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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.
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
3.
Impact of aging on immune modulation by tumor 总被引:1,自引:0,他引:1
Young MR Kolesiak K Achille NJ Meisinger J Gonzalez E Liu SW Wrone-Smith T Lathers DM 《Cancer immunology, immunotherapy : CII》2001,50(6):315-320
Tumor development and aging can each alter immune competence. The present study aimed to determine the impact of Lewis lung
carcinoma (LLC) presence on immune parameters of middle-aged (averaging 6.5 months) versus aged (averaging 21.3 months) mice.
An age-associated decline in the CD4+ cell frequency was seen in freshly isolated spleen and lymph node cells, as well as in cultures stimulated with immobilized
anti-CD3. This decline was not further exacerbated by tumor presence. What was prominently inhibited by tumor was the capacity
of either splenic or lymph node CD4+ cells to become stimulated to express IFN-γ. Spleen and lymph node cultures from aged tumor-bearing mice had the lowest frequency of CD4+IFN-γ
+ cells and the least amount of secreted IFN-γ. CD8+ cells were not affected by aging, but tumor presence reduced the induction of CD8+IFN-γ
+ cells in lymph node cultures. We previously showed that LLC growth stimulates myelopoiesis, as seen by splenomegaly and the
mobilization of immune inhibitory CD34+ progenitor cells. Tumor presence in middle-aged mice reduced spleen cell blastogenesis, which was mediated by CD34+ cells. Aged mice had reduced blastogenesis, and this was further reduced by presence of tumor. However, neither the age-associated
immune dysfunction nor the tumor-induced immune suppression in aged mice was due to CD34+ progenitor cells. These studies show how tumor presence can further compromise the immune dysfunction that accompanies aging.
In addition, they show that aging impacts on the mechanisms by which tumors inhibit T-cell capabilities, with myelopoiesis-associated
CD34+ cells mediating the immune depression of middle-aged tumor-bearers and an independent mechanism being responsible for the
immune depression in aged tumor-bearing mice.
Received: 19 March 2001 / Accepted: 4 May 2001 相似文献
4.
Mazaheri Z Movahedin M Rahbarizadeh F Amanpour S 《In vitro cellular & developmental biology. Animal》2011,47(8):521-525
Bone morphogenetic protein (BMP)-4 has a crucial role on primordial germ cells (PGCs) development in vivo which can promote
stem cell differentiation to PG-like cells. In this study, we investigated the expression of Mvh as one of the specific genes
in primordial germ cells after treatment with different doses of BMP4 on bone mesenchymal stem cells (BMSCs)-derived PGCs.
Following isolation of BMSCs from male mouse femur and tibia, cells were cultured in medium for 72 h. Passage 4 murine BMSCs
were characterized by CD90, CD105, CD34, and CD45 markers and osteo-adipogenic differentiation. Different doses of BMP4 (0,
0.01, 0.1, 1, 5, 25, 50, and 100 ng/ml) were added to BMSCs for PGCs differentiation during 4-days culture. Viability percent,
proliferation rates, and expression of Mvh gene were analyzed by RT-qPCR. Data analysis was done with ANOVA test. CD90+, CD105+, CD34−, and CD45− BMSCs were able to differentiate to osteo-adipogenic lineages. The results revealed that proliferation rate and viability
percent were raised significantly (p ≤ 0.05) by adding 1, 5, 25 ng/ml of BMP4 and there were decreased to the lowest rate after adding 100 ng/ml BMP4 (p ≤ 0.05). There were significant up regulation (p ≤ 0.05) in Mvh expression between 25, 50, and 100 ng/ml BMP4 with other doses. So the selective dose of BMP-4 for treatment
during 4-day culture was 25 ng/ml. The results suggest that addition of 25 ng/ml BMP4 had the best effects based on gene-specific
marker expression. 相似文献
5.
Randall F. Holcombe Ruby M. Stewart Kenneth W. Betzing Krishnaswamy Kannan 《Cancer immunology, immunotherapy : CII》1994,38(6):394-398
Levamisole (LMS) and 5-fluorouracil (5FU) administered adjuvantly are effective in reducing the relapse rate following surgical resection of Duke's stage C colon carcinoma. It has been postulated that LMS acts to stimulate the immune system and that this is one mechanism through which this drug exerts its antitumor effects. In this study, peripheral blood mononuclear cells (PBMC) were analyzed in nine patients with surgically resected colon carcinoma prior to initiation of adjuvant LMS/5FU and at several subsequent times while patients were on therapy. Changes in lymphocyte phenotype and soluble interleukin-2 receptor (sIL-2R) between pre-study samples and samples obtained during adjuvant LMS/5FU were evaluated. Significant increases were seen in the proportion of PBMC expressing natural killer (NK) antigen CD56 (14.7±2.4% versus 18.1±2.6%;P<0.05) and surface IL-2R (CD25; 0% versus 0.42±0.15%;P<0.05), in sIL-2R (314±86 U/ml versus 736±173 U/ml;P<0.05), and in the CD4CD8 ratio (2.34±0.93 versus 3.47±1.23;P<0.01). A significant decrease in the proportion of CD8+ PBMC (24.7±3.8% versus 18.8±2.6%;P<0.01) and total CD8+ PBMC (537±118 versus 324±37;P<0.01) was seen. The increase in CD56+ cells correlated with sIL2R levels (r=0.46;P<0.05). No changes were noted for CD3, CD4, CD5, CD14, CD16, CD19, CDw49a, or TCR. The greatest increase in CD56+ cells and the smallest reduction in CD8+ cells were seen in the subgroup of patients who remained disease-free following adjuvant chemotherapy. This study suggests that adjuvant LMS/5FU has significant stimulatory effects on the immune system, which correlate with patient outcome and may account at least in part for its clinical efficacy.Grant support: supported by a grant from the Elsa U. Pardee Foundation (R.F.H.) and the Centers for Excellence in Cancer Research and Arthritis & Rheumatology, LSU Medical Center, Shreveport, La., USA 相似文献
6.
Lymphocyte subpopulations of regional lymph nodes in human colon and gastric adenocarcinomas 总被引:3,自引:0,他引:3
Beatriz Lores-Vazquez Margarita Pacheco-Carracedo Josefina Oliver-Morales Purificación Parada-Gonzalez F. Gambón-Deza 《Cancer immunology, immunotherapy : CII》1996,42(6):339-342
In order to study the host immune response to tumours, previous knowledge of the cellular composition of regional draining
lymph nodes is necessary. Enlarged regional lymph nodes are a common finding in colon and gastric adenocarcinomas. We have
studied the cellular composition of normal non-reactive and of regional draining lymph nodes of colon and gastric adenocarcinomas.
In normal non-reactive lymph nodes, T lymphocytes (CD2+, CD7+) constituted the largest fraction of the lymphoreticular cells. These lymphocytes were mainly CD4+, and there were more cells expressing the CD45RA isoform of the CD45 antigen than CD45RO. Reactive lymph nodes presented
a decreased proportion of CD4+ CD45RA+ cells and an increased number of B cells. Although most of the T cells in the reactive nodes were CD4+ CD45RO+, their proportion was similar to that found in normal non-reactive nodes. We studied the presence of the molecules CD28 and
CD80 involved in the processes of interaction and activation of T and B lymphocytes. The CD28 molecule was found in all the
T lymphocytes, while the CD80 molecule was weakly expressed on the B lymphocyte membrane.
Received: 4 January 1996 / Accepted: 28 May 1996 相似文献
7.
Cytotoxic T cells infiltrating a glioma express an aberrant phenotype that is associated with decreased function and apoptosis 总被引:5,自引:0,他引:5
In this study, we report on novel alterations found in rat intracranial (i.c.) tumor-infiltrating T lymphocytes (TIL) that
are indicative of T cell defects and death. FACS analysis showed that the cytotoxic T cells (CTL) infiltrating rat T9.F gliomas
were CD3ɛ+, αβTCR+, CD8α
+, but CD8β
−. These lymphocytes also stained positive for the B cell-specific marker, CD45RA, as well as Annexin-V, signifying apoptotic
changes. Functional and biochemical analyses were performed to assess whether the aberrant phenotype was linked to other defects.
When CD8α
+ TIL were purified and stimulated in vitro, their proliferative capacity was markedly diminished in comparison with CD3+CD8α
+CD8β
+ T cells isolated from the spleens of naive, non tumor-bearing rats. Furthermore, the mean fluorescence intensity of surface
CD3ɛ was dramatically reduced in the CD3+CD8α
+CD8β
− TIL population as compared with CD3+CD8α
+CD8β
+ TIL from the same tumor-bearing animal. Biochemical studies revealed that the expression of TCRζ and LAT were reduced in
lysates generated from CD8α-purified TIL with respect to CD8α-purified T cells from naive spleen. We believe that these degenerative changes are reflective of chronic T cell receptor
ligation, because in vitro culture of rat splenocytes or purified T cells with ConA or anti-CD3 mAb induced the same alterations.
In vitro, the downregulation of CD8β could be inhibited by the caspase inhibitor, z-VAD. These results suggest that the aberrant CTL phenotype found in the TIL
of glioma-bearing rats may be novel signals for their impending death and degenerating anti-tumor immune function.
Received: 27 February 2001 / Accepted: 26 April 2001 相似文献
8.
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
9.
Tumor-derived Fas ligand induces toxicity in lymphoid organs and plays an important role in successful chemotherapy 总被引:7,自引:0,他引:7
Nagarkatti N 《Cancer immunology, immunotherapy : CII》2000,49(1):46-55
Recent studies have suggested that Fas ligand (FasL+) tumor cells can induce apoptosis in Fas+ T cells. However, the effect of growth of FasL+ tumors in vivo, on lymphoid tissues of the host is not clear and therefore was the subject of this investigation. Injection
of FasL+ LSA tumor caused a significant decrease in cellularity of the thymus and spleen, resulting from marked apoptosis, in syngeneic
C57BL/6+/+ (wild-type) but not C57BL/6-lpr/lpr (Fas-deficient) mice. The tumor-induced toxicity resulted from tumor-derived rather than host-derived FasL, inasmuch as LSA
tumor growth in C57BL/6-gld/gld (FasL-defective) mice, induced marked apoptosis and toxicity in the thymus and spleen. The LSA tumor growth induced a significant
decrease in the percentage of CD4+CD8+ T cells in the thymus of C57BL/6+/+ mice and an increase in the percentage of CD4+, CD8+ and CD4−CD8− T cells. Of the four subpopulations tested, the CD4+CD8+ T cells showed maximum apoptosis. The LSA (FasL+) but not P815(FasL−) tumor cell lysates and culture supernatants induced marked apoptosis in Fas+ thymocytes, when tested both in vitro and in vivo. The LSA-tumor-induced apoptosis in vitro was inhibited by antibodies against
FasL or by caspase and other inhibitors of apoptosis. Chemotherapy of LSA-tumor-bearing C57BL/6+/+ mice at advanced stages
of tumor growth failed to cure the mice, whereas, more than 80% of LSA-tumor-bearing C57BL/6-lpr/lpr mice, similarly treated, survived. Together, the current study demonstrates that FasL produced by LSA tumor cells is functional
in vivo and can cause severe toxicity in lymphoid organs of the host. Also, Fas/FasL interactions may play an important role
in the successful chemotherapy of FasL-bearing tumor.
Received: 31 August 1999 / Accepted: 12 November 1999 相似文献
10.
Haibo Xue Weiwei Wang Zhongyan Shan Yuanbin Li Yushu Li Xiaochun Teng Yun Gao Chenling Fan Weiping Teng 《Biological trace element research》2011,143(1):292-301
Iodine is an essential trace element for thyroid hormone synthesis and metabolism, either low or high intake may lead to thyroid
disease, but the pathogenetic mechanisms by which iodine interacts with the thyroid autoimmune are poorly understood. We investigated
the dynamic changes of CD4+CD25+ regulatory T cells in NOD.H-2h4 mice with iodine-induced autoimmune thyroiditis (AIT), and explore potential immune mechanism of AIT induced by iodine. NOD.H-2h4 mice were randomly divided into two groups, and received plain water or water containing 0.005% sodium iodide. Eight weeks
after iodine provision, the incidences of thyroiditis, relative weights of thyroids, and serum thyroglobulin antibody titers
in the iodine-supplied groups were significantly increased compared to the control groups (p < 0.05). The AIT mice had fewer CD4+CD25+Foxp3+ T cells and reduced Foxp3 mRNA expression in splenocytes compared with the controls (p < 0.01), and maintained relatively low levels during the development of thyroiditis. The changes described above aggravated
gradually with the extension of iodine treatment. These data suggest that CD4+CD25+ regulatory T cells may be involved in the pathogenesis and development of AIT induced by iodine. 相似文献
11.
M. Klokker N. H. Secher P. Madsen H. L. Olesen S. Matzen U. Knigge J. Warberg B. K. Pedersen 《European journal of applied physiology and occupational physiology》1997,76(5):415-420
To evaluate a possible role for β-endorphin in the stress-induced modulation of natural killer (NK) cells, immunologically
competent blood cells were followed in eight male volunteers administered either Naloxone or saline (control) during head-up
tilt maintained until the appearance of presyncopal symptoms (PS). The PS appeared more rapidly with Naloxone compared to
control [5.7 (SEM 1.1) vs 22.3 (SEM 5.1) min; P = 0.01]. The NK cell activity increased threefold during PS partly due to an increase in CD16+ and CD56+ NK cells in blood. In support, NK cell activity boosted with interferon-α and interleukin 2 rose in parallel with unboosted
NK cell activity and NK cell concentration and activities returned to the baseline level after 105 min. The total lymphocyte
count and the concentrations of CD3+, CD4+, CD8+, CD16+, and CD56+ cells increased during PS. Head-up tilt also induced an increase in plasma adrenaline concentration during control PS and
a rise in plasma cortisol and adrenocorticotropic hormone concentrations up to 30 min thereafter, whereas no significant changes
were found in plasma concentrations of noradrenaline, growth hormone, or β-endorphin. The results would indicate an influence
of endorphin on the increase in plasma adrenaline concentration during head-up tilt and at the same time contra-indicate a
significant role for adrenaline in the provocation of PS. The influence of head-up tilt on plasma β-endorphin was too small
to influence the modulation of the cellular immune system.
Accepted: 22 May 1997 相似文献
12.
Cheng WH Holmstrom A Li X Wu RT Zeng H Xiao Z 《Biological trace element research》2012,146(2):230-235
Selenium (Se) is known to regulate tumorigenesis and immunity at the nutritional and supranutritional levels. Because the
immune system provides critical defenses against cancer and the athymic, immune-deficient NU/J nude mice are known to gradually
develop CD8+ and CD4+ T cells, we investigated whether B and T cell maturation could be modulated by dietary Se and by tumorigenesis in nude mice.
Fifteen homozygous nude mice were fed a Se-deficient, Torula yeast basal diet alone (Se−) or supplemented with 0.15 (Se+)
or 1.0 (Se++) mg Se/kg (as Na2SeO4) for 6 months, followed by a 7-week time course of PC-3 prostate cancer cell xenograft (2 × 106 cells/site, 2 sites/mouse). Here, we show that peripheral B cell levels decreased in nude mice fed the Se − or Se++ diet
and the CD4+ T cell levels increased in mice fed the Se++ diet. During the PC-3 cell tumorigenesis, dietary Se status did not affect peripheral
CD4+ or CD8+ T cells in nude mice whereas mice fed with the Se++ diet appeared to exhibit greater peripheral CD25+CD4+ T cells on day 9. Dietary Se status did not affect spleen weight in nude mice 7 weeks after the xenograft. Spleen weight
was associated with frequency of peripheral CD4+, but not CD8+ T cells. Taken together, dietary Se at the nutritional and supranutritional levels regulates peripheral B and T cells in
adult nude mice before and after xenograft with PC-3 prostate cancer cells. 相似文献
13.
Sobel ES Brusko TM Butfiloski EJ Hou W Li S Cuda CM Abid AN Reeves WH Morel L 《Arthritis research & therapy》2011,13(3):R106
Introduction
CD25+ FOXP3+ CD4+ regulatory T cells (Tregs) are induced by transforming growth factor β (TGFβ) and further expanded by retinoic acid (RA). We have previously shown that this process was defective in T cells from lupus-prone mice expressing the novel isoform of the Pbx1 gene, Pbx1-d. This study tested the hypothesis that CD4+ T cells from systemic lupus erythematosus (SLE) patients exhibited similar defects in Treg induction in response to TGFβ and RA, and that PBX1-d expression is associated with this defect. 相似文献14.
Ursula Grohmann Maria Laura Belladonna Roberta Bianchi Ciriana Orabona Silvia Silla Giuseppe Squillacioti Maria Cristina Fioretti Paolo Puccetti 《Cancer immunology, immunotherapy : CII》1999,48(4):195-203
Nonameric P815AB, a cytotoxic-T-lymphocyte-defined minimal core peptide encoded by the murine mastocytoma gene P1A, fails to initiate CD4+ cell-dependent reactivity in vivo to class-I-restricted epitopes when mice are administered peptide-pulsed dendritic cells.
Effective immunization requires T helper effects, such as those mediated by coimmunization with class-II-restricted (helper)
peptides or by the use of recombinant interleukin-12 (rIL-12). Although P815AB does possess class-II-restricted epitopes,
they are likely suboptimal, resulting in poor affinity and/or stability of MHC/P815AB complexes and inadequate activation
of the antigen-presenting cell function of dendritic cells. The present study has examined a series of longer, P815AB-centered
peptides (11–14 amino acids in length, all P1A-encoded) for their ability to initiate CD4+ and CD8+ cell-mediated responses to the nonamer in vivo, their ability to bind class II MHC in vitro, and their ability to assemble
class II molecules stably. By means of a class-I-restricted skin test assay in mice receiving peptide-pulsed dendritic cells,
we found that a 12-mer and a 13-mer effectively immunized against the core P815AB peptide, and that this correlated with IL-2
production in vitro by CD4+ cells in response to the nonamer. In vitro studies, involving affinity-purified class II molecules, showed that the capacity
to assemble class II molecules stably, more than the affinity for class II MHC, correlated with the ability of the different
P815AB peptides to prime the host to the core peptide seen by the T cells.
Received: 25 February 1999 / Accepted: 14 April 1999 相似文献
15.
Pascale Hubert Roland Greimers Elizabeth Franzen-Detrooz Jean Doyen Pierre Delanaye Jacques Boniver Philippe Delvenne 《Cancer immunology, immunotherapy : CII》1998,47(2):81-89
Dendritic cells (DC) are the most efficient antigen presenting cells. The clinical use of DC as vectors for antitumor and
anti-infectious disease immunotherapy has been limited by their low level and accessibility in normal tissue. Substantial
numbers of DC can be generated from peripheral blood cultured in the presence of interleukin-4 (IL-4) and granulocyte/macrophage-colony-stimulating
factor (GM-CSF). We showed in this study that substantial numbers of DC can be obtained from the peripheral blood of patients
with (pre)neoplastic lesions of the uterine cervix. The procedure required relatively small blood samples (10 ml) and the
presence of 100 U/ml IL-4 and 800 U/ml GM-CSF in the culture medium. There was no significant difference in the morphology,
yield, phenotype and function of generated DC between patients with cervical (pre)neoplastic lesions and healthy individuals.
When the hematopoietic factor Flt3 ligand (Flt3L, 40 ng/ml) was added, there was an average increase in the DC population
of 26% compared to cultures with GM-CSF and IL-4 alone. Approximately 1.2 × 106 cells with the characteristics of dendritic cells could be obtained when Flt3L was included in the medium. The addition of
Flt3L did not modify the phenotypic profile of DC (HLA-DR+, CD1a+, CD4+, CD54+, CD80+, CD86+, CD40+, CD3− and CD14−). In addition, Flt3L generated functional DC capable of stimulating the proliferation of alloreactive T cells. These results
suggest that Flt3L, in association with GM-CSF and IL-4, provides an advantageous tool for the large-scale generation of DC
and that an immunotherapy based on the use of DC generated in vitro is possible in patients with (pre)neoplastic lesions of
the uterine cervix.
Received: 8 January 1998 / Accepted: 30 April 1998 相似文献
16.
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
17.
The expression of monocyte cell-surface receptors represents one index of immune dysfunction, which is common with aging.
Although mouse models of aging are prevalent, monocyte subset assessment is rare. Our purpose was to compare cell receptor
expression on classic (CD115+/Gr-1high) and non-classic (CD115+/Gr-1low) monocytes from 80- or 20-week-old CD-1 mice. Three-colour flow cytometry was used to determine the concentration of monocyte
subsets and their respective cell-surface expression of TLR2, TLR4, CD80, CD86, MHC II and CD54. These receptors were selected
because they have been previously associated with altered monocyte function. Data were analysed with independent t-tests; significance was set at P < 0.05. Old mice had a greater concentration of both classic (258%, P = 0.003) and non-classic (70%, P = 0.026) monocytes. The classic : non-classic monocyte ratio doubled in old as compared with that in young mice (P = 0.006), indicating a pro-inflammatory shift. TLR4 (↓27%, P = 0.001) and CD80 (↓37%, P = 0.004) were decreased on classic monocytes from old as compared with those from young mice. TLR2 (↑24%, P = 0.002) and MHCII (↓21%, P = 0.026) were altered on non-classic monocytes from old as compared with those from young mice. The increased classic : non-classic
monocyte ratio combined with changes in the cell-surface receptor expression on both monocyte subsets is indicative of immune
dysfunction, which may increase age-associated disease risk. 相似文献
18.
N. Uematsu C. Matsuoka Y. Agemizu E. Nagoshi K. Yamamoto 《Molecular & general genetics : MGG》1999,261(3):523-529
The chromosomal tonB gene of Escherichia coli was used as a target for the detection of spontaneous deletion mutations. The deletions were isolated in both recA
+ and recA
− cells, and mutants carrying large deletions were identified because they also lacked part or all of the trp operon. The frequencies of tonB-trp deletion were 1.79 × 10−9 and 1.09 × 10−9 for recA
+ and recA
− cells, respectively. We analyzed 12 deletions from recA
+ and 10 from recA
− cells by cloning and direct sequencing. The deletions ranged in size from 5612 bp to 15142 bp for recA
+ and from 5428 bp to 13289 for recA
− cells. Three deletions from recA
+ cells and five deletions from recA
− cells were found to have occurred between short sequence repeats at the termini of the deletion, leaving one copy of the
repeat in the mutant sequence. Seven deletions from recA
+ cells and three deletions from recA
− cells did not have repeats at their termini; in these cases, the DNA sequences that are adjacent to the deletion termini
in the wild-type are characterized by short (2–4 bp) repeats. From these results, a model is presented for the generation
of deletion mutations which involves formation of an asymmetric crossover mediated by repeated sequences of 2- to 4-bp.
Received: 14 September 1998 / Accepted: 22 December 1998 相似文献
19.
We focus on the role of CD8+ Treg cell in Intravenous methyl-prednisolone (IVMP) pulse therapy in forty patients with active Class III/IV childhood lupus nephritis (LN) with heavy proteinuria. IVMP therapy for five days. From peripheral blood mononuclear cells (PBMCs) and renal tissues, we saw IVMP therapy definitely restoring both CD4+CD25+FoxP3+ and CD8+CD25+Foxp3+ Treg cell number plus greater expression with intracellular IL-10 and granzyme B in CD8+FoxP3+ Treg from PBMCs. IVMP-treated CD8+CD25+ Treg cells directly suppressed CD4+ T proliferation and induced CD4+CD45RO+ apoptosis. Histologically, CD4+FoxP3+ as well as CD8+FoxP3+ Treg cells appeared in renal tissue of LN patients before IVMP by double immunohistochemical stain. CD8+FoxP3+ Treg cells increased in 10 follow-up renal biopsy specimens after IVMP. Reverse correlation of serum anti-C1q antibody and FoxP3+ Treg cells in PBMNCs (r = −0.714, P<0.01). After IVMP, serum anti-C1q antibody decrease accompanied increase of CD4+FoxP3+ Treg cells. CD8+Treg cells reduced interferon-r response in PBMCs to major peptide autoepitopes from nucleosomes after IVMP therapy; siRNA of FoxP3 suppressed granzyme B expression while decreasing CD8+CD25+Treg-induced CD4+CD45RO+ apoptosis. Renal activity of LN by SLEDAI-2k in childhood LN was significantly higher than two weeks after IVMP (P<0.01). CD8+FoxP3+ Treg cells return in post-IVMP therapy and exert crucial immune modulatory effect to control autoimmune response in LN.
Trial Registration
DMR97-IRB-259 相似文献20.
Müller F Aschenbach JR Gäbel G 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2000,170(4):337-343
This study sought to investigate effects of short-chain fatty acids and CO2 on intracellular pH (pHi) and mechanisms that mediate pHi recovery from intracellular acidification in cultured ruminal epithelial cells of sheep. pHi was studied by spectrofluorometry using the pH-sensitive fluorescent indicator 2′,7′-bis (carboxyethyl)-5(6′)-carboxyfluorescein
acetoxymethyl ester (BCECF/AM). The resting pHi in N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)-buffered solution was 7.37 ± 0.03. In HEPES-buffered solution,
a NH4
+/NH3-prepulse (20 mM) or addition of butyrate (20 mM) led to a rapid intracellular acidification (P < 0.05). Addition of 5-(N-ethyl-N-isopropyl)-amiloride (EIPA; 10 μM) or HOE-694 (200 μM) inhibited pHi recovery from an NH4
+/NH3-induced acid load by 58% and 70%, respectively. pHi recovery from acidification by butyrate was reduced by 62% and 69% in the presence of EIPA (10 μM) and HOE-694 (200 μM),
respectively. Changing from HEPES- (20 mM) to CO2/HCO3
−-buffered (5%/20 mM) solution caused a rapid decrease of pHi (P < 0.01), followed by an effective counter-regulation. 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS; 100 μM) blocked
the pHi recovery by 88%. The results indicate that intracellular acidification by butyrate and CO2 is effectively counter-regulated by an Na+/H+ exchanger and by DIDS-sensitive, HCO3
−-dependent mechanism(s). Considering the large amount of intraruminal weak acids in vivo, both mechanisms are of major importance
for maintaining the pHi homeostasis of ruminal epithelial cells.
Accepted: 8 March 2000 相似文献