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1.
A. B. Geldhof Thierry VandenDriessche Ghislain Opdenakker Patrick De Baetselier 《Cancer immunology, immunotherapy : CII》1996,42(6):329-338
Interferon-γ(IFNγ)-induced up-regulation of MHC class I expression on tumor cells can induce a potent CD8-mediated antitumor
response. Consequently, many investigators have proposed IFNγ gene transfection as a means to immunogenize tumor cells and
to vaccinate against metastatic disease. In this study, we demonstrate that transfection of the IFNγ gene in a BW5147 variant
(LiDlo) with low MHC class I expression results in a selective induction of H-2Dk but unaltered H-2Kk expression. In earlier reports we demonstrated a positive correlation between H-2Dk expression and enhanced metastatic potential of BW variants. In accordance with these observations, we observed that intravenous
inoculation of LiDlo(IFNγ) variants into syngeneic AKR mice led to enhanced metastasis as compared to parental LiDlo and LiDlo(neo) control transfectants. Tumor cells, derived from local subcutaneous tumors or sporadic metastases from mice inoculated
with LiDlo tumor cells, were found to up-regulate H-2Dk selectively. Anti-asialoGM1 treatment of AKR mice allowed rapid experimental metastasis formation by the LiDlo and LiDlo(neo) variants, indicating that natural killer (NK) cells control the metastatic behavior of these tumor cells. This was corroborated
by in vitro cytotoxicity experiments, demonstrating that LiDlo and LiDlo(neo) tumor cells were NK-sensitive, while the BW IFNγ transfectants became resistant to lymphokine-activated killer cells
and poly(I)·poly(C)-induced NK cells. We thus conclude that (a) IFNγ up-regulates selectively the MHC class I antigen H-2Dk, (b) H-2Dk governs susceptibility towards NK cells, and (c) NK susceptibility determines the experimental metastatic behavior of BW
tumor cells.
Received: 2 May 1996/Accepted: 21 May 1996 相似文献
2.
Øystein Bruserud Laila Mentzoni Brynjar Foss Jann Bergheim Sigbjørn Berentsen Ingerid Nesthus 《Cancer immunology, immunotherapy : CII》1997,43(5):275-282
Normal peripheral blood mononuclear cells (PBMC responders) were cultured together with non-irradiated allogeneic PBMC (more
than 95% leukaemia blasts) derived from patients with acute leukaemia (referred to as leukaemic PBMC stimulators). Cytokine
secretion was determined as cytokine concentrations in supernatants. Both normal PBMC and enriched CD4+ and CD8+ T cells responded to allostimulation with interferon (IFNγ) secretion. Interleukin-1 (IL-1) receptor antagonist and IL-2-neutralizing
antibodies decreased IFNγ secretion. Exogenous IL-1β, IL-2 and IL-7 increased allostimulated IFNγ secretion, whereas decreased
levels were seen in the presence of IL-6, IL-10 and granulocyte-colony-stimulating factor (G-CSF). During allorecognition
IFNγ -neutralizing antibodies decreased acute myelogenous leukaemia (AML) blast secretion of G-CSF. We conclude that (i) both
CD4+ and CD8+ T cells show allostimulated cytokine secretion in response to allogeneic stimulator cells containing a dominating population
of native, cytokine-secreting leukaemia blasts, and (ii) IFNγ released during this response can modulate the function of allogeneic
AML blasts.
Received: 4 June 1996 / Accepted: 15 October 1996 相似文献
3.
Oral delivery of BCG in a lipid formulation (Liporale™-BCG) targets delivery of viable bacilli to the mesenteric lymph nodes and confers protection against an aerosol Mycobacterium tuberculosis challenge. The magnitude, quality and duration of the effector and memory immune response induced by Liporale™-BCG vaccination is unknown. Therefore, we compared the effector and memory CD4+ T cell response in the spleen and lungs of mice vaccinated with Liporale™-BCG to the response induced by subcutaneous BCG vaccination. Liporale™-BCG vaccination induced a long-lived CD4+ T cell response, evident by the detection of effector CD4+ T cells in the lungs and a significant increase in the number of Ag85B tetramer-specific CD4+ T cells in the spleen up to 30 weeks post vaccination. Moreover, following polyclonal stimulation, Liporale™-BCG vaccination, but not s.c. BCG vaccination, induced a significant increase in both the percentage of CD4+ T cells in the lungs capable of producing IFNγ and the number of multifunctional CD4+ T cells in the lungs at 30 weeks post vaccination. These results demonstrate that orally delivered Liporale™-BCG vaccine induces a long-lived multifunctional immune response, and could therefore represent a practical and effective means of delivering novel BCG-based TB vaccines. 相似文献
4.
Brady MS Lee F Petrie H Eckels DD Lee JS 《Cancer immunology, immunotherapy : CII》2000,48(11):621-626
Purpose: Most melanoma cell lines express HLA class II antigens constitutively or can be induced to do so with interferon γ (IFNγ).
We have previously demonstrated that peptide-specific CD4+ T cells proliferate in response to HLA-class-II-antigen-mediated peptide presentation by melanoma cells in vitro and produce
interleukin-10 (IL-10) and (IFNγ). We asked whether the responding T cells kill the tumor cells and, if so, whether direct
cell contact was required. Methods: Two HLA class II+ melanoma cell lines derived from metastases were co-cultured with a human CD4+ T cell clone specific for influenza hemagglutinin peptide (HA). T cells, melanoma, and HA were co-cultured for 48 h. Melanoma
cells with and without HA and/or T cells served as controls. After 36 h, the medium was removed for cytokine analysis by enzyme-linked
immunosorbent assay (ELISA). Twelve hours later non-adherent cells were washed away and the adherent melanoma cells were trypsinized
and counted. Dual-chamber culture plates were used to determine whether cell contact and/or exposure to cytokine were required
for tumor cell death. Results: Melanoma cell counts were over 80% lower in wells containing T cells than in wells with melanoma and peptide alone (P < 0.05). ELISA of supernatants revealed production of IFNγ and IL-10 by the responding T cells. Direct T cell contact with
tumor cells was not required for tumor cell death, as melanoma cells were killed when they shared medium but had no contact
with T cells responding to peptide presentation by HLA-class-II-antigen-positive melanoma cells in a separate chamber. Blocking
antibody to IFNγ but not IL-10 prevented melanoma cell death at levels of cytokine similar to that present in co-culture assays.
Conclusions: Peptide-specific CD4+ T cells kill melanoma cells in vitro when they recognize peptide presented by the tumor cell in the context of HLA class
II antigen. Direct cell contact is not required, suggesting that it is a cytokine-mediated event. Immunotherapy, using primed
CD4+ T cells and peptide, may be beneficial in patients whose tumors express HLA class II antigens or can be induced to do so
with IFNγ.
Received: 1 July 1999 / Accepted: 17 September 1999 相似文献
5.
Effector cell functions are regulated by a number of positive signals for the mediation of antitumor immunity. The CD40 and
CD40 ligand (CD40L) interaction has been implicated in the generation of effective cell-mediated and humoral immune responses,
where cytokines have been shown to play a significant role in the expression of these molecules. Our earlier studies have
shown that spontaneous regression of a rat histiocytoma transplanted s.c. is mediated by CD8+ CD3− NK cells. The CD40-CD40L mediation during tumor regression was of interest. Tumor-transplanted animals showed enhanced expression
of CD40L on natural killer (NK) and T cells, when compared to cells from normal animals. CD40 expression on AK-5 tumor cells
was also induced after s.c. transplantation. Administration of anti-(interleukin-12) (anti-IL-12) and anti-(interferon γ)
(anti-IFNγ) antibodies in tumor-bearing animals showed down-regulation of the expression of CD40L on NK and T cells with simultaneous
inhibition of cytotoxic acitivity of NK cells, cytokine release and the production of antitumor antibody. Naive NK cells,
when co-cultured with fixed AK-5 cells, were induced to express CD40L. CD40L expression modulated the immune response exerted
by NK cells, in part by the activation of nuclear factor kB (NF-kB). Furthermore, the signaling via CD40L through the use
of anti-CD40L antibody promoted the in vitro activation of cytotoxic as well as NF-kB binding activity in NK cells from tumor-transplanted
animals. These observations demonstrate that the expression of CD40L by the effector cells is regulated by IL-12 and IFNγ,
and could effectively modulate the NK-cell-mediated immune response during the regression of AK-5 tumor.
Received: 1 June 2000 / Accepted: 27 July 2000 相似文献
6.
Lodge A Yu P Nicholl MB Brown IE Jackson CC Schreiber K Sugg SL Schreiber H Shilyansky J 《Cancer immunology, immunotherapy : CII》2006,55(12):1542-1552
Absence of CD4+ T cell help has been suggested as a mechanism for failed anti-tumor cytotoxic T lymphocytes (CTL) response. We examined the requirement for CD4+ T cells to eliminate an immunogenic murine fibrosarcoma (6132A) inoculated into the peritoneal cavity. Immunocompetent C3H mice eliminated both single and repeat intraperitoneal (IP) inoculums, and developed high frequency of 6132A-specific interferon-γ (IFNγ)-producing CTL in the peritoneal cavity. Adoptive transfer of peritoneal exudate cells (PEC) isolated from control mice, protected SCID mice from challenge with 6132A. In contrast, CD4 depleted mice had diminished ability to eliminate tumor and succumbed to repeat IP challenges. Mice depleted of CD4+ T cells lacked tumor-specific IFNγ producing CTL in the peritoneal cavity. Adoptive transfer of PEC from CD4 depleted mice failed to protect SCID mice from 6132A. However, splenocytes isolated from same CD4 depleted mice prevented tumor growth in SCID mice, suggesting that 6132A-specific CTL response was generated, but was not sustained in the peritoneum. Treating CD4 depleted mice with agonist anti-CD40 antibody, starting on days 3 or 8 after initiating tumor challenge, led to persistence of 6132A-specific IFNγ producing CTL in the peritoneum, and eliminated 6132A tumor. The findings suggest that CTL can be activated in the absence of CD4+ T cells, but CD4+ T cells are required for a persistent CTL response at the tumor site. Exogenous stimulation through CD40 can restore tumor-specific CTL activity to the peritoneum and promote tumor clearance in the absence of CD4+ T cells.Supported in part by grants from Children’s Hospital of Wisconsin Foundation, Society of University Surgeons Foundation, Florence and Marshall Schwid Foundation, Elsa Pardee Foundation, Kathy Duffy Fogarty Fund of the Greater Milwaukee Foundation (JS) and NIH grant RO1-CA-37156 (HS); Andrew Lodge and Ping Yu have contributed equally to this work. 相似文献
7.
Øystein Bruserud 《Cancer immunology, immunotherapy : CII》1998,46(4):221-228
T lymphocytes are important both for the host defence against infections and probably also as antileukaemic effector cells
in patients with acute leukaemia. To investigate the T lymphocyte cytokine repertoire of clonogenic T lymphocytes, CD4+ and CD8+ T lymphocyte clones were prepared from acute leukaemia patients with chemotherapy-induced cytopenia (leucocytes <0.5×109/l). A majority of both CD4+ and CD8+ clones secreted detectable interleukin-2 (IL-2), IL-10, IL-13, granulocyte/macrophage-colony-stimulating factor and interferon
γ (IFNγ) in response to phytohaemagglutinin + accessory cells (Epstein-Barr-virus-transformed B cell line, 80-Gy-irradiated).
The CD4+ clones showed significantly higher levels of IL-10 secretion than the CD8+ clones. Decreased levels of IL-2, IL-13 and IFNγ were observed when acute myelogenous leukaemia (AML) blasts were used instead
of cells from the B cell line as accessory cells during phytohaemagglutinin activation, but the differences in IL-13 and IFNγ
levels were reversed by addition of exogenous IL-2. On the basis of these results we conclude: (i) the remaining clonogenic
T lymphocytes derived from acute leukaemia patients with therapy-induced leucopenia can respond to activation with a broad
cytokine response, and T-cell-derived cytokines may then contribute to cytokine responses during complicating infections in
these patients; (ii) although T cells can modulate AML blast functions and mediate antileukaemic effects, the leukaemia blasts
will also modulate T cell functions and alter the cytokine profile of activated T lymphocytes.
Received: 6 November 1997 / Accepted: 5 March 1998 相似文献
8.
We have recently (Kawakami et al, Immunol. Lett. 1995;46: 143) demonstrated that unusual Mac-1+CD4?CD8? T cells bearing αβ antigen receptor (Mac-1+ αβ T cells) reside in a considerable proportion in murine lungs. The present study was performed to examine the dynamics of accumulation of these cells in the lungs following intravenous administration of Mycobacterium bovis BCG (BCG). Mac-1+ αβ T cells accumulated rapidly 24 hr after infection, followed by a gradual increase over the observation period of 15 days. Furthermore, the expression of Ia, ICAM-1 and FcγR II/III on their surface intensified dramatically after BCG infection. The kinetics of enhancement of Ia expression was slower than that of ICAM-1, with the maximum level attained in one day in the latter molecule but in two weeks in the former. Neutralization of endogenous IFN-γ by specific mAb completely blocked the augmented expression of Ia on Mac-1+ αβ T cells after BCG infection, but did not have any significant effect on that of ICAM-1. In contrast, in vivo administration of IFN-γ enhanced the expression of ICAM-1 as well as that of Ia. Our results indicate that accumulation of Mac-1 αβ T cells within the lung is associated with a differential change in the expression of surface antigens, and suggest that these cells may play a role in the host defense against mycobacterial infection. 相似文献
9.
T cell clones (CD4+CD8–TCRαβ+γδ–) derived from bone marrow transplant recipients were stimulated with phytohaemagglutinin (PHA) +interleukin-2 (IL-2) in the
presence of irradiated (50 Gy) peripheral blood mononuclear cells (PBMC) derived from acute leukaemia patients(leukaemic PBMC
containing more than 95% blast cells). Leukaemic PBMC could function as accessory cells during mitogenic T cell activation
resulting in both T cell proliferation and a broad T cell cytokine response [IL-3, IL-4, IL-10, granulocyte/macrophage-colony-stimulating
factor (GM-CSF) tumour necrosis factor α (TNFα) and interferon γ (IFNγ) secretion]. Blockade of IL-1 effects by adding IL-1
receptor antagonist together with PHA+IL-2+leukaemia blasts increased T cell proliferation, whereas IL-6-neutralizing antibodies
did not alter T cell proliferation. A qualitatively similar T cell cytokine response and a similar cytokine profile (highest
levels detected for GM-CSF and IFNγ) were detected when normal polyclonal T cell lines were stimulated with PHA in the presence
of non-irradiated leukaemic PBMC. When leukaemic PBMC derived from 18 acute myelogenous leukaemia patients were cultured with
PHA and cells from a polyclonal T cell line, increased concentrations of the T cell cytokines IFNγ and IL-4 were detected
for all patients. We conclude that T cell activation resulting in proliferation and a broad cytokine response can take place
in the presence of excess acute myelogenous leukaemia blasts.
Received: 30 November 1995 / Accepted: 9 January 1996 相似文献
10.
Jennifer Konopa Mulligan M. Rita I. Young 《Cancer immunology, immunotherapy : CII》2010,59(2):267-277
Patients with solid tumors have defects in immune effector cells, which have been associated with a poorer prognosis. Previous
studies by our laboratory have shown that exposure to Lewis lung carcinoma (LLC)-secreted products induces the formation of
suppressor endothelial cells in vitro. The current studies examined if tumors could induce the formation of suppressor endothelial
cells in vivo. Endothelial cells were immunomagnetically isolated from the lungs of tumor-bearing mice or normal controls
and examined for their ability to modulate NK cell, T-cell and macrophage functions. Compared to normal controls, supernatants
from endothelial cells isolated from tumor-bearing lungs had elevated secretion of PGE2, IL-6, IL-10 and VEGF. Conditioned media from endothelial cells isolated from normal lungs increased CD8+ T-cell IFN-γ and CD4+ T-cell IL-2 production in response to anti-CD3 stimulation, while media conditioned by endothelial cells from tumor-bearing
lungs had a diminished stimulatory capacity. Examination of NK cell functions showed that supernatants from endothelial cells
isolated from normal lungs were potent activators of NK cells, as indicated by their secretion of TNF-α and IFN-γ. Endothelial
cells isolated from tumor-bearing lungs had a significantly diminished capacity to activate NK cells. Finally, supernatants
from endothelial cells of tumor-bearing lungs diminished macrophage phagocytosis compared to either treatment with supernatants
of normal endothelial cells or treatment with media alone. The results of these studies demonstrate that tumors induce the
formation of suppressor endothelial cells in vivo and provide support for the role of endothelial cells in tumor-induced immune
suppression. 相似文献
11.
Background
The Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine is given to >120 million infants each year worldwide. Most studies investigating the immune response to BCG have focused on adaptive immunity. However the importance of TCR-gamma/delta (γδ) T cells and NK cells in the mycobacterial-specific immune response is of increasing interest.Methods
Participants in four age-groups were BCG-immunized. Ten weeks later, in vitro BCG-stimulated blood was analyzed for NK and T cell markers, and intracellular IFNgamma (IFNγ) by flow cytometry. Total functional IFNγ response was calculated using integrated median fluorescence intensity (iMFI).Results
In infants and children, CD4 and CD4-CD8- (double-negative (DN)) T cells were the main IFNγ-expressing cells representing 43-56% and 27-37% of total CD3+ IFNγ+ T cells respectively. The iMFI was higher in DN T cells compared to CD4 T cells in all age groups, with the greatest differences seen in infants immunized at birth (p=0.002) or 2 months of age (p<0.0001). When NK cells were included in the analysis, they accounted for the majority of total IFNγ-expressing cells and, together with DN Vδ2 γδ T cells, had the highest iMFI in infants immunized at birth or 2 months of age.Conclusion
In addition to CD4 T cells, NK cells and DN T cells, including Vδ2 γδ T cells, are the key populations producing IFNγ in response to BCG immunization in infants and children. This suggests that innate immunity and unconventional T cells play a greater role in the mycobacterial immune response than previously recognized and should be considered in the design and assessment of novel tuberculosis vaccines. 相似文献12.
Anja ten Brinke Gijs van Schijndel Remco Visser Tanja D. de Gruijl Jaap Jan Zwaginga S. Marieke van Ham 《Cancer immunology, immunotherapy : CII》2010,59(8):1185-1195
Dendritic cells (DCs) are promising antigen presenting cells for cancer treatment. Previously, we showed that the combination
of monophosphoryl lipid A (MPLA) with IFNγ generates mature DCs that produce IL-12 and polarize CD4+ T cells towards a Th1 phenotype. Here, we extended these observations by showing that the DCs generated with the clinical
grade maturation cocktail of MPLA/IFNγ induce superior tumour antigen-specific CD8+ CTL responses compared to the cytokine cocktail matured DCs that are currently used in the clinic. MPLA/IFNγ DCs can induce
CTL responses in healthy individuals as well as in melanoma patients. The CTL induction was mainly dependent on the IL-12
produced by the MPLA/IFNγ DCs. The high amounts of induced CTLs are functional as they produce IFNγ and lyse target cells
and this cytolytic activity is antigen specific and HLA restricted. Furthermore, the CTLs proved to kill tumour cells expressing
endogenous tumour antigen in vitro. Therefore, MPLA/IFNγ DCs are very promising for the use in future cancer immunotherapy. 相似文献
13.
Xue G Liu RY Li Y Cheng Y Liang ZH Wu JX Zeng MS Tian FZ Huang W 《Cancer immunology, immunotherapy : CII》2007,56(11):1831-1843
Backgroud and objective Dendritic cells play an important role in initiation and regulation of immune responses. Previous studies demonstrated that
intratumoral administration of 6Ckine-modified DCs enhanced local and systemic antitumor effects. Herein we report the investigation
of the specific CTL responses elicited by adenoviral 6Ckine/IFNγ fusion gene-modified DCs in vitro.
Methods Human monocyte-derived DCs were modified with an adenoviral vector encoding 6Ckine/IFNγ fusion protein (Ad-6Ckine/IFNγ), and
then investigated the effect of 6Ckine/IFNγ fusion protein on the maturation, cytokine and chemokine secretion of DCs, and
their activities of recruiting and activating T cells in vitro were investigated.
Results 6Ckine/IFNγ fusion protein induced DC maturation characterized with the upregulation of CD83 and CCR7. And it up-regulated
the expression of RANTES and IL-12p70, down-regulated that of IL-10 in DCs. Additionally, 6Ckine/IFNγ markedly increased DC’s
recruiting ability for naive T cells, benefiting from the enhanced expression of chemokines 6Ckine and RANTES in DCs. Fusion
gene-modified DCs significantly promoted the proliferation of autologous T cells, induced Th1 differentiation by upregulating
the expression of IL-2 and T-bet in T cells, and increased specific cytotoxicity of CTLs against specific tumor cells, HepG2
or LoVo cells, respectively.
Conclusion Combining the effects of 6Ckine and IFNγ, Ad-6Ckine/IFNγ modified DCs induced enhanced CTL responses in vitro, which indicated
that Ad-6Ckine/IFNγ modified DCs might be used as an adjuvant to trigger an effective antitumor immune response.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Gang Xue, Ran-yi Liu, Yan Li contributed equally to this work. 相似文献
14.
Mazorra Z Mesa C Fernández A Fernández LE 《Cancer immunology, immunotherapy : CII》2008,57(12):1771-1780
Preventive immunotherapy is an attractive strategy for patients at a high risk of having cancer. The success of prophylactic
cancer vaccines would depend on the selection of target antigens that are essential for tumour growth and progression. The
overexpression of GM3 ganglioside in murine and human melanomas and its important role in tumour progression makes this self
antigen a potential target for preventive immunotherapy of this neoplasm. We have previously shown that preventive administration
of a GM3-based vaccine to C57BL/6 mice elicited the rejection of the GM3 positive-B16 melanoma cells in most of the animals.
Despite the crucial role of cellular immune response in tumour protection, the involvement of T cells in anti-tumour immunity
of ganglioside vaccines is not described. Here, we examined the mechanisms by which this immunogen confers tumour protection.
We have found that induction of anti-GM3 IgG antibodies correlated with tumour protection. Surprisingly, CD8+ T cells, but not NK1.1+ cells, are required in the effector phase of the antitumour immune response. The depletion of CD4+ T cells during immunization phase did not affect the anti-tumour activity. In addition, T cells from surviving-immunized
animals secreted IFNγ when were co-cultured with IFNα-treated B16 melanoma cells or DCs pulsed with melanoma extract. Paradoxically,
in spite of the glycolipidic nature of this antigen, these findings demonstrate the direct involvement of the cellular immune
response in the anti-tumour protection induced by a ganglioside-based vaccine.
Grant support: Center of Molecular Immunology, Elea Laboratories and Recombio. 相似文献
15.
NK cells inhibit anti‐Mycobacterium bovis BCG T cell responses and aggravate pulmonary inflammation in a direct lung infection mouse model 下载免费PDF全文
Dongfang Wang Xiuling Gu Xiaoman Liu Songtao Wei Bin Wang Min Fang 《Cellular microbiology》2018,20(7)
Tuberculosis remains a threat to public health. The major problem for curing this disease is latent infection, of which the underlying mechanisms are still not fully understood. Previous studies indicate that natural killer (NK) cells do not play a role in inhibiting the growth of Mycobacterium tuberculosis in the lung, and recent studies have revealed that NK cells regulate the adaptive immunity during mycobacterial infection. By using a mouse model of direct lung infection with Mycobacterium bovis bacillus Calmette‐Guerin (BCG), we found that the presence of NK cells postponed the priming and activation of T cells after BCG infection. In addition, depletion of NK cells before infection alleviated pulmonary pathology. Further studies showed that NK cells lysed BCG‐infected macrophages in an NKG2D dependent manner. Thus, NK cells did not play a direct role in control BCG, but aggravated the pulmonary inflammation and impaired anti‐BCG T cell immunity, likely through killing BCG‐infected macrophages. Our results may have important implications for the design of immune therapy to treat tuberculosis. 相似文献
16.
Gao Y Zhang D Sun B Fujii H Kosuna K Yin Z 《Cancer immunology, immunotherapy : CII》2006,55(10):1258-1266
Active hexose correlated compound (AHCC) is a mixture of polysaccharides, amino acids, lipids and minerals derived from cocultured mycelia of several species of Basidiomycete mushrooms. AHCC has been implicated to modulate immune functions and plays a protective role against infection. However, the potential role of AHCC in tumor immune surveillance is unknown. In this study, C57BL/6 mice were orally administered AHCC or water, followed by tumor cell inoculation. We showed that compared to pure water-treated mice, AHCC treatment significantly delayed tumor development after inoculation of either melanoma cell line B16F0 or lymphoma cell line EL4. Treatment with AHCC enhanced both Ag-specific activation and proliferation of CD4+ and CD8+ T cells, increased the number of tumor Ag-specific CD8+ T cells, and more importantly, increased the frequency of tumor Ag-specific IFN-γ producing CD8+ T cells. Interestingly, AHCC treatment also showed increased cell number of NK and γδ T cells, indicating the role of AHCC in activating these innate-like lymphocytes. In summary, our results demonstrate that AHCC can enhance tumor immune surveillance through regulating both innate and adaptive immune responses. 相似文献
17.
Wujiang Liu Michael A. O’Donnell Xiaohong Chen Ruifa Han Yi Luo 《Cancer immunology, immunotherapy : CII》2009,58(10):1647-1655
Purpose The proper induction of cellular immunity is required for effective bacillus Calmette-Guérin (BCG) immunotherapy of bladder
cancer. It has been known that BCG stimulation of human peripheral blood mononuclear cells (PBMC) leads to the generation
of effector cells cytotoxic to bladder cancer cells in vitro. To improve BCG therapy, we previously developed human interferon
(IFN)-α 2B secreting recombinant (r) BCG (rBCG-IFN-α). We demonstrated that rBCG-IFN-α augmented T helper type 1 (Th1) cytokine
IFN-γ production by PBMC. In this study, we further investigated whether rBCG-IFN-α could also enhance PBMC cytotoxicity toward
bladder cancer cells.
Materials and methods PBMC were prepared from healthy individuals, left alone or stimulated with rBCG-IFN-α or control MV261 BCG, and used as effector
cells in 51Cr-release assays. Human bladder cancer cell lines T24, J82, 5637, TCCSUP, and UMUC-3 were used as target cells. To determine
the role of secreted rIFN-α as well as endogenously expressed IFN-γ and IL-2 in inducing the cytotoxicity, PBMC were stimulated
with rBCG-IFN-α in the presence of neutralizing antibodies to IFN-α, IFN-γ or IL-2. To determine the role of natural killer
(NK) and CD8+ T cells in inducing the cytotoxicity, both cell types were isolated after BCG stimulation of PBMC and used as effector cells
in 51Cr-release assays.
Results Non-stimulated PBMC showed basal levels of cytotoxicity against all target cell lines tested. MV261 BCG increased the PBMC
cytotoxicity by 1.8- to 4.2-fold. rBCG-IFN-α further increased the PBMC cytotoxicity by up to 2-fold. Elevated production
of IFN-γ and IL-2 by PBMC was observed after rBCG-IFN-α stimulation. Blockage of IFN-α, IFN-γ or IL-2 by neutralizing antibodies
during rBCG-IFN-α stimulation reduced or abolished the induction of PBMC cytotoxicity. Both NK and CD8+ T cells were found to be responsible for the enhanced PBMC cytotoxicity induced by rBCG-IFN-α with the former cell type being
more predominant.
Conclusions rBCG-IFN-α is an improved BCG agent that induces enhanced PBMC cytotoxicity against bladder cancer cells in vitro. This rBCG
strain may serve as an alternative to BCG for the treatment of superficial bladder cancer. 相似文献
18.
Pulaski BA Clements VK Pipeling MR Ostrand-Rosenberg S 《Cancer immunology, immunotherapy : CII》2000,49(1):34-45
Because they are difficult to treat, animal models of widespread, established metastatic cancer are rarely used to test novel
immunotherapies. Two such mouse models are used in this report to demonstrate the therapeutic efficacy and to probe the mechanisms
of a novel combination immunotherapy consisting of the cytokine interleukin-12 (IL-12) combined with a previously described
vaccine based on MHC class II, CD80-expressing cells. BALB/c mice with 3-week established primary 4T1 mammary carcinomas up
to 6 mm in diameter and with extensive, spontaneous lung metastases show a significant reduction in lung metastases following
a 3-week course of immunotherapy consisting of weekly injections of the cell-based vaccine plus injections of IL-12 three
times per week. C57BL/6 mice with 7-day established intravenous B16 melF10 lung metastases show a similar response following
immunotherapy with IL-12 plus a vaccine based on B16 MHC class II, CD80-expressing cells. In both systems the combination
therapy of cells plus IL-12 is more effective than IL-12 or the cellular vaccine alone, although, in the 4T1 system, optimal
activity does not require MHC class II and CD80 expression in the vaccine cells. The cell-based vaccines were originally designed
to activate tumor-specific CD4+ T lymphocytes specifically and thereby provide helper activity to tumor-cytotoxic CD8+ T cells, and IL-12 was added to the therapy to facilitate T helper type 1 lymphocyte (Th1) differentiation. In vivo depletion
experiments for CD4+ and CD8+ T cells and natural killer (NK) cells and tumor challenge experiments in beige/nude/XID immunodeficient mice demonstrate
that the therapeutic effect is not exclusively dependent on a single cell population, suggesting that T and NK cells are acting
together to optimize the response. IL-12 may also be enhancing the immunotherapy via induction of the chemokine Mig (monokine
induced by interferon γ), because reverse PCR experiments demonstrate that Mig is present in the lungs of mice receiving therapy
and is most likely synthesized by the tumor cells. These results demonstrate that the combination therapy of systemic IL-12
and a cell-based vaccine is an effective agent for the treatment of advanced, disseminated metastatic cancers in experimental
mouse models and that multiple effector cell populations and anti-angiostatic factors are likely to mediate the effect.
Received: 15 October 1999 / Accepted: 24 November 1999 相似文献
19.
The presence of a relatively mature CD4+ CD8− (SP) T cell subset in mouse thymus has been demonstrated. Composing of 10% of total CD4SP thymocytes, this subset is defined
by the absence of 3G11 and 6C10 expression with a phenotype of CD69+/−, HSAmed/lo and heterogeneous for Qa-2 expression. The proliferation capability of TCRαβ+ 3Gl l− 6C10− CD4+ CD8− thymocytes was high while using Con A stimulus. And Con A stimulation could result in secretion of IL4, IL-10, IL-6 and a
little amount of IFNγ. IL-2 was barely detectable. This is distinct from typical Th0 type cytokines. The cells of this subset
were NK1.1 negative, but strongly expressed GATA-3 mRNA. The results suggest that the CD4+ subset of 3G11− 6C10− NK1.1− phenotype possesses immunocompetent cells with functions characteristic of Th2-like cytokines, which may indicate the cells
at transitional status from Th0 to Th2, with a propensity to Th2.
Project supported by the National Natural Science Foundation of China (Grant No. 39730410). 相似文献
20.
The presence of a relatively mature CD4+ CD8− (SP) T cell subset in mouse thymus has been demonstrated. Composing of 10% of total CD4SP thymocytes, this subset is defined by the absence of 3G11 and 6C10 expression with a phenotype of CD69+/−, HSAmed/lo and heterogeneous for Qa-2 expression. The proliferation capability of TCRαβ+ 3Gl l− 6C10− CD4+ CD8− thymocytes was high while using Con A stimulus. And Con A stimulation could result in secretion of IL4, IL-10, IL-6 and a little amount of IFNγ. IL-2 was barely detectable. This is distinct from typical Th0 type cytokines. The cells of this subset were NK1.1 negative, but strongly expressed GATA-3 mRNA. The results suggest that the CD4+ subset of 3G11− 6C10− NK1.1− phenotype possesses immunocompetent cells with functions characteristic of Th2-like cytokines, which may indicate the cells at transitional status from Th0 to Th2, with a propensity to Th2. 相似文献