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1.
Intracellular cytokine profile of T cells from children with acute lymphoblastic leukemia 总被引:12,自引:0,他引:12
Zhang XL Komada Y Chipeta J Li QS Inaba H Azuma E Yamamoto H Sakurai M 《Cancer immunology, immunotherapy : CII》2000,49(3):165-172
Purpose: During an ongoing immune response, cytokines produced by T helper types 1 (Th1) and 2 (Th2) together with T cytotoxic types
1 (Tc1) and 2 (Tc2) are critical to the effectiveness of that response. Dysregulated expansion of one or the other subset
may contribute to the impaired function of the T-cell-mediated immune system in cancer patients. In the present study we have
investigated whether such dysregulation might exist in children with acute lymphoblastic leukemia (ALL). Methods: We analyzed 61 blood samples from 45 children with B cell precursor ALL and 16 healthy children. Interleukin(IL)-2, IL-4,
and interferon γ (IFNγ) production of their respective purified CD4+ and CD8+ T cells were assessed at the single-cell level by intracellular-cytokine-staining flow cytometry. Results: At the time of diagnosis, IL-2-producing cell populations in CD4+ and CD8+ T cells were reduced below the normal range in 31 of 44 (70.5%) and 23 of 38 (60.5%) cases respectively. Similarly, IFNγ-producing
cell populations in CD4+ and CD8+ T cells decreased in 17 of 44 (38.6%) and 18 of 38 (47.4%) cases respectively. Conversely cell populations capable of IL-4
production in CD4+ and CD8+ T cell subsets were increased in 13 of 30 (43.3%) and 15 of 30 (50.0%) cases respectively. Therefore, the Th1-to-Th2 and
Tc1-to-Tc2 ratios (1.6 ± 2.2 and 7.7 ± 6.7 respectively) were significantly lower in peripheral blood T cells of ALL patients
(n = 30) than those (6.0 ± 2.9 and 20.1 ± 10.3 respectively) in 15 healthy controls (P < 0.0001). Although both CD45RA+/CD4+ and CD45RA+/CD8+ cells significantly increased in 43 ALL patients (P < 0.05), there existed no apparent correlation between CD45 isoform expression and cytokine (IL-2 and IFNγ) production. Interestingly,
the ability to produce both IL-2 and IFNγ was recovered in 8 cases examined, after complete remission had been achieved. Conclusion: These observations suggest that, in both CD4+ and CD8+ T cells of ALL patients, there is a dysregulation in the functionality of Th1 (Tc1) and Th2 (Tc2) cells with a gross reduction
of Th1 (Tc1) cell populations and an expansion in Th2 (Tc2).
Received: 12 November 1999 / Accepted: 2 January 2000 相似文献
2.
Response of plasma IL-6 and its soluble receptors during submaximal exercise to fatigue in sedentary middle-aged men
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The pleiotropic cytokine interleukin-6 (IL-6) has been demonstrated to increase during exercise. Little is known regarding
the response of the soluble IL-6 receptors (sIL-6R and sgp130) during such exercise. The aim of the current study was to investigate
the response of plasma IL-6, sIL-6R and sgp130 during fatiguing submaximal exercise in humans. Twelve participants underwent
an incremental exercise test to exhaustion and one week later performed a submaximal exercise bout (96 ± 6% lactate threshold)
to volitional exhaustion. Blood samples taken at rest and immediately post exercise were analyzed for IL-6, sIL-6R and sgp130.
IL-6 increased (P < 0.01) by 8.4 ± 8.9 pg ml−1 (75.7%) during the exercise period. sIL-6R and sgp130 also increased (P < 0.05) by 2.7 ± 3.9 ng ml−1 (9.6%) and 37.7 ± 55.6 ng ml−1 (9.6%), respectively. The current study is the first investigation to demonstrate that alongside IL-6, acute exercise stress
results in an increase in both sIL-6R and sgp130. 相似文献
3.
Schmidinger M Steger GG Wenzel C Locker GJ Brodowicz T Budinsky AC Wiltschke C Kramer G Marberger M Zielinski CC 《Cancer immunology, immunotherapy : CII》2000,49(7):395-400
Background: Because of the known efficacy of several cytokines in the treatment of advanced renal cell cancer (RCC), we have conducted
a phase II trial of the efficacy and toxicity of subcutaneous interferon γ (IFNγ) and interleukin-2 (IL-2). Methods: 63 patients with progressive metastatic RCC were treated with 100 μg recombinant IFNγ1b administered three times weekly during
weeks 1 and 2 and with 4.5 MU recombinant IL-2 administered on 4 consecutive days during weeks 3 and 4, every 6 weeks. Results: 11% of patients had an objective response (CR: 3%, PR: 8%), 33% had SD. Toxicity was generally mild. The median duration
of remissions (CR + PR) was 9.6 months; the median duration of SD 8 months. A significant survival benefit was evident at
a median observation time of 51 months for patients (44%) responding to therapy (P < 0.0001). Conclusions: we conclude that sequential treatment with IFNγ and IL-2 may prolong survival in patients with metastatic RCC responding
to therapy.
Received: 2 April 2000 / Accepted: 21 April 2000 相似文献
4.
Long-term treatment with low doses of interleukin-2 and interferon-α: immunological effects in advanced renal cell cancer 总被引:2,自引:0,他引:2
Pavone L Andrulli S Santi R Majori M Buzio C 《Cancer immunology, immunotherapy : CII》2001,50(2):82-86
We aimed to determine the immunological effects of low doses of recombinant interleukin-2 (rIL-2) and recombinant interferon-α
(rIFN-α) in patients bearing advanced renal cell carcinoma.
Methods: Twenty-seven patients received therapeutic cycles consisting of subcutaneous rIL-2 for 5 days per week and intramuscular
rIFN-α twice weekly, for 4 consecutive weeks. The cycle was repeated indefinitely at regular 4-month intervals, for all patients.
rIL-2 (1 × 106 IU/m2) was administered every 12 h on days 1 and 2 and once a day on days 3–5 of each week; rIFN-α (1.8 × 106 IU/m2) was given on days 3 and 5.
In the enrolled patients, total and differential white blood cell counts, phenotypic analysis of some lymphocyte subsets,
and soluble IL-2 receptor (sIL-2R), were investigated before and after each of the first six cycles of therapy (about 24 months
of follow-up).
Results: The cycles of immunotherapy induced a significant increase of total lymphocytes (37%, P < 0.001), eosinophils (222%, P < 0.001), CD25+ cells (27%, P=0.004), sIL-2R (174%, P < 0.001) and natural killer (NK) cells (CD3-CD56+) (61%, P < 0.001); the subset that expresses CD56 with high density (CD56+ bright) expanded more (233%, P < 0.001) than the subset expressing the same marker with low density (CD56+ dimmer) (15%, P=0.043). Unlike the previous subsets, the treatment decreased significantly T-lymphocytes with NK cell marker (CD3+ CD56+)
(28%, P=0.011).
No significant differences of effectiveness were found among the subsequent treatment cycles, except for CD25+ cells and sIL-2R
(P=0.036 and P=0.005, respectively): the increase induced by immunotherapy was maximum after the first cycle and decreased progressively
thereafter.
Conclusions: Long-term repeated cycles of low-dose immunotherapy induced repeated and significant expansion of one of the most important
lymphocyte subsets for the non-MHC-restricted immune response to the tumour mass: CD3–CD56+ cells.
Received: 8 November 2000 / Accepted: 11 January 2001 相似文献
5.
《Biomarkers》2013,18(3):204-215
AbstractContext: The roles of interleukin 10 (IL-10) and IL-12 in regulation of cancer growth and Th1/Th2 immune responses towards cancer are unclear.Objective: To establish the prognostic significance of serum IL-10 and IL-12 in paediatric soft tissue sarcomas (STS).Materials and methods: ELISA determinations of cytokines were performed as pre-treatment in 59 children with STS and 30 healthy controls.Results: Elevated IL-10 and decreased IL-12 serum levels correlated with advanced disease, poor response to chemotherapy and poor outcome. IL-10?≥?9.5?pg/ml, IL-12?≤?65?pg/ml and lymph nodes involvement independently predicted poor overall survival (OS) in multivariate Cox analysis.Conclusion: Serum IL-10/IL-12 balance determination may facilitate to assess risk groups and prognosis in childhood STS. 相似文献
6.
Phase I trial of interleukin-2 and high-dose arginine butyrate in metastatic colorectal cancer 总被引:4,自引:0,他引:4
Douillard JY Bennouna J Vavasseur F Deporte-Fety R Thomare P Giacalone F Meflah K 《Cancer immunology, immunotherapy : CII》2000,49(1):56-61
Interleukin-2 (IL-2) and sodium butyrate allow rats to be cured of peritoneal carcinomatosis from colon cancer. We performed
a phase I trial of IL-2 and high-dose arginine butyrate (ArgB) in patients with advanced metastatic colorectal cancer. Patients and methods: From April to July 1997, six patients were included in the trail; they had a median age of 52 years, four had a performance
status of 0, two had a performance status of 1 with normal biological functions. All patients had received at least two prior
lines of chemotherapy. A fixed dose of 18 MIU/m2 IL-2,was administered by subcutaneous injection and ArgB was delivered via continuous intravenous infusion on days 1–6 with
escalating doses starting at 2 g kg−1 day−1. Results: The planned dose escalation was not possible because of toxicities. A daily ArgB dose of 2 g/kg was delivered for nine cycles.
Level 2 (4 g/kg) could not be delivered in three of the six patients because of liver toxicity. The dose-limiting toxicities
were fatigue and liver function disturbances. The maximum tolerated dose for ArgB was 3 g kg−1 day−1, in combination with IL-2 at 12 MIU m2 day−1. No clinical response was seen. Pharmacokinetic analysis showed large intra- and interindividual variations. Conclusion: This schedule with a high dose of ArgB proved to be highly toxic with liver insufficiency. We will be running another trial
with lower doses of ArgB calculated from the schedule used in the experimental model, starting at a dose of 20 mg kg−1 day−1 for ArgB and 200 000 UI kg−1 day−1 IL-2, every 8 h.
Received: 13 May 1999 / Accepted: 28 October 1999 相似文献
7.
Behaviour of interleukin-2 serum levels in advanced non-small-cell lung cancer patients: relationship with response to therapy and survival 总被引:8,自引:0,他引:8
Orditura M Romano C De Vita F Galizia G Lieto E Infusino S De Cataldis G Catalano G 《Cancer immunology, immunotherapy : CII》2000,49(10):530-536
Interleukin(IL)-2 is a T helper (Th) 1 type cytokine that has been shown to play an important role in antitumour immune responses.
In this study, the prognostic significance of serum IL-2 levels was investigated in 60 advanced non-small-cell lung cancer
(NSCLC) patients. IL-2 serum levels were determined before chemotherapy, at the end of chemotherapy and during follow-up,
using a commercially available enzyme-linked immunoadsorbent assay kit. The results were analysed according to the response
to therapy and were used to generate a model predicting overall survival and time to treatment failure. All 60 patients were
shown to have higher IL-2 serum levels than controls (P < 0.0001). Stage IV patients had significantly lower IL-2 levels than stage III patients (P < 0.0001), although they were still significantly higher than controls (P < 0.0001). It is interesting that, when patients were divided into responders and non-responders according to the response
to therapy, the former were shown to have significantly higher pre-chemotherapy levels than the latter (P < 0.0001). Moreover, a further significant increase in IL-2 serum levels (P=0.004) and a significant decrease (P < 0.0001) were shown in responders and non-responders, respectively at the end of the therapy. Using univariate and multivariate
analyses, both overall survival and time to treatment failure were shown to be affected by the mean pathological levels of
IL-2. Furthermore, the prognostic significance of the serum level of IL-2 was confirmed by the stepwise regression analysis.
In conclusion, determination of pre-treatment IL-2 serum levels was shown to be of independent prognostic utility in patients
with advanced NSCLC; therefore, its possible use for prediction of outcome is proposed.
Received: 16 March 2000 / Accepted: 27 July 2000 相似文献
8.
Agarwal A Verma S Burra U Murthy NS Mohanty NK Saxena S 《Cancer immunology, immunotherapy : CII》2006,55(6):734-743
Transitional cell carcinoma (TCC) is the commonest cancer of the bladder. Although majority of TCC can be diagnosed at an
early stage and removed easily by transurethral resection of tumor (TURT), the management of this carcinoma is complicated
due to frequent recurrences usually within 6 months to one-year period. An imbalance between the Th1 and Th2 immune responses
has been attributed to immune dysregulation in various malignancies. The present study aims to evaluate the Th1 and Th2 balance
in Peripheral Blood Mononuclear Cells of 41 TCC patients (20 recurrent and 21 non-recurrent) using flow cytometry. It also
further assesses immunological and cellular factors influencing the anti-neoplastic activity of the TCC patients and in 21
normal healthy subjects in terms of their cytokine expression and various cell surface markers. The findings of the study
revealed that the cell surface markers CD3+, CD4+ and CD8+ along with NK cells were found to be significantly lower in patients
than healthy controls (p<0.01). The mean percent expression of CD4+ was significantly lower in patients showing recurrence
(23.9±9.84) as compared to patients with non-recurrence (31.1±12.27). The percentage of CD4+T-cells (mean±SD) producing IFN-γ,
IL-2 and TNF-α were statistically significantly reduced in patients (19.1±4.94, 52.3±20.86 and 12.8±4.49) as compared to healthy
controls (23.3±3.67, 67.5±12.0 and 17.6±5.96 respectively), (p<0.01, 0.018, 0.001). On the contrary, the mean levels of IL-4,
IL-6 and IL-10 in patients (63.8±17.01, 60.4±14.79 and 65.7±14.84 respectively) were significantly higher as compared to healthy
controls (24.4±8.77, 26.5±5.28 and 20.6±3.81 respectively), (p<0.001). No statistically significant difference was observed
in the cytokine expression between patients showing recurrence and non-recurrence. Patients with bladder cancer seem to develop
a Th2 dominant status with a deficient type1 immune response. The lymphocyte evaluation along with cytokine measurement can
provide a sensitive and valuable tool for evaluating the function of cell-mediated immunity in these patients and can also
find application in therapeutic monitoring of bladder cancer patients as new targets for immunotherapy. 相似文献
9.
Chistiakov DA Voronova NV Turakulov RI Savost'anov KV 《Journal of applied genetics》2011,52(2):201-207
The human secretoglobin 3A2 (SCGB3A2) gene encoding secretory uteroglobin-related protein 1 (UGRP1) resides on the chromosome region 5q31-33 that harbors a susceptibility
locus to several autoimmune and inflammatory diseases, including asthma and Graves’ disease (GD). Recently, association between
the marker rs1368408 (−112G > A), located in the promoter region of the SCGB3A2 gene, and susceptibility to GD was found in Chinese and UK Caucasians. The study aim was to evaluate whether this polymorphism
confers GD susceptibility in a large population cohort comprising 1,474 Russian GD patients and 1,619 controls. The marker
rs1368408 was studied using a TaqMan allele discrimination assay. Serum levels of UGRP1 and immunoglobulin E (IgE) were assessed
using enzyme-linked immunosorbent assay (ELISA) analyses. Association between the allele A of SCGB3A2 and a higher risk of GD (odds ratio [OR] = 1.33, P = 2.9 × 10−5) was shown. Both affected and non-affected carriers of the higher risk genotype A/A had significantly decreased levels of
serum UGRP1 compared to the subjects homozygous for G/G (93 ± 37 pg/ml vs. 132 ± 45 pg/ml, P = 0.0011 for GD patients; 77 ± 28 pg/ml vs. 119 ± 33 pg/ml, P = 0.0019 for controls). Serum IgE levels were significantly higher in non-affected subjects homozygous for A/A compared to
control individuals homozygous for G/G (153 ± 46 IU/ml vs. 122 ± 40 IU/ml, P = 0.0095). Our data suggest that the carriage of the SCGB3A2 −112A/A variant increases the risk for GD in subsets of patients with elevated levels of IgE, a hallmark of allergic asthma.
Therefore, the SCGB3A2 −112G > A polymorphism may be considered as a likely marker linking susceptibility to allergy/asthma and GD on chromosome
5q31-33. 相似文献
10.
Hörig H Lee DS Conkright W Divito J Hasson H LaMare M Rivera A Park D Tine J Guito K Tsang KW Schlom J Kaufman HL 《Cancer immunology, immunotherapy : CII》2000,49(9):504-514
The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope
and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC)
constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study
in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses.
Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an
ALVAC-CEA-B7.1 vaccine (4.5 × 106, 4.5 × 107, and 4.5 × 108 plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored
for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA- B7.1 at doses up to 4.5 × 108 PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable
disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-γ enzyme-linked immunoassay
spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses.
This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted
in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific
T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1
to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with
tolerable toxicity.
Received: 6 May 2000 / Accepted: 13 July 2000 相似文献
11.
Summary. There are no reliable mean values of NG-monomethylarginine (NMMA) in blood and urine of patients with renal insufficiency available in the literature. Therefore
we investigate whether the NMMA levels are changed in blood and urinary excretion of nondialysed and dialysed patients with
chronic renal insufficiency to evaluate whether NMMA may reach sufficiently increased concentrations in blood of the patients
to exert toxic biological activity.
In nondialysed as well as in dialysed patients we find no significant difference in serum concentration of NMMA between patients
and controls. In nondialysed patients (all with a residual creatinine clearance lower than 15 ml/min), we find 94.5 ± 26.1 nM
(mean ± SD) versus 94.6 ± 19.5 nM in controls. Similar levels are found in serum of haemodialysed patients (each with serum
creatinine levels >700 μM): 83.0 ± 20.2 nM. The urinary excretion of NMMA in nondialysed patients is also not significantly different from the excretion
of controls: 123 ± 110 in patients versus 157 ± 117 nmol/24 hrs in controls. Furthermore, the clearance of NMMA is much lower
compared to the clearance of the dimethylarginine derivatives.
Based on the literature, the low nanomolar levels of NMMA found in blood of patients with renal insufficiency do not support
the statement that NMMA proper may act as a uremic toxin.
Received April 3, 2002 Accepted October 7, 2002 Published online January 20, 2003
Acknowledgements We thank the University of Antwerp, FWO (Fonds voor Wetenschappelijk Onderzoek) (G.0027.97 and G.0394.00), the Born-Bunge
Foundation, the OCMW Medical Research Foundation and Neurosearch Antwerp for the financial support.
Authors' address: Bart Marescau, Laboratory of Neurochemistry and Behaviour, UIA T504, University of Antwerp, Universiteitsplein 1, B-2610
Wilrijk, Belgium, Fax: 00 32 3 8202618; E-mail: bartold.marescau@ua.ac.be 相似文献
12.
摘要 目的:观察瑞芬太尼靶控输注对宫颈癌根治术患者麻醉苏醒质量、应激反应及辅助T细胞(Th)1/Th2免疫平衡的影响。方法:按照随机数字表法将2023年1月到2023年6月期间我院接受的120例宫颈癌根治术患者分为舒芬太尼组(n=60,舒芬太尼麻醉)和瑞芬太尼组(n=60,瑞芬太尼麻醉)。对比两组的麻醉苏醒质量、应激反应指标[皮质醇(Cor)、去甲肾上腺素(NE)、血管紧张素1(Ang-1)、血管紧张素2(Ang-2)]、Th1/Th2免疫平衡指标[包括Th1、Th2及调节性T细胞(Treg)、Th1/Th2比值],术后记录不良反应发生情况。结果:与舒芬太尼组相比,瑞芬太尼组的应激呼吸恢复时间、睁眼时间、拔管时间更短(P<0.05)。术后1 d,两组Cor、NE、Ang-1、Ang-2升高,但瑞芬太尼组低于舒芬太尼组(P<0.05)。术后1 d,两组Th1、Treg、Th1/Th2升高,但瑞芬太尼组低于舒芬太尼组;Th2下降,但瑞芬太尼组高于舒芬太尼组(P<0.05)。两组不良反应发生率组间对比未见差异(P>0.05)。结论:瑞芬太尼靶控输注用于宫颈癌根治术患者,可改善麻醉苏醒质量,减轻应激反应,调节Th1/Th2免疫平衡,且不增加不良反应的发生率,效果较好。 相似文献
13.
Asfour IA Fayek M Raouf S Soliman M Hegab HM El-Desoky H Saleh R Moussa MA 《Biological trace element research》2007,120(1-3):1-10
The present study was undertaken to explore the effect of administration of high doses of sodium selenite on the expression
of Bcl-2 in patients with non-Hodgkin’s lymphoma (NHL). Fifty patients with newly diagnosed NHL were randomly divided into
two groups. Group A-I received standard chemotherapy whereas group A-II received adjuvant sodium selenite 0.2 mg kg−1 day−1 for 30 days in addition to chemotherapy. Enzyme-linked immunosorbent assay was used to assess Bcl-2 at the time of diagnosis
and after therapy in the two groups. Sodium selenite administration resulted in significant decline of Bcl-2 level after therapy
in group A-II (8.6 ± 6.9 ng/ml vs 3 6.9 ± 7.9 ng/ml, P < 0.05). Also, complete response reached 60% in group A-II compared to 40% in group A-I. Significant increase in CD4/CD8
ratio was noticed in group A-II compared to group A-I after therapy (1.45 ± 0.36 vs 1.10 ± 0.28 p 0.04). Overall survival
time in months was significantly longer in complete remission patients in group A-II (21.87 ± 1.41) compared to group A-I
(19.70 ± 1.95) (p = 0.01). It is concluded that sodium selenite administration at the dosage and duration chosen acts as a downregulator of
Bcl-2 and improves clinical outcome. 相似文献
14.
S. Prabodh D. S. R. S. Prakash G. Sudhakar N. V. S. Chowdary V. Desai R. Shekhar 《Biological trace element research》2011,142(1):29-35
Diabetic nephropathy is a complication of diabetes mellitus. This present study investigates the status of copper and magnesium
in diabetic nephropathy cases to establish a possible relation. Forty patients of diabetic nephropathy participated in the
study as cases. Forty age- and sex-matched healthy individuals served as controls. Blood samples were collected from both
cases and controls for determination of FBS, PPBS, HbA1c, microalbumin, copper, and magnesium levels. The mean concentrations
of FBS, PPBS, HbA1c, and microalbumin of cases were significantly higher than that of controls. The mean magnesium levels
of cases (1.60 ± 0.32 meq/L) were significantly lower than controls 2.14 ± 0.16 meq/L (p < 0.05). But the mean copper levels of cases, 165.42 ± 5.71 μg/dl, shows no significant difference with controls, 166.6 ± 5.48 μg/dl, (p > 0.05).The findings in the present study suggest that hypomagnesemia may be linked with development of diabetic nephropathy. 相似文献
15.
Jon Amund Kyte Sissel Trachsel Bente Risberg Per thor Straten Kari Lislerud Gustav Gaudernack 《Cancer immunology, immunotherapy : CII》2009,58(10):1609-1626
Cancer vaccine trials frequently report on immunological responses, without any clinical benefit. This paradox may reflect
the challenge of discriminating between effective and pointless immune responses and sparse knowledge on their long-term development.
Here, we have analyzed T cell responses in long-term survivors after peptide vaccination. There were three main study aims:
(1) to characterize the immune response in patients with a possible clinical benefit. (2) To analyze the long-term development
of responses and effects of booster vaccination. (3) To investigate whether the Th1/Th2-delineation applies to cancer vaccine
responses. T cell clones were generated from all nine patients studied. We find that surviving patients harbor durable tumor-specific
responses against vaccine antigens from telomerase, RAS or TGFβ receptor II. Analyses of consecutive samples suggest that
booster vaccination is required to induce robust T cell memory. The responses exhibit several features of possible clinical
advantage, including combined T-helper and cytotoxic functionality, recognition of naturally processed antigens and diverse
HLA-restriction and fine-specificity. CD4−CD8− T cell clones display unconventional cytotoxicity and specifically kill tumor cells expressing mutated TGFβ receptor II.
Cytokine profiling on the long-term survivors demonstrates high IFNγ/IL10-ratios, favoring immunity over tolerance, and secretion
of multiple chemokines likely to mobilize the innate and adaptive immune system. Interestingly, these pro-inflammatory cytokine
profiles do not follow a Th1/Th2-delineation. Most IFNγhigh/IL4low/IL10low cultures include high concentrations of hallmark Th2-cytokines IL-5 and IL-13. This does not reflect a mixture of Th1- and
Th2-clones, but applies to 19/20 T cell clones confirmed to be monoclonal through TCR clonotype mapping. The present study
identifies several factors that may promote clinical efficacy and suggests that cytokine profiling should not rely on the
Th1/Th2-paradigm, but assess the overall inflammatory milieu and the balance between key cytokines.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
16.
Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment 总被引:1,自引:0,他引:1
Bergmann C Strauss L Zeidler R Lang S Whiteside TL 《Cancer immunology, immunotherapy : CII》2007,56(9):1429-1442
Objective Chronic inflammation and cancer development are associated with dysregulated immune responses and the presence of regulatory
T cells (Treg). To study the role of Treg in tumor cell escape from immune surveillance, an in vitro model simulating the tumor microenvironment and promoting the
induction and expansion of IL-10+ Treg type 1 (Tr1) was established.
Methods An in vitro co-culture system (IVA) included an irradiated head and neck squamous cell carcinoma cell line, immature dendritic
cells (iDC), CD4+CD25− T cells and cytokines, IL-2 (10 IU/ml), IL-10 (20 IU/ml), IL-15 (20 IU/ml) ± 1 nM rapamycin. Autologous iDC and CD4+CD25− T cells were obtained from the peripheral blood of 15 normal donors. Co-cultures were expanded for 10 days. Proliferating
lymphocytes were phenotyped by multi-color flow cytometry. Their suppressor function was measured in CFSE inhibition assays ± neutralizing
anti-IL-10 mAb and using transwell cultures. Culture supernatants were tested for IL-4, IL-10, TGF-β and IFN-γ in ELISA.
Results In the IVA, low doses of IL-2, IL-10 and IL-15 promoted induction and expansion of CD3+CD4+CD25−IL2Rβ+IL2Rγ+FoxP3+CTLA-4+IL-10+ cells with suppressor activity (mean suppression ± SD = 58 ± 12%). These suppressor cells produced IL-10 (mean ± SD = 535 ± 12 pg/ml)
and TGF-β (mean ± SD = 512 ± 38 pg/ml), but no IL-4 or IFN-γ. Suppressor function of co-cultures correlated with the percent
of expanding IL-10+ Tr1 cells (r
2 = 0.9; P < 0.001). The addition of rapamycin enriched Tr1 cells in all co-cultures. Neutralizing anti-IL-10 mAb abolished suppressive
activity. Suppression was cell-contact independent.
Conclusion The tumor microenvironment promotes generation of Tr1 cells which have the phenotype distinct from that of CD4+CD25highFoxP3+ nTreg and mediate IL-10 dependent immune suppression in a cell-contact independent manner. Tr1 cells may play a critical
role in cancer progression. 相似文献
17.
Ozkaya M Sahin M Cakal E Gisi K Bilge F Kilinc M 《Biological trace element research》2009,128(2):144-151
The present study was conducted to evaluate the serum selenium levels in first-degree relatives of diabetic patients (FDR)
according to controls. Insulin resistance, serum lipid levels, inflammation markers, and blood pressure were also studied
in these patients. Serum levels of selenium in FDR were significantly lower than control group (74.65 ± 5.9 vs 88.7 ± 8.7 μg/dl,
p < 0.0001). HsCRP, HOMA-IR, insulin, homocysteine levels were significantly higher in FDR according to the control group (1.32 ± 0.9
vs 0.63 ± 0.4 mg/dL, p < 0.0001; 2.07 ± 0.84 vs 1.51 ± 0.69, p < 0.0001; 9.26 ± 3.8 vs 6.8 ± 2.98 μU/MI, p < 0.0001; 15.7 ± 7.4 vs 11.5 ± 5.1 μmol/L, p < 0.0001, respectively). There was significant correlation between selenium levels and hsCRP (r = − 0.450, p < 0.0001). There was also weak significant correlation also between HOMA-IR and selenium levels (r = −0.227, p = 0.003). There was a correlation between systolic blood pressure and BMI (r = 0.365, p < 0.0001). But there was no correlation between selenium levels and blood pressure or other parameters. HsCRP, HOMA-IR, homocysteine
levels in individuals with selenium levels < 80 μg/L (n = 78) was significantly higher than hsCRP HOMA-IR, homocysteine levels in individuals with selenium levels ≥ 80 (n = 91; 1.23 ± 0.98 vs 0.81 ± 0.76 mg/dL, p < 0.003; 1.99 ± 0.88 vs 1.64 ± 0.74, p < 0.005; 15.0 ± 7.6 vs 12.9 ± 5.7 μmol/L, p < 0.049, respectively). Selenium deficiency may contribute to cardiovascular disease risk in FDR. 相似文献
18.
The generation of anti-tumoral cells using dentritic cells from the peripheral bloood of patients with malignant brain tumors 总被引:3,自引:0,他引:3
Yoshida S Morii K Watanabe M Saito T Yamamoto K Tanaka R 《Cancer immunology, immunotherapy : CII》2001,50(6):321-327
Dendritic cells (DCs) can be the principal initiators of antigen-specific immune responses. We analyzed the in vitro-responses
against brain tumor cells using DCs from the peripheral blood of patients with brain tumors. Peripheral blood mononuclear
cells (PBMC) were obtained from 19 patients with malignant brain tumors: 12 metastatic brain tumors of lung adenocarcinoma,
7 high-grade astrocytomas. PBMC were cultured with 100 ng/ml of GM-CSF and 10 ng/ml of IL-4 for 5–7 days in order to produce
mature DCs. The autologous tumor lysate (5 mg/ml, containing 1 × 106 cells) was then added to the cultured DCs. Using the DCs generated by these treatments, we assessed the changes that occurred
in their immune responses against brain tumor via 51Cr-release and lymphocyte proliferation assays. We found that the matured DCs displayed the typical surface phenotype of CD3+, CD45+, CD80+ and CD86+. After the pulsation treatment with tumor lysate, DCs were found to have strong cytotoxic T lymphocyte activity, showing
42.5 ± 12.7% killing of autologous tumor cells. We also found an enhancement of allogeneic T cell proliferation after pulsing
the DC with tumor lysate. These data support the efficacy of DC-based immunotherapy for patients with malignant brain tumors.
Received: 2 October 2000 / Accepted: 26 April 2001 相似文献
19.
《Cytokine》2016
Objective & designInvestigation was carried out on Saponin 1 (SAP-1), a novel molecule isolated from Parthenium hysterophorus, on proinflammatory (Th1) & anti-inflammatory (Th2) cytokines in blood of arthritic balb/c mice.MethodsAdjuvant induced developing inflammatory arthritis was induced in mice which were treated with SAP-1 in graded oral doses. The molecular markers were determined using Flow Cytometry which uses sensitivity of amplified fluorescence detection to measure soluble analytes in particle based immune assay. The T-helper (Th1) deviated cells produce detectable level of Tumor necrosis factor (TNF-alpha), interleukin-2 (IL-2) & interferon-gamma (IFN-gamma), while the Th2 deviated cells produce significant amount of interleukin-4 (IL-4) and interleukin-5 (IL-5).ResultsSAP-1 at graded oral doses inhibited expression of IFN-gamma & TNF-alpha in serum & correspondingly increased expression of IL-4 significantly. SAP-1 also inhibited IL-17 and CD4+CD25+ cell population showing to have suppressive effect on Th-17 pathway as well as T-regulatory cells. It also suppressed the increased levels of pro-inflammatory mediators like IL-1β and NO. Inhibitors of Cox-2 and MCP-1 provide effective improvements in signs and symptoms of Rheumatoid Arthritis. SAP-1 decreased the elevated concentration of both COX-2 and MCP-1 in arthritic animals.ConclusionsSAP-1 diminishes Th1 immunity activation, a primary cause of arthritis, in favour of Th2 dominance, which reduces arthritic condition in mice displaying immune-modulatory potential. 相似文献
20.
Mucins have been implicated in tumor-associated immunosuppression. The possibility that colon cancer mucin (CCM) may modulate
T-helper 1 (TH1) activity was evaluated by investigating its effect on the production of interleukin-2 (IL-2) by CD4+ cells, a process that requires antigen-specific and costimulatory signals. Methods: CCM was purified from human colorectal cancer cells by gel-exclusion fast-pressure liquid chromatography. Cytokine production
of purified CD4+ cells was evaluated at the protein and gene level in the presence of a phorbol ester or an anti-CD3 monoclonal antibody (mAb)
plus mAb against the CD28 costimulatory receptor to mimic two-signal activation. Results: Soluble CCM, which contains mucins MUC2 as well as MUC1, inhibited IL-2 mRNA expression and secretion of CD4+ stimulated with a phorbol ester or an anti-CD3 mAb plus anti-CD28 mAb. Pretreatment of CD4+ cells with anti-CD28 mAb abrogated the suppressive effects of CCM on IL-2 production, and flow cytometry showed decreased
binding of anti-CD28 mAb to its receptor in the presence of mucin. In addition, Ca2+ mobilization after T cell receptor cross-linking with anti-CD3 mAb was maintained in the presence of CCM. Although interferon
γ production was also diminished, CCM did not induce a general inhibition of cytokine production, nor did it decrease cell
viability. Macrophage inflammatory protein 1α production was up-regulated; the production of IL-10 and transforming growth
factor β was unchanged. Conclusions: The results indicate that CCM can alter TH1 activity and suggest that the modulation of costimulatory interactions is involved.
They provide another mechanism of immunosuppression mediated by these highly expressed tumor products.
Received: 23 March 1999 / Accepted: 3 August 1999 相似文献