immunodeficient SCID mice, supporting
a non-T-lymphocyte-dependent mechanism for the tumor retardation. In SCID mice, the TGFβ1-transfected tumor demonstrated significantly
greater infiltration of both granulocytes and macrophages than did the vector control transfectant. We also demonstrated a
direct inhibitory effect of rat TNFα on tumor proliferation in vitro. These results suggest that TGFβ1 induces a local secretion
of immunomodulating cytokines and that this may influence monocytes, lymphocytes and granulocytes to retard tumor outgrowth.
Received: 7 July 1999 / Accepted: 12 August 1999 相似文献
5.
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
6.
Nath A Chattopadhya S Chattopadhyay U Sharma NK 《Cancer immunology, immunotherapy : CII》2006,55(12):1534-1541
The C–C chemokines, macrophage inflammatory protein (MIP)1α and MIP1β are potent chemoattractants for the monocytes, which form an important component of the stroma of tumor tissue and may regulate tumor growth and associated inflammation. We examined the role of MIP1α and MIP1β in inducing the release of inflammatory cytokines and the generation of tumoricidal monocytes from the peripheral blood monocytes (PBM) of healthy women and patients with carcinoma of breast (CaBr). Interleukin-1 (IL-1) and tumor necrosis factor (TNF) α release by the PBM was markedly stimulated by MIP1α in CaBr patients, but only marginally so in healthy women. In contrast, MIP1β stimulated the release of these cytokines by the PBM of healthy women, but failed to do so in CaBr patients. MIP1α, but not MIP1β, synergized with LPS in inducing the release of IL-1 from the PBM of both healthy women and CaBr patients. Both MIP1α and MIP1β augmented respiratory bursts in PBM and generated tumoricidal PBM that killed T24 cells, MIP1α being more effective in CaBr patients and MIP1β in healthy women. IFN-γ co-stimulated and IL-4 suppressed MIP1α and β-induced cytotoxicity in PBM. The synergy of IFN-γ was more marked with MIP1α than with MIP1β. The differential effects of MIP1α and MIP1β on the PBM of healthy women and CaBr patients co-related with the levels of expression of CCR1 and CCR5 in these monocytes. The expression of CCR5 was higher than that of CCR1 in the PBM of healthy women and the PBM of the CaBr patients showed overexpression of CCR1 and downregulation of CCR5. 相似文献
7.
Li Q Li L Shi W Jiang X Xu Y Gong F Zhou M Edwards CK Li Z 《Cancer immunology, immunotherapy : CII》2006,55(12):1470-1479
The proinflammatory cytokine tumor necrosis factor-alpha (TNFα) exists naturally in two forms, a 26 kDa transmembrane form (TM-TNFα), and a 17 kDa secretory form (S-TNFα). The biological roles for each of these forms of TNFα in tumor killing have not been completely elucidated. Therefore, in this study, three different recombinant retroviral vectors, wild-type TNFα, solely secretable TNFα mutant, and uncleavable transmembrane TNFα mutant, were constructed by molecular techniques and stably transfected into a murine hepatic carcinoma cell line (H22). TNFα, either secreted in cell culture supernatants by secretable TNFα mutant- or wild-type TNFα-producing tumor cells, or as a treansmembrane form expressed on the cell surface of uncleavable TNFα mutant- or wild-type TNFα-synthesizing tumor cells, was demonstrated to be cytotoxic against the TNF sensitive L929 cell line. The H22 cells transfected with the three different forms of TNFα were shown to kill parental H22 cells in an in vitro cytotoxicity assay [effect/target (E/T) ratio-dependent manner], and their maximal killing rates were ~38–43% at E/T ratio of 5:1. The injection of total 2.5×105 mixed cells containing transfected and parental H22 tumor cells at different ratios into syngeneic mice resulted in the inhibition of tumor growth with a maximal inhibition rates of ~57~72% at E/T ratio of 5:1. A transient weight loss was found in mice bearing solely secretable TNFα mutant producing tumors, whereas no obvious side effects were seen in mice bearing uncleavable TNFα mutant or wild-type TNFα expressing tumors. Finally, we demonstrate that tumors secreting S-TNFα promoted the subsequent infiltration of CD4+ T cells, and to a lesser extent CD8+ T cells, to the tumor site. The TM-TNFα expressing tumors up-regulated Fas (CD95) expression and inhibited the expression of tumor metastasis associated molecule CD44v3. These results suggest that S-TNFα and TM-TNFα kill cancer cells in vivo through different mechanisms of action. We conclude that the non-secreted form of TNFα may be an ideal candidate for cancer gene therapy due to its therapeutic potential and lowered side effect profile. 相似文献
8.
Effects of interleukin-12 on in vitro culture with interleukin-2 of regional lymph node lymphocytes from lung cancer patients 总被引:2,自引:0,他引:2
T. Hanagiri Mitsuhiro Takenoyama Takashi Yoshimatsu Chikashi Hirashima Ichiro Yoshino Kozo Nakanishi Akira Nagashima Kikuo Nomoto Kosei Yasumoto 《Cancer immunology, immunotherapy : CII》1996,43(2):87-93
In the present study, we carried out a functional analysis of regional lymph node lymphocytes (RLNL) from patients with lung
cancer after in vitro activation by interleukin-2 (IL-2) and interleukin-12 (IL-12). IL-12 (100 U/ml) enhanced both the proliferation
and cytotoxic activity of RLNL in a culture with low doses of IL-2 (5 – 10 JRU/ml). After comparing an RLNL culture with a
low dose of IL-2 alone, a higher proportion of CD8+ cells and CD56+ cells and a lower proportion of CD4+ cells were found in the culture with both IL-12 and a low dose of IL-2. Such a combination of the cytokines effectively activated
RLNL in terms of the expression of IL-2 receptors. In the culture condition of IL-12 and a low dose of IL-2, a synergistic
effect was observed in the production of such cytokines as interferon γ, tumor necrosis factor α (TNFα), and TNFβ, as well
as in tumor cytotoxicity. However, the addition of IL-12 inhibited the cytotoxicity of RLNL in the culture with a high dose
of IL-2 (100 JRU/ml). This inhibition is considered to be partially due to the endogenous production of TNFα by lymphocytes,
because the neutralization of TNFα bioactivity partially restored the cytotoxic activities of RLNL. Furthermore, in the presence
of hydrocortisone, IL-12 synergistically enhanced the cytotoxic activity of RLNL cultured with a high dose of IL-2. These
results provide useful information about the improvement of adoptive immunotherapy against cancer using RLNL.
Received: 2 February 1996 / Accepted: 30 July 1996 相似文献
9.
Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins
and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair
and inflammation, where TNF cytokines are also expressed. Although TNFα is an apoptotic inducer in some cancer cells, it activates
NFκB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis
or NFκB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFα,
thus converting TNFα from a proliferation-promoting protein into an apoptotic inducer. These CCN proteins also enhance the
cytotoxicity of other TNF cytokines, including LTα, FasL, and TRAIL. Mechanistically, CCNs function through integrin α6β1 and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation, which is essential
for apoptotic synergism. Mutant CCN1 proteins defective for binding α6β1-HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an α6β1-HSPG-binding defective CCN1 are blunted in TNFα- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator
of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating
or enhancing the cytotoxicity of TNFα and related cytokines. 相似文献
10.
Cecilia Bergenwald Gunilla Westermark B. Sander 《Cancer immunology, immunotherapy : CII》1997,44(6):335-340
Tumor necrosis factor α (TNFα) is a cytokine, produced by lymphocytes and monocytes, with cytotoxic activity against some
but not all tumor cell lines. Resistance to the cytolytic effects of TNFα has been reported in cell lines with autocrine TNFα
production. The purpose of this study was to investigate whether human primary malignant melanoma and tumor infiltrating lymphocytes
produce TNFα in vivo. Optimal conditions for in situ hybridization for TNFα mRNA in paraffin-embedded tissue were established.
Analysis of 13 primary malignant melanomas and 3 metastatic lesions with different degrees of immunohistochemical TNFα positivity
demonstrated that, in some tumors, both melanoma cells and leukocytes contained TNFα mRNA and protein. These findings demonstrate
variable production of TNFα in primary and metastatic melanoma in vivo.The previously described resistance to TNFα cytolytic
activity may, therefore, be clinically important.
Received: 18 December 1996 / Accepted: 12 June 1997 相似文献
11.
Wujiang Liu Michael A. O’Donnell Xiaohong Chen Ruifa Han Yi Luo 《Cancer immunology, immunotherapy : CII》2009,58(10):1647-1655
Purpose The proper induction of cellular immunity is required for effective bacillus Calmette-Guérin (BCG) immunotherapy of bladder
cancer. It has been known that BCG stimulation of human peripheral blood mononuclear cells (PBMC) leads to the generation
of effector cells cytotoxic to bladder cancer cells in vitro. To improve BCG therapy, we previously developed human interferon
(IFN)-α 2B secreting recombinant (r) BCG (rBCG-IFN-α). We demonstrated that rBCG-IFN-α augmented T helper type 1 (Th1) cytokine
IFN-γ production by PBMC. In this study, we further investigated whether rBCG-IFN-α could also enhance PBMC cytotoxicity toward
bladder cancer cells.
Materials and methods PBMC were prepared from healthy individuals, left alone or stimulated with rBCG-IFN-α or control MV261 BCG, and used as effector
cells in 51Cr-release assays. Human bladder cancer cell lines T24, J82, 5637, TCCSUP, and UMUC-3 were used as target cells. To determine
the role of secreted rIFN-α as well as endogenously expressed IFN-γ and IL-2 in inducing the cytotoxicity, PBMC were stimulated
with rBCG-IFN-α in the presence of neutralizing antibodies to IFN-α, IFN-γ or IL-2. To determine the role of natural killer
(NK) and CD8+ T cells in inducing the cytotoxicity, both cell types were isolated after BCG stimulation of PBMC and used as effector cells
in 51Cr-release assays.
Results Non-stimulated PBMC showed basal levels of cytotoxicity against all target cell lines tested. MV261 BCG increased the PBMC
cytotoxicity by 1.8- to 4.2-fold. rBCG-IFN-α further increased the PBMC cytotoxicity by up to 2-fold. Elevated production
of IFN-γ and IL-2 by PBMC was observed after rBCG-IFN-α stimulation. Blockage of IFN-α, IFN-γ or IL-2 by neutralizing antibodies
during rBCG-IFN-α stimulation reduced or abolished the induction of PBMC cytotoxicity. Both NK and CD8+ T cells were found to be responsible for the enhanced PBMC cytotoxicity induced by rBCG-IFN-α with the former cell type being
more predominant.
Conclusions rBCG-IFN-α is an improved BCG agent that induces enhanced PBMC cytotoxicity against bladder cancer cells in vitro. This rBCG
strain may serve as an alternative to BCG for the treatment of superficial bladder cancer. 相似文献
12.
Hasem Habelhah Futoshi Okada Kazumoto Nakai Sung Ki Choi Jun-ichi Hamada Masanobu Kobayashi M. Hosokawa 《Cancer immunology, immunotherapy : CII》1998,46(6):338-344
Previously we reported the malignant progression of QR-32, a regressor-type tumor clone, following co-implantation with foreign
bodies (gelatin sponge or plastic plate) in normal syngeneic C57BL/6 mice. We also reported that the progression of QR-32
cells by a gelatin sponge was significantly inhibited in the mice administered polysaccharide K (PSK) and that PSK induced
an increase of radical scavengers, especially manganese superoxide dismutase (Mn-SOD), locally at the site of tumor tissues.
In this study, to reveal the possible mechanism by which PSK induced Mn-SOD in the tumor tissues, we examined the mRNA expression
and protein levels of inflammatory cytokines in the tissues. We found that mRNAs of tumor necrosis factor α (TNFα) and interleukin-1α
(IL-1α) were considerably expressed in both PSK-treated and phosphate-buffered-saline-treated tumors, and that the mRNA expression
and protein level of interferon γ (IFNγ) increased in the tumor tissues treated with PSK. In vitro treatment of QR-32 cells
with IFNγ did not significantly increase the production of Mn-SOD; however, the combination of IFNγ with TNFα increased the
Mn-SOD production more effectively than did any of the cytokines used singly. Furthermore, we observed the down-regulation
of the mRNA expression and protein level of transforming growth factor β (TGFβ) in the tumor tissues treated with PSK, and
that in vitro treatment of QR-32 cells with TGFβ decreased the production of Mn-SOD. These results suggest that PSK suppresses
the progression of QR-32 cells by increasing Mn-SOD via the modulation of inflammatory cytokines; that is, by decreasing TGF-β
and increasing IFN-γ.
Received: 7 October 1997 / Accepted: 31 March 1998 相似文献
13.
Hirofumi Shoda Keishi Fujio Yumi Yamaguchi Akiko Okamoto Tetsuji Sawada Yuta Kochi Kazuhiko Yamamoto 《Arthritis research & therapy》2007,8(6):R166
IL-32 is a newly described cytokine in the human found to be an in vitro inducer of tumor necrosis factor alpha (TNFα). We examined the in vivo relationship between IL-32 and TNFα, and the pathologic role of IL-32 in the TNFα-related diseases – arthritis and colitis.
We demonstrated by quantitative PCR assay that IL-32 mRNA was expressed in the lymphoid tissues, and in stimulated peripheral
T cells, monocytes, and B cells. Activated T cells were important for IL-32 mRNA expression in monocytes and B cells. Interestingly,
TNFα reciprocally induced IL-32 mRNA expression in T cells, monocyte-derived dendritic cells, and synovial fibroblasts. Moreover,
IL-32 mRNA expression was prominent in the synovial tissues of rheumatoid arthritis patients, especially in synovial-infiltrated
lymphocytes by in situ hybridization. To examine the in vivo relationship of IL-32 and TNFα, we prepared an overexpression model mouse of human IL-32β (BM-hIL-32) by bone marrow transplantation.
Splenocytes of BM-hIL-32 mice showed increased expression and secretion of TNFα, IL-1β, and IL-6 especially in response to
lipopolysaccharide stimulation. Moreover, serum TNFα concentration showed a clear increase in BM-hIL-32 mice. Cell-sorting
analysis of splenocytes showed that the expression of TNFα was increased in resting F4/80+ macrophages, and the expression of TNFα, IL-1β and IL-6 was increased in lipopolysaccharide-stimulated F4/80+ macrophages and CD11c+ dendritic cells. In fact, BM-hIL-32 mice showed exacerbation of collagen-antibody-induced arthritis and trinitrobenzen sulfonic
acid-induced colitis. In addition, the transfer of hIL-32β-producing CD4+ T cells significantly exacerbated collagen-induced arthritis, and a TNFα blockade cancelled the exacerbating effects of hIL-32β.
We therefore conclude that IL-32 is closely associated with TNFα, and contributes to the exacerbation of TNFα-related inflammatory
arthritis and colitis. 相似文献
14.
Dendritic cells engineered to express CD40L continuously produce IL12 and resist negative signals from Tr1/Th3 dominated tumors 总被引:1,自引:0,他引:1
TNFα-matured dendritic cells (DCs) pulsed with tumor antigens are being evaluated as cancer vaccines. It has been shown that DCs produce IL12 during a limited time span and subsequently enter a stage of IL12 exhaustion. If DCs are generated ex vivo, the patient could receive IL12-exhausted DCs which may be detrimental for stimulating anti-tumor Th1 responses. Furthermore, many cancer patients exhibit a cytokine profile skewed toward IL10 and TGFβ. This immunological profile, called the Tr1/Th3 response, is associated with the presence of regulatory T-cells. Tr1/Th3 responses potently inhibit DC maturation, thereby regulating Th1 responses. In the present study, we produced genetically engineered DCs that continuously express Th1-related cytokines such as IL12, and resist negative signals from Tr1/Th3-dominated bladder carcinoma cells. Human immature DCs were genetically engineered by adenoviral vectors to express CD40L, or were treated with TNFα as a positive control for maturation. The expression of different Th1/Th3 and inflammatory cytokines was monitored. IL12 and IFNγ were expressed by CD40L-engineered DCs, while TNFα-matured DCs lacked IFNγ and exhibited low IL12 expression. The addition of recombinant IL10 to genetically engineered DCs did not abolish their Th1 profile. Likewise, coculture with tumor cell lines expressing TGFβ with or without recombinant IL10 did not revert to the engineered DCs. We further demonstrate that the resistance of CD40L-expressing DCs to TGFβ and IL10 may be due to decreased levels of TGFβ and IL10 receptors. Thus, CD40L-engineered DCs are robust Th1-promoting ones that are resistant to Tr1/Th3-signaling via IL10 and TGFβ. 相似文献
15.
Tomoe Higuchi Masumi Shimizu Atsuko Owaki Megumi Takahashi Eiji Shinya Taiji Nishimura Hidemi Takahashi 《Cancer immunology, immunotherapy : CII》2009,58(8):1245-1255
Intravesical bacillus Calmette-Guerin (BCG) therapy is considered the most successful immunotherapy against solid tumors of
human bladder carcinoma. To determine the actual effector cells activated by intravesical BCG therapy to inhibit the growth
of bladder carcinoma, T24 human bladder tumor cells, expressing very low levels of class I MHC, were co-cultured with allogeneic
peripheral blood mononuclear cells (PBMCs) with live BCG. The proliferation of T24 cells was markedly inhibited when BCG-infected
dendritic cells (DCs) were added to the culture although the addition of either BCG or uninfected DCs alone did not result
in any inhibition. The inhibitory effect was much stronger when the DCs were infected with live BCG rather than with heat-inactivated
BCG. The live BCG-infected DCs secreted TNF-α and IL-12 within a day and this secretion continued for at least a week, while
the heat-inactivated BCG-infected DCs secreted no IL-12 and little TNF-α. Such secretion of cytokines may activate innate
alert cells, and indeed NKT cells expressing IL-12 receptors apparently proliferated and were activated to produce cytocidal
perforin among the PBMCs when live BCG-infected DCs were externally added. Moreover, depletion of γδ T-cells from PBMCs significantly
reduced the cytotoxic effect on T24 cells, while depletion of CD8β cells did not affect T24 cell growth. Furthermore, the
innate effectors seem to recognize MICA/MICB molecules on T24 via NKG2D receptors. These findings suggest the involvement
of innate alert cells activated by the live BCG-infected DCs to inhibit the growth of bladder carcinoma and provide a possible
mechanism of intravesical BCG therapy. 相似文献
16.
Eveline S. J. M. de Bont Anita E. Niemarkt Rienk Y. J. Tamminga Jan L. L. Kimpen Willem A. Kamps Lou H. M. F. de Leij 《Histochemistry and cell biology》1996,106(6):593-598
Lipopolysaccharide (LPS) can induce monocytes to produce various cytokines such as tumor necrosis factor α (TNFα) and interleukin
1β (IL-1β). In the present study, the kinetics of both intracellular and extracellular accumulation of TNFα and IL-1β in LPS
stimulated mononuclear cell (MNC) cultures has been determined. A three-color-immunofluorescence technique was used to detect
intracellular accumulation of cytokines. Intracellular accumulation of TNFα in monocytes starts shortly after initiation of
the culture; i.e., TNFα is detectable after 1 h, reaching a peak level after 3–4 hours with 50–65% of monocytes staining positive.
In parallel with its increased intracellular presence, TNFα was also found in the culture supernatant. The intracellular accumulation
of IL-1β in monocytes became detectable after 2 h of culture in the presence of LPS. After 4 h, a plateau was reached, with
90% of the monocytes being positive. In parallel, but with a little delay, IL-1β could be detected in the culture supernatant.
TNFα and IL-1β can be produced simultaneously in the same monocytes as was shown by a three-color-immunofluorescence technique.
It is concluded that TNFα and IL-1β are good parameters for the early measurement of monocyte activation and that both the
intracellular accumulation in monocytes and the amount of secreted cytokines can be used for such a purpose. The intracellular
accumulation in monocytes can be measured by the three-color-immunofluorescence technique described.
Accepted: 27 August 1996 相似文献
17.
18.
P Antunovic D Marisavljevic N Kraguljac V Jelusic 《Cancer immunology, immunotherapy : CII》1998,15(1):58-60
Hypercalcaemia is a rare feature of acute lymphoblastic leukaemia (ALL) in adults, particularly of the T cell type. We report
on a 24-year-old patient with T-ALL, who presented with symptoms of hypercalcaemia (vomitus, acute renal failure), bone pain,
extensive osteolytic lesions and normal white cell count without circulating blasts. An increased serum tumor necrosis factor
(TNF-α) concentration of 35 pg/ml was found; it remained elevated at, 52 pg/ml four weeks later, after having achieved haematological
remission. Serum concentrations of IL-1β, IL-6 and IL-2 were within the control range. The pathophysiology of hypercalcaemia
in malignancy and possible mediators of bone resorption, in particular TNF-α, are discussed. 相似文献
19.
Richard O Williams 《Arthritis research & therapy》2008,10(3):113
Anti-tumour necrosis factor (TNF)α therapy is highly effective in rheumatoid arthritis and it is surprising, therefore, that
a recent study showed that intraperitoneal administration of recombinant TNFα reduced the severity of adjuvant-induced arthritis
and decreased IFNγ expression in cultured draining lymph node cells. Furthermore, in untreated arthritic rats, maximal TNFα
expression in draining lymph node cells coincided with spontaneous disease remission, suggesting a role for endogenous TNFα
in recovery from arthritis. If confirmed in further studies, these findings suggest that, in addition to its well-established
pro-inflammatory properties, TNFα may also play a disease-limiting role in this model of rheumatoid arthritis by suppressing
effector T cell responses. 相似文献
20.
IL-1β is a major cytokine driving the inflammatory processes leading to the pathophysiology of osteoarthritis and other inflammatory
diseases. Blockade of IL-1β activity using substances such as the naturally occurring IL-1 receptor antagonist or anti-IL-1β
monoclonal antibody are currently being used or tested as therapy. However, such treatments are ineffective in osteoarthritis.
In a recent study, epigallocatechin-3-gallate, a green tea polyphenol, was found to be effective in reducing IL-1β-induced
inflammatory cytokines, TNFα, IL-6, granulocyte-macrophage colony-stimulating factor and several chemokines from human chondrocytes.
The use of green tea polyphenols may be beneficial as a therapeutic addition to biologics that control IL-1β activity by increasing
effectiveness and/or reducing dosage. 相似文献