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1.
Guenterberg KD Lesinski GB Mundy-Bosse BL Karpa VI Jaime-Ramirez AC Wei L Carson WE 《Cancer immunology, immunotherapy : CII》2011,60(9):1281-1288
Interferon-alpha (IFN-α) is an immunomodulatory cytokine that is used clinically for the treatment of melanoma in the adjuvant
setting. The cellular actions of IFN-α are regulated by the suppressors of cytokine signaling (SOCS) family of proteins. We
hypothesized that the anti-tumor activity of exogenous IFN-α would be enhanced in SOCS1-deficient mice. SOCS1-deficient (SOCS1−/−) or control (SOCS1+/+) mice on an IFN-γ−/− C57BL/6 background bearing intraperitoneal (i.p.) JB/MS murine melanoma cells were treated for 30 days with i.p. injections
of IFN-A/D or PBS (vehicle). Log-rank Kaplan-Meier survival curves were used to evaluate survival. Tumor-bearing control SOCS1+/+ mice receiving IFN-A/D had significantly enhanced survival versus PBS–treated mice (P = 0.0048). The anti-tumor effects of IFN-A/D therapy were significantly enhanced in tumor-bearing SOCS1−/− mice; 75% of these mice survived tumor challenge, whereas PBS-treated SOCS1−/− mice all died at 13-16 days (P = 0.00038). Antibody (Ab) depletion of CD8+ T cells abrogated the anti-tumor effects of IFN-A/D in SOCS1−/− mice as compared with mice receiving a control antibody (P = 0.0021). CD4+ T-cell depletion from SOCS1−/− mice also inhibited the effects of IFN-A/D (P = 0.0003). IFN-A/D did not alter expression of CD80 or CD86 on splenocytes of SOCS1+/+ or SOCS1−/− mice, or the proportion of T regulatory cells or myeloid-derived suppressor cells in SOCS1+/+ or SOCS1−/− mice. An analysis of T-cell function did reveal increased proliferation of SOCS1-deficient splenocytes at baseline and in
response to mitogenic stimuli. These data suggest that modulation of SOCS1 function in T-cell subsets could enhance the anti-tumor
effects of IFN-α in the setting of melanoma. 相似文献
2.
Thakur A Schalk D Sarkar SH Al-Khadimi Z Sarkar FH Lum LG 《Cancer immunology, immunotherapy : CII》2012,61(4):497-509
In this study, we investigated whether activated T cells (ATC) armed with bispecific antibodies (aATC) can inhibits tumor
growth and MDSC development in a Th1 cytokine–enriched (IL-2 and IFN-γ) microenvironment. Cytotoxicity mediated by aATC was significantly higher (P < 0.001) against breast cancer cell lines in the presence of Th1 cytokines as compared with control co-cultures. In the presence of aATC, CD33+/CD11b+/CD14−/HLA-DR− MDSC population was reduced significantly under both control (P < 0.03) and Th1-enriched (P < 0.036) culture conditions. Cytokine analysis in the culture supernatants showed high levels of MDSC suppressive chemokines
CXCL9 and CXCL10 in Th1-enriched culture supernatants with highly significant increase (P < 0.001) in the presence of aATC. Interestingly, MDSC recovered from co-cultures without aATC showed potent ability to suppress
activated T-cell-mediated cytotoxicity (P < 0.001), IFN-γ production (P < 0.01) and T-cell proliferation (P < 0.05) compared to those recovered from aATC-containing co-cultures. These data suggest that aATC can mediate enhanced killing
of tumor cells and may suppress MDSC and Treg differentiation, and presence of Th1 cytokines potentiates aATC-induced suppression of MDSC, suggesting that Th1-enriching immunotherapy may be beneficial in cancer treatment. 相似文献
3.
Olga Radkevich-Brown Marie P. Piechocki Jessica B. Back Amy M. Weise Shari Pilon-Thomas Wei-Zen Wei 《Cancer immunology, immunotherapy : CII》2010,59(3):409-417
In situ expression of a foreign antigen and an immune-modulating cytokine by intratumoral DNA electroporation was tested as
a cancer therapy regimen. Transgene expression in the tumors was sustained for 2–3 weeks after intratumoral electroporation
with mammalian expression plasmid containing firefly luciferase cDNA. Electroporation with cDNA encoding tetanus toxin fragment
C (TetC) induced tetanus toxin-binding antibody, demonstrating immune recognition of the transgene product. Intratumoral electroporation
with TetC and IL-12 cDNA after mice were treated with CD25 mAb to remove regulatory T cells induced IFN-γ producing T-cell
response to tumor-associated antigen, heavy inflammatory infiltration, regression of established tumors and immune memory
to protect mice from repeated tumor challenge. Intratumoral expression of immune-modulating molecules may be most suitable
in the neoadjuvant setting to enhance the therapeutic efficacy and provide long-term protection. 相似文献
4.
Miki Watanabe Sulaiman Sheriff Theresa A. Ramelot Nijiati Kadeer Junho Cho Kenneth B. Lewis Ambikaipakan Balasubramaniam Michael A. Kennedy 《International journal of peptide research and therapeutics》2011,17(4):281-299
After severe burn injury, proinflammatory cytokine levels are elevated in serum and skeletal muscle, which in turn increases
protein breakdown and decreases protein synthesis. In this study, C2C12 mouse skeletal muscle cell line myotubes were exposed
to proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) as an in vitro cell-line model of catabolic
response to burn injury and then treated with des-acyl ghrelin (DAG), a 28 amino acid polypeptide hormone thought to inhibit
protein breakdown and increase protein synthesis, to assess its therapeutic potential. Nuclear magnetic resonance-based metabonomics
was used to monitor metabolic activity of C2C12 myotubes under four treatment conditions: (1) control, (2) TNF-α/IFN-γ (TI),
(3) DAG (DA), and (4) TNF-α/IFN-γ followed by DAG (TIDA) to assess the effect of DAG treatment on cellular metabolic response
during basal or catabolic conditions. Twelve metabolites showed significant changes in concentrations following treatments
in the hydrophilic cell extracts. Lactate (P < 10−4) and citrulline (P < 10−9) increased with TNF-α/IFN-γ treatment, indicating increased protein degradation, and returned to control levels in the TIDA
group. Adenosine nucleotide levels had decreased trends in TI myotubes that returned to baseline levels after DAG treatment
(P < 10−4). Guanidinoacetate and pantothenate, metabolites involved in protein synthesis and cell proliferation, had increased concentration
trends following DAG treatment in both the DA and TIDA groups. Our metabonomics analysis provides further evidence that DAG
counteracts the catabolic response caused by elevated muscle TNF-α/IFN-γ cytokine levels following severe burns and can play
a potential therapeutic role in treatment of burn injury. 相似文献
5.
Christoph Domschke Florian Schuetz Nora Sommerfeldt Joachim Rom Alexander Scharf Christof Sohn Andreas Schneeweiss Philipp Beckhove 《Cancer immunology, immunotherapy : CII》2010,59(3):479-486
Tumor-specific memory T cells are detectable in the bone marrow (BM) of a majority of breast cancer patients. In vitro they
can be reactivated to IFN-γ producing, cytotoxic effector cells and reject autologous, xenotransplanted tumors in NOD/SCID
mice after specific restimulation with autologous dendritic cells (DC). In this study, we demonstrate the presence of specific
tumor-reactive BM memory T cells in altogether 56 out of 129 primarily operated breast cancer patients by short-term IFN-γ
EliSpot assays with unstimulated T cells and tumor antigen presenting, autologous DCs. We observed tumor-reactive BM memory
T cells predominantly in patients with primarily metastatic disease (P = 0.011) or with increased concentrations of tumor marker CA 15-3 in the peripheral blood (P = 0.004), respectively. Memory T cell reactivity against HLA-A*0201-restricted peptides from the tumor-associated antigens MUC1, Hpa16–24 and Hpa183–191 was also detected particularly in patients with elevated peripheral CA 15-3 concentrations (P < 0.05). Altogether these data indicate that the systemic presence of tumor-derived antigens promotes an induction of tumor-specific
cellular immune responses in the human BM. 相似文献
6.
Mukesh Kumar Xiaoyuan Kong Aruna K Behera Gary R Hellermann Richard F Lockey Shyam S Mohapatra 《Genetic vaccines and therapy》2003,1(1):3
Background
Allergic subjects produce relatively low amounts of IFN-γ, a pleiotropic Th-1 cytokine that downregulates Th2-associated airway inflammation and hyperresponsiveness (AHR), the hallmarks of allergic asthma. Adenovirus-mediated IFN-γ gene transfer reduces AHR, Th2 cytokine levels and lung inflammation in mice, but its use would be limited by the frequency of gene delivery required; therefore, we tested chitosan/IFN-γ pDNA nanoparticles (CIN) for in situ production of IFN-γ and its in vivo effects. 相似文献7.
S. Bhattacharyya S. N. Das A. B. Dey K. Nagarkar J. Lobo S. K. Kapoor H. K. Prasad 《Journal of biosciences》1997,22(1):99-109
Interferon-(IFN-γ) has been considered to be a critical protective immunomodulatory component against
Mycobacterium tuberculosis (M. tb.) infection. In this study T-cell proliferation and IFN-γ production upon stimulation with M. tb. were assessed in
patients of pulmonary tuberculosis and healthy contacts. The studies were based on lymphocyte transformation test and detection
of intracellular IFN-γ production by CD4 + ve T-cells by flowcytometry. Patients showed lower levels of proliferation, the
stimulation index being in the range of 2.17 1.1 (mean + SD) compared to the contacts (SI = 4 59±1.6) (P < 0.01). The kinetics
of intracellular induction of IFN-γ on M. tb. stimulation showed a proportional increase in the CD4 + ve T-cell population.
The increase was maximal between 96–120 h of culture. In healthy contacts the number of IFN-γ expressing CD + ve T-cells increased
to 2.5 to 41 × 104 cells/ml in M. tb. stimulated cultures compared to control cultures (0.1 – 15 × 104). In contrast patients showed no/marginal increase in CD4 + ve T-cell population expressing intracellular IFN-γ Thus the
lack of induction of IFN in CD4 + ve T-cells in patients could be a critical shortcoming in their ability to combat tubercle
bacilli infection. 相似文献
8.
T. Y. C. Massuda L. A. Nagashima P. C. Leonello M. S. Kaminami M. S. Mantovani A. Sano J. Uno E. J. Venancio Z. P. Camargo E. N. Itano 《Mycopathologia》2011,171(3):161-169
Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the fungus Paracoccidioides brasiliensis (Pb). The cyclosporin A (CsA) is an immunosuppressant drug that inhibits calcineurin and has been described as a potential
antifungal drug. The present study investigated the effect of CsA on the immune response, fungal load/antigenemia in experimental
murine PCM. It was used four groups of BALB/c mice: (a) infected with 1 × 105 Pb18 yeast cells (Pb), (b) infected and treated with CsA every other day 10 mg/kg of CsA (s.c.) during 30 days (Pb/CsA),
(c) treated with CsA (CsA) and (d) no infected/treated (PBS). The immune response was evaluated by lymphocyte proliferation,
DTH assays to exoAgs, ELISA for IgG anti-gp43 (specific immune responses) and cytokine serum levels (IFN-γ, TNF-α, IL-4 and
IL-10). Fungal load was determined by lung colony-forming units (CFU) counts, lung and liver histopathology analysis and antigenemia
determined by inhibition-ELISA. As expected, CsA was able to inhibit the specific cellular and humoral immune response (P < 0.05), with decrease in serum IFN-γ, TNF-α and IL-4 levels (P < 0.05). Cyclosporin A treatment also resulted in significantly decreased lung Pb CFU (P < 0.05) as well as a lower number of yeasts in the lung and liver (P < 0.05) by histopathology. In concordance, the decreased antigenemia was observed in Pb/CsA group (P < 0.05). In conclusion, even with immunosuppressive action, treatment with CsA results in decreased lung fungal load/antigenemia
in experimental PCM in BALB/c mice. Further study is required to determine whether this represents less severe disease or
protection by CsA. 相似文献
9.
Commercially available DOTAP is a racemic mixture of two enantiomers. The adjuvanticity of each isomer was examined using
a peptide/lipid complex as a therapeutic vaccine in an established murine cervical cancer model. This simple vaccine consists
of a cationic lipid (DOTAP) and a major histocompatibility complex (MHC) class I–restricted epitope of the Human Papillomavirus
(HPV) 16 protein E7. Dose-dependent tumor regression experiments have been completed for racemic DOTAP/E7, (R)-DOTAP/E7 and
(S)-DOTAP/E7. Tumor-bearing mice treated with (R)-DOTAP/E7 complexes have shown tumor regression in a dose-dependent manner
comparable to those mice treated with a racemic DOTAP with E7 peptide. These data are supported by IFN-γ production by CD8+ splenocytes, in vivo cytotoxic T-lymphocytes (CTL) response, CD8+ tumor-infiltrating lymphocytes (TIL), and IFN-γ production by CD8+ TIL in (R)-DOTAP/E7-vaccinated mice. When (S)-DOTAP/E7 is delivered, tumor progression is delayed. While IFN-γ production
is absent from CD8+ splenocytes in mice vaccinated with (S)-DOTAP/E7, IFN-γ production by CD8+ TIL is present, supporting our hypothesis that (S)-DOTAP has limited activity. Activation of bone marrow-derived dendritic
cells by the enantiomeric formulations has also been evaluated, as well as cytokine production and toxicity with no considerable
differences between the groups. The results show the DOTAP enantiomers act differently as adjuvants in vivo, with (R)-DOTAP
being more effective at stimulating a CD8+ anti-tumor response. 相似文献
10.
Establishment of a detection platform for glioblastoma-dendritic cell (DC) vaccine preparation and to determine the efficacy
of the vaccine in a clinical trial. Autologous glioblastoma-DC vaccine was prepared from a glioblast specimen procured from
surgical resection. The specimen was used to enrich the vaccine with peripherally blood-derived DCs after heat-shock induced,
glioblastoma apoptosis. The control group received conventional treatment of surgery and radio-chemotherapy post-operation.
The therapeutic group received a combination of glioblastoma-DC vaccine and conventional therapy. A comparison of the functional
immune parameters, including tumor control, rate live time, Karnofsky scores, and complications occurring in each group were
observed and recorded. The proportions of peripheral CD3+, CD3+CD4+, CD4+/CD8+, and NK cells were significantly higher after DC vaccination than the control group (P < 0.05). Serum levels of IL-2, IL-12, and IFN-γwere significantly higher after DC vaccination than in the control group (P < 0.05). Nine months after vaccination, tumor control rate is significantly improved in the DC group compared with the control
group (P < 0.05); survival rate was significantly higher in DC group than in control group (P < 0.05) and the time to relapse was significantly longer in DC group than that in control group (P < 0.05). Karnofsky scores were better in DC vaccination group 6 and 9 months post-treatment compared with the control group
(P < 0.05). The combination of glioma DC vaccine and radiotherapy/chemotherapy post-operatively enhances the immune function
of patients, increases the tumor control rate, prolongs the survival time and relapse duration, improves the quality of life,
and therefore provides a more effective intervention of treating glioblastoma. 相似文献
11.
Hilde Kelchtermans Evelien Schurgers Lies Geboes Tania Mitera Jo Van Damme Jacques Van Snick Catherine Uyttenhove Patrick Matthys 《Arthritis research & therapy》2009,11(4):R122-13
Introduction
Interleukin (IL)-17 is a pro-inflammatory cytokine in rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Since interferon (IFN)-γ inhibits Th17 cell development, IFN-γ receptor knockout (IFN-γR KO) mice develop CIA more readily. We took advantage of this model to analyse the mechanisms of action of IL-17 in arthritis. The role of IFN-γ on the effector mechanisms of IL-17 in an in vitro system was also investigated. 相似文献12.
The role of cytokines in the pathophysiology of amyotrophic lateral sclerosis (ALS) and its relation to clinical outcome has
not been clearly defined. We evaluated tumor necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ) and nitric oxide (NO) levels
in the serum of 22 ALS patients and 20 controls. Serum TNF-α levels and IFN-γ levels were significantly (P < 0.001) elevated in ALS patients. We also observed NO levels to be significantly (P < 0.05) increased with respect to normal subjects. We further noticed positive correlation between the duration of ALS and
these proinflammatory molecule levels. Exitotoxicity and oxidative stress are known to play a crucial role in the neurodegeneration
observed in ALS. Since high levels of TNF-α are known to be cytotoxic, it could be that a complex interplay of these effectors
may be one of the factors underlying the progression of ALS. This study confirms the involvement of inflammation in ALS and
the need to develop surrogate markers to check the progression of this disease. 相似文献
13.
14.
Flávia Gomes de Góes Rocha Karen Cristina Barbosa Chaves Roger Chammas Jean Pierre Schatzmann Peron Luiz Vicente Rizzo Nestor Schor Maria Helena Bellini 《Cancer immunology, immunotherapy : CII》2010,59(9):1357-1365
We investigated whether the administration of IL-2 combined with endostatin gene therapy was able to produce additive or even
synergistic immunomodulatory activity in a mouse model of metastatic renal carcinoma. Renca cells were injected into the tail
vein of BALB/c mice. After 24 h, the animals were randomly divided into four groups (5 mice/group). One group of mice was
the control, the second group received treatment with 100,000 UI of Recombinant IL-2 (Proleukin, Chiron) twice a day, 1 day
per week during 2 weeks (IL-2), the third group received treatment with a subcutaneous inoculation of 3.6 × 106 endostatin-producing cells, and the fourth group received both therapies (IL-2 + ES). Mice were treated for 2 weeks. In the
survival studies, 10 mice/group daily, mice were monitored daily until they died. The presence of metastases led to a twofold
increase in endostatin levels. Subcutaneous inoculation of NIH/3T3-LendSN cells resulted in a 2.75 and 2.78-fold increase
in endostatin levels in the ES and IL-2 + ES group, respectively. At the end of the study, there was a significant decrease
in lung wet weight, lung nodules area, and microvascular area (MVA) in all treated groups compared with the control group
(P < 0.001). The significant difference in lung wet weight and lung nodules area between groups IL-2 and IL-2 + ES revealed
a synergistic antitumor effect of the combined treatment (P < 0.05). The IL-2 + ES therapy Kaplan–Meier survival curves showed that the probability of survival was significantly higher
for mice treated with the combined therapy (log-rank test, P = 0.0028). Conjugated therapy caused an increase in the infiltration of CD4, CD8 and CD49b lymphocytes. An increase in the
amount of CD8 cells (P < 0.01) was observed when animals received both ES and IL-2, suggesting an additive effect of ES over IL-2 treatment. A synergistic
effect of ES on the infiltration of CD4 (P < 0.001) and CD49b cells (P < 0.01) was also observed over the effect of IL-2. Here, we show that ES led to an increase in CD4 T helper cells as well
as cytotoxic lymphocytes, such as NK cells and CD8 cells, within tumors of IL-2 treated mice. This means that ES plays a role
in supporting the actions of T cells. 相似文献
15.
T cell activation and retargeting using staphylococcal enterotoxin B and bispecific antibody: An effective in vivo antitumor strategy 总被引:5,自引:0,他引:5
Lewis E. Porter Heidi Nelson I. Ethem Gecim David C. Rice Claude Thibault Andrei I. Chapoval 《Cancer immunology, immunotherapy : CII》1997,45(3-4):180-183
The aim of this work was to test for cure and immunity in a micrometastatic tumor model using in vivo T cell activation with
staphylococcal enterotoxin B (SEB) and retargeting with antitumor×anti-CD3 F(ab′)2 bispecific antibodies (bsAb). All studies were performed in C3H/HeN mice using syngeneic tumor cell lines. For survival studies,
mice were injected intravenously on day 0 with CL62 (a p97-transfected clone of the K1735 murine melanoma tumor). Day-3 treatments
included saline (control), SEB (50 γg intraperitoneal) with or without bsAb (5 μg i.v.). Cured mice, surviving beyond 60 days,
were rechallenged with subcutaneous CL62, K1735, or a nonmelanoma control, AG104. SEB activation studies were performed with
pulmonary tumor-infiltrating lymphocytes isolated from 10-day established CL62 tumors. Maximal tumor-infiltrating lymphocyte
cytotoxicity was demonstrated 24 h following SEB injection, therefore bsAb treatments were administered 24 h after SEB. When
survival was examined at 60 days, there were significantly more survivors in the group receiving SEB plus bsAb (70%) compared
to the group receiving SEB alone (30%), and the controls (0%) (P=0.02 and P<0.01, respectively). Mice cured of CL62 using SEB alone or with bsAb demonstrated equal immunity to CL62, however, mice treated
with SEB plus bsAb were more often immune to the p97– parental cell line, K1735(P=0.001). Ag104 consistently grew in all mice. Results of these studies demonstrate that SEB plus bsAb can be effective, not
only in curing tumors but also in providing protective immunity against targeted and nontargeted tumor antigens.
Accepted: 14 October 1997 相似文献
16.
Dumitru CD Antonysamy MA Gorski KS Johnson DD Reddy LG Lutterman JL Piri MM Proksch J McGurran SM Egging EA Cochran FR Lipson KE Tomai MA Gullikson GW 《Cancer immunology, immunotherapy : CII》2009,58(4):575-587
Innate immune stimulation with Toll-like receptor (TLR) agonists is a proposed modality for immunotherapy of melanoma. Here,
a TLR7/8 agonist, 3M-011, was used effectively as a single systemic agent against disseminated mouse B16-F10 melanoma. The investigation of the mechanism of antitumor action revealed that the agonist had no direct cytotoxic effects
on tumor cells tested in vitro. In addition, 3M-011 retained its effectiveness in scid/B6 mice and scid/NOD mice, eliminating the requirement for T and B cells, but lost its activity in beige (bg/bg) and NK1.1-immunodepleted mice, suggesting a critical role for natural killer (NK) cells in the antitumor response.
NK cytotoxicity was enhanced in vivo by the TLR7/8 agonist; this activation was long lasting, as determined by sustained expression of the activation marker CD69. Also, in human in vitro studies, 3M-011 potentiated
NK cytotoxicity. TLR7/8-mediated NK-dependent antitumor activity was retained in IFN-α/β receptor-deficient as well as perforin-deficient
mice, while depletion of IFN-γ significantly decreased the ability of 3M-011 to delay tumor growth. Thus, IFN-γ-dependent
functions of NK cell populations appear essential for cancer immunotherapy with TLR7/8 agonists.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
All authors are or were employed by 3M while this work was being conducted. 相似文献
17.
Local delivery of IL-12 and GM-CSF to advanced primary tumors results in T- and NK-cell-dependent cure of disseminated disease
in a murine spontaneous lung metastasis model. Post-therapy functional dynamics of cytotoxic T- and NK-cells were analyzed
in primary and metastatic tumors to determine the specific roles of each subset in tumor eradication. Time-dependent depletion
of CD8+ T and NK-cells demonstrated that CD8+ T-cells were critical to eradication of metastatic tumors within 3 days of treatment,
but not later. In contrast, NK-cells were found to be essential to tumor regression for at least 10 days after cytokine delivery.
Analysis of tumor-infiltrating lymphocyte populations in post-therapy primary tumors demonstrated that treatment resulted
in the activation of tumor-associated CD8+ T-cells within 24 h as determined by IFNγ and perforin production. T-cell activity
peaked between days 1 and 3 and subsided rapidly thereafter. Activation was not accompanied with an increase in cell numbers
suggesting that treatment mobilized pre-existing T-effector/memory cells without inducing proliferation. In contrast, therapy
resulted in a ≥3-fold enhancement of both the quantity and the cytotoxic activity of NK-cells in primary and metastatic tumors
on day 3 post-therapy. NK-cell activity was also transient and subsided to pre-therapy levels by day 5. Depletion of CD4+
and CD8+ T-cells prior to treatment completely abrogated NK-cell infiltration into primary and metastatic tumors demonstrating
the strict dependence of NK-cell recruitment on pre-existing T-effector/memory cells. Treatment failed to induce significant
NK-cell infiltration in IFNγ-knockout mice establishing the central role of IFNγ in NK-cell chemotaxis to tumors. These data
show that transient activation of tumor-associated T-effector/memory and NK-cells, but not long-term CD8+ T-cell responses,
are critical to suppression of metastatic disease in this model; and reveal a novel role for pre-existing adaptive T-cell
immunity in the recruitment of innate effectors to tumors.
This work was supported by NIH/NCI grant R01-CA100656-01A1 to N.K.E. 相似文献
18.
Superiority of the ear pinna over a subcutaneous tumour inoculation site for induction of a Th1-type cytokine response 总被引:1,自引:0,他引:1
This study examines whether a correlation may be found between Th1- or Th2-type cytokine responses and resistance or susceptibility
to tumour growth. Cytokine profiles were investigated in a well-defined mouse tumour model in which the injection site and
the genetic background determine the phenotype of either tumour resistance or tumour susceptibility. DBA/2-derived ESb lymphoma
variant cells with high metastatic capacity were inoculated into syngeneic mice either s.c., where they grow and metastasize,
or into the ear pinna (i.e.), where they do not grow because of induction of protective immunity. Alternatively, the tumour
cells were injected s.c. or i.e. into allogeneic B10.D2 mice, which are resistant to the tumour although they are identical
at the MHC locus. Between 1 and 10 days after tumour cell injection the spleen-derived mRNA was tested for cytokine gene expression
or the spleen cells were analysed by FACScan for T cell activation. The strongest cytokine response was observed in i.e. inoculated
B10.D2 mice. This was characterized by an early (days 2–3) peak of interferon γ (INF-γ), interleukin-2 (IL-2), IL-2 receptor
α (IL-2Rα) and IL-4. The cytokine mRNA response of i.e. inoculated DBA/2 mice was quite similar except that no IFN-γ could
be detected. In s.c. inoculated B10.D2 mice, the IL-2, IL-2Rα and IFN-γ responses were weaker than after i.e. injection while
the IL-4 response was comparable. The most striking difference between these cytokine profiles from tumour-resistant mice
and those of s.c. inoculated tumour-susceptible DBA/2 mice was a delay in the latter in the IL-2, IL-2Rα and IFN-γ responses
and the observation that the IL-4 response was not down-regulated. The persisting IL-4 response could down-regulate a Th1-type
response and thereby explain tumour susceptibility as a consequence of host conditioning.
Received: 4 September 1997 / Accepted: 2 October 1997 相似文献
19.
Objective: To assess whether a specific cytotoxic T-cell response can be induced in patients with prostate cancer after cryoablation.Material and Methods: Twenty Patients with high-risk prostate cancer underwent cryoablation. Blood was sampled prior to, 4 and 8 weeks after treatment. Serum cytokine levels were analyzed by ELISA, and the Th1/Th2 ratio was estimated from the IFN-γ/IL-4 ratio. Peripheral blood mononuclear cells (PBMC) were stimulated with autologous prostate cancer-derived protein lysates, and frequency of tumor-specific T-cells was tested ex vivo in an IFN-γ ELISPOT assay. To assess cytolytic activity, T-cells were co-incubated with human prostate cancer cells, LNCaP, or with renal cancer cells, GRC-1, and release of cytosolic adenylate kinase was measured by a luciferase assay.Result: 4 weeks after cryoablation significantly higher levels of TNF-α and IFN-γ were observed compared to before treatment, and to 8 weeks after treatment. No changes in IL-4 or IL-10 were observed. The Th1/Th2 ratio (10.47 ± 0.80), 4 weeks after treatment, was increased compared to before treatment (3.98 ± 0.45), but decreased 8 weeks later (7.65 ± 0.64). Tumor-specific T-cell responses were evident after cryosurgery in PBMC. Cytolytic activity against LNCaP was increased 4 weeks after treatment compared to before treatment (594.49 ± 154.84 versus 4.20 ± 0.68, P < 0.01), but was decreased 8 weeks later (79.70 ± 18.73). No response was found in cytolytic activity against GRC-1.Conclusion: Cryoablation of prostate cancer can improve tumor-specific cytotoxic T-cell stimulation with a dramatically increased tumor specific cytolytic activity. However, the response is not sufficiently maintained to prevent cancer relapse. 相似文献
20.
Conghui Han Zhen Gong Lin Hao Jianjun Yang Jianpeng Hu Bingzheng Dong Tao Fan Wenhao Tang Gaojun Teng 《Cell biochemistry and biophysics》2011,61(3):679-684
To investigate the mechanism of apoptosis induced by BDI-1 monoclonal antibody (MAb) coupled Staphylococcal superantigen-A
(SEA) in human bladder cancer cell line BIU-87. Human PBMC (effector cells) mediated cytotoxic killing of BIU-87 cells (target
cells) was studied by culturing the BIU-87 cells in the presence of effector cells plus medium after their activation by treatment
with SEA-targeted by MAb, SEA alone or vehicle (control). Proliferation and apoptosis of BIU-87 cells was measured after the
treatments. Expression of Bax and Bcl-2 and cytokine concentration in co-culture supernatants were detected by Western blot
and ELISA, respectively. Proliferation of MAb-targeted SEA BIU-87 cells decreased significantly (P < 0.05) as compared to control and SEA groups. Flow cytometry revealed apoptosis in SEA alone and more prominently in targeted-SEA
treated in BIU-87 cells, which is significantly more than in controI cells (P < 0.05). In addition, Western blot analysis indicated that the ratio of Bax/Bcl-2 significantly increased by targeted SEA
treatment, even at low concentration, as compared to cells treated with SEA alone or control cells (P < 0.05). However, there were no significant differences in IL-2, TNF-α and IFN-γ levels in the culture medium between SEA
and targeted SEA groups, even though they are several folds higher than in control cells. SEA targeting by MAb significantly
increases apoptosis in BIU-87 cells, possibly through the up-regulation of proapoptotic protein Bax and down regulation of
antiapoptotic protein, Bcl-2. 相似文献