共查询到20条相似文献,搜索用时 218 毫秒
1.
Tae-Young Lee Yang-Hyun Kim Sun-Woo Yoon Jai-Chul Choi Jai-Myung Yang Chul-Joong Kim John T. Schiller Moon-Hee Sung Haryoung Poo 《Cancer immunology, immunotherapy : CII》2009,58(11):1781-1794
Previously, we reported that the oral administration of high molecular mass poly-γ-glutamate (γ-PGA) induced antitumor immunity
but the mechanism underlying this antitumor activity was not understood. In the present study, we found that application of
high molecular mass γ-PGA induced secretion of tumor necrosis factor (TNF)-α from the bone-marrow-derived macrophages of wild
type (C57BL/6 and C3H/HeN) and Toll-like receptor 2 knockout (TLR2−/−) mice, but not those of myeloid differentiation factor 88 knockout (MyD88−/−) and TLR4-defective mice (C3H/HeJ). Production of interferon (IFN)-γ-inducible protein 10 (IP-10) in response to treatment
with γ-PGA was almost abolished in C3H/HeJ mice. In contrast to LPS, γ-PGA induced productions of TNF-α and IP-10 could not
be blocked by polymyxin B. Furthermore, γ-PGA-induced interleukin-12 production was also impaired in immature dendritic cells
(iDCs) from MyD88−/− and C3H/HeJ mice. Downregulation of MyD88 and TLR4 expression using small interfering RNA (siRNA) significantly inhibited
γ-PGA-induced TNF-α secretion from the RAW264.7 cells. γ-PGA-mediated intracellular signaling was markedly inhibited in C3H/HeJ
cells. The antitumor effect of γ-PGA was completely abrogated in C3H/HeJ mice compared with control mice (C3H/HeN) but significant
antitumor effect was generated by the intratumoral administration of C3H/HeN mice-derived iDCs followed by 2,000 kDa γ-PGA
in C3H/HeJ. These findings strongly suggest that the antitumor activity of γ-PGA is mediated by TLR4.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
2.
Background
There is an urgent need to develop new innovative therapies for the control of advanced cancer. The combination of antigen-specific immunotherapy with the employment of immunomodulatory agents has emerged as a potentially plausible approach for the control of advanced cancer.Methods
In the current study, we explored the combination of the DNA vaccine encoding calreticulin (CRT) linked to human papillomavirus type 16 (HPV-16) E7 antigen (CRT/E7) with the TLR7 agonist imiquimod for their ability to generate E7-specific immune responses and antitumor effects in tumor-bearing mice.Results
We observed that treatment with CRT/E7 DNA in combination with imiquimod leads to an enhancement in the E7-specific CD8+ T cell immune responses and a decrease in the number of myeloid-derived suppressor cells in the tumor microenvironment of tumor-bearing mice. Furthermore, treatment with CRT/E7 DNA in combination with imiquimod leads to significantly improved antitumor effects and prolonged survival in treated mice. In addition, treatment with imiquimod led to increased number of NK1.1+ cells and F4/80+ cells in the tumor microenvironment. Macrophages and NK1.1+ cells were found to play an important role in the antitumor effects mediated by treatment with CRT/E7 DNA in combination with imiquimod.Conclusions
Thus, our data suggests that the combination of therapeutic HPV DNA vaccination with topical treatment with the TLR7 agonist imiquimod enhances the antitumor immunity induced by DNA vaccination. The current study has significant implications for future clinical translation.3.
E. Arefian T. Bamdad H. Soleimanjahi M. R. Akhoond M. Parsania A. Ghaemi 《Molecular Biology》2009,43(3):388-393
The vast majority of the world’s population is infected with Herpes simplex virus (HSV). Although antiviral therapy can reduce the incidence of reactivation and asymptomatic viral shedding and limits morbidity
and mortality from active disease, it cannot cure infection. Therefore, the development of an effective vaccine is an important
global health priority. In this study, the induction of IFN-γ production was compared in different herpes simplex virus 1
(HSV-1) vaccines. Glycoprotein D (gD1) as a major immunogenic HSV-1 glycoprotein was chosen to our study. Balb/c mice were administered with DNA vaccine encoding gD1, subunit glycoprotein vaccine
including insect cells infected by a gD1 recombinant Baculovirus, prime DNA vaccine boosted by subunit glycoprotein vaccine, inactivated KOS strain as a positive control, pcDNA3 plasmid and Sf9 cells as negative controls. Evaluation tests showed that the amount
of IFN-γ mRNA at 8, 16 and 32 hours after restimulation sharply decreased whereas, the IFN-γ protein level is significantly
increased. Our results revealed that at 14 days after immunization IFN-γ secretion of stimulated cells in all of the vaccinated
groups dramatically raised rather than secreted IFN-γ levels in mice that were analyzed at 7 days after vaccination. In comparison
to other groups; Prime-Boost immunization dramatically caused vigorous and prompt IFN-γ production at 7 days after immunization
and 8 hours after restimulation.
The article is published in the original. 相似文献
4.
Amos SM Pegram HJ Westwood JA John LB Devaud C Clarke CJ Restifo NP Smyth MJ Darcy PK Kershaw MH 《Cancer immunology, immunotherapy : CII》2011,60(5):671-683
Toll-like receptor (TLR) agonists can trigger broad inflammatory responses that elicit rapid innate immunity and promote the
activities of lymphocytes, which can potentially enhance adoptive immunotherapy in the tumor-bearing setting. In the present
study, we found that Polyinosinic:Polycytidylic Acid [Poly(I:C)] and CpG oligodeoxynucleotide 1826 [CpG], agonists for TLR
3 and 9, respectively, potently activated adoptively transferred T cells against a murine model of established melanoma. Intratumoral
injection of Poly(I:C) and CpG, combined with systemic transfer of activated pmel-1 T cells, specific for gp10025–33, led to enhanced survival and eradication of 9-day established subcutaneous B16F10 melanomas in a proportion of mice. A series
of survival studies in knockout mice supported a key mechanistic pathway, whereby TLR agonists acted via host cells to enhance
IFN-γ production by adoptively transferred T cells. IFN-γ, in turn, enhanced the immunogenicity of the B16F10 melanoma line,
leading to increased killing by adoptively transferred T cells. Thus, this combination approach counteracted tumor escape
from immunotherapy via downregulation of immunogenicity. In conclusion, TLR agonists may represent advanced adjuvants within
the setting of adoptive T-cell immunotherapy of cancer and hold promise as a safe means of enhancing this approach within
the clinic. 相似文献
5.
Kimura K Nishimura H Matsuzaki T Yokokura T Nimura Y Yoshikai Y 《Cancer immunology, immunotherapy : CII》2000,49(2):71-77
Interleukin(IL)-15, which uses IL-2 receptor (R) β and γ chains for signal transduction, shares many of the biological activities
of IL-2. We examined the effects of exogenous IL-15 on protection in a murine malignant pleurisy model using BALB/c mice and
syngeneic MethA fibrosarcoma (MethA). Intrapleural administration of IL-15 significantly prolonged the survival time of mice
after an intrapleural inoculation of MethA, whereas the same dose of IL-2 did not. The in vivo antitumor effect of IL-15 was
synergistically enhanced by additive administration of IL-12. Combination therapy of IL-15 and IL-12 protected mice from death
from bloody pleural fluid. Such treatment induced marked increases in the number of CD3-IL-2Rβ+ cells corresponding to natural killer (NK) cells and the production of interferon γ (IFNγ) by T cells in the thoracic exudate
cells (TEC). Administration of anti-IFNγ mAb partly inhibited the protective effect of a combination of IL-15 and IL-12. A
tumor-neutralizing (Winn) assay revealed that the antitumor activity of effector cells in the TEC was abrogated by treatment
with anti-CD8 mAb or anti-asialoGM1 Ab plus complement. Thus, treatment with IL-15 in combination with IL-12 may enhance the
activities of NK and CD8+ T cells in the TEC, providing strong antitumor activity against the malignant pleurisy. These results suggest that IL-15
together with IL-12 may have potential for the immunotherapy of some types of malignant pleurisy.
Received: 13 July 1999 / Accepted: 3 December 1999 相似文献
6.
Zhang J Zhou Z Wang C Shen J Zheng Y Zhang L Wang J Xia D 《Cancer immunology, immunotherapy : CII》2011,60(4):559-573
Although interleukin-10 (IL-10) is commonly regarded as an immunosuppressive cytokine, a wealth of evidence is accumulating
that IL-10 also possesses some immunostimulating antitumor properties. Previous studies demonstrated that forced expression
of the IL-10 gene in tumor cells could unexpectedly produce antitumor effects. In this study, we explored the tumorigenesis
of EG7 cells transduced with IL-10 gene. In vivo, IL-10 gene transfer reduced tumorigenic capacity of EG7 cells and prolonged
survival of the EG7 tumor-bearing mice. It was found that the cytotoxicities of cytotoxic T lymphocytes (CTL) and natural
killer cells (NK cells) were enhanced. Assessment of the immune status of the animals showed prevalence of a systemic and
tumor-specific Th2 response (high levels of IL-4 and IL-10). To improve the therapeutic efficacy, we combined with intratumoral
injection of adenovirus-mediated lymphotactin (Ad-Lptn) into the overestablished EG7 tumor model. More significant inhibition
of tumor growth were observed in EG7 tumor-bearing mice that received combined treatment with IL-10 and Lptn gene than those
of mice treated with IL-10 or Lptn gene alone. The highest NK cells and CTL activity was induced in the combined therapy group,
increasing the production of IL-2 and interferon-γ (IFN-γ) significantly but decreasing the expression of immune suppressive
cells (CD4+Foxp3+ Treg cells and Gr1+CD11b+ MDSCs). The necrosis of tumor cells was markedly observed in the tumor tissues, accompanying with strongest expression of
Mig (monokine induced by interferon-gamma) and IP-10 (interferon-inducible protein 10), weakest expression of vascular endothelial
growth factor (VEGF) and matrix metalloproteinases-2 (MMP-2). In vivo, depletion analysis demonstrated that CD8+ T cells and NK cells were the predominant effector cell subset responsible for the antitumor effect of IL-10 or Lptn gene.
These findings may provide a potential strategy to improve the antitumor efficacy of IL-10 and Lptn. 相似文献
7.
Hollie J. Pegram Nicole M. Haynes Mark J. Smyth Michael H. Kershaw Phillip K. Darcy 《Cancer immunology, immunotherapy : CII》2010,59(8):1235-1246
Natural killer (NK) cells represent a promising cell type to utilize for effective adoptive immunotherapy. However, little
is known about the important cytolytic molecules and signaling pathways used by NK cells in the adoptive transfer setting.
To address this issue, we developed a novel mouse model to investigate the trafficking and mechanism of action of these cells.
We demonstrate that methylcholanthrene-induced RKIK sarcoma cells were susceptible to NK cell-mediated lysis in vitro and
in vivo following adoptive transfer of NK cells in C57BL/6 RAG-2−/−γc−/− mice. Cytotoxic molecules perforin, granzymes B and M as well as the death ligand TRAIL and pro-inflammatory cytokine IFN-γ
were found to be important in the anti-tumor effect mediated by adoptively transferred NK cells. Importantly, we demonstrate
that adoptively transferred NK cells could traffic to the tumor site and persisted in vivo which correlated with the anti-tumor
effect observed. Overall, the results of this study have important implications for enhancing NK cell-based immunotherapies. 相似文献
8.
Maitake D-Fraction is a polysaccharide extracted from the maitake mushroom (Grifola frondosa S.F. Gray). It is a β-glucan with a β-1,6 main chain with β-1,3 branches. Using normal C3H/Hej mice, its effects on the natural
immune system, including macrophages, dendritic cells, and natural killer (NK) cells, were investigated. NK cells attack cells
infected with pathogens such as bacteria and virus and produce cytokines, such as interferon-gamma (IFN-γ), that can modulate
natural and specific immune responses. D-Fraction was administered to the mice intraperitoneally for 3 consecutive days; spleen
cells containing macrophages and dendritic cells were then cultured and the culture supernatants were analyzed for IL-12.
At the same time, IFN-γ expression in splenic NK cells was investigated. The levels of these cytokines were increased by D-Fraction.
To elucidate NK cell activation by D-Fraction, CD69 expression on the surface of activated NK cells was examined, resulting
in an increase in CD69-positive ratio for splenic NK cells. These results indicate that D-Fraction stimulates the natural
immunity related to the activation of NK cells indirectly through IL-12 produced by macrophages and dendritic cells. Therefore,
administration of D-Fraction to healthy individuals may serve to prevent infection.
Received: August 1, 2002 / Accepted: February 10, 2003 相似文献
9.
Cornforth AN Fowler AW Carbonell DJ Dillman RO 《Cancer immunology, immunotherapy : CII》2011,60(1):123-131
The use of whole cell tumor vaccines and various means of loading antigen onto dendritic cells have been under investigation
for over a decade. Induction of apoptosis and the exposure of immune-stimulating proteins are thought to be beneficial for
the use in immunotherapy protocols, but conclusive evidence in the clinical setting has been lacking. Incubation of melanoma
cell lines with interferon-gamma (IFN-γ) increased phosphatidylserine and calreticulin exposure, but not in the IFN-γ-resistant
cell line Lu-1205. Short-term autologous melanoma cell lines used for loading dendritic cells for immunotherapy showed differential
response to the pro-apoptotic effects of IFN-γ. These IFN-γ-treated tumor cells (TCs) were irradiated and used for loading
antigen for dendritic cell therapy. A log-rank comparison of survival for patients whose TCs were found to be either sensitive
(upregulated phosphatidylserine and calreticulin) or insensitive to IFN-γ revealed a strongly significant correlation to progression-free
(p = 0.003) and overall survival (p = 0.002) favorably in those patients whose cell lines were resistant to the proapoptotic effect of IFN-γ. These results suggest
that the use of IFN-γ in anti-melanoma dendritic cell-based immunotherapy may only be beneficial when the cells do not undergo
apoptosis in response to IFN-γ and support the contention that the use of some apoptotic cells in vaccines may be detrimental. 相似文献
10.
Martinson JA Roman-Gonzalez A Tenorio AR Montoya CJ Gichinga CN Rugeles MT Tomai M Krieg AM Ghanekar S Baum LL Landay AL 《Cellular immunology》2007,250(1-2):75-84
We compared TLR responsiveness in PBMC from HIV-1-infected and uninfected individuals using the TLR agonists: TLR7 (3M-001), TLR8 (3M-002), and TLR7/8 (3M-011). Activation and maturation of plasmacytoid dendritic cells (pDC) were measured by evaluating CD86, CD40, and CD83 expression and myeloid dendritic cell (mDC) activation was measured by evaluating CD40 expression. All agonists tested induced activation and maturation of pDC in PBMC cultures of cells from HIV+ and HIV- individuals. The TLR7 agonist induced significantly less pDC maturation in cells from HIV+ individuals. Quantitative assessment of secreted IFN-alpha and pro-inflammatory cytokines at the single cell level showed that pDC from HIV+ individuals stimulated with TLR7 and TLR7/8 induced IFN-alpha. TLR8 and TLR7/8 agonists induced IL-12 and COX-2 expression in mDC from HIV+ and HIV- individuals. Understanding pDC and mDC activation and maturation in HIV-1 infection could lead to more rational development of immunotherapeutic strategies to stimulate the adaptive immune response to HIV-1. 相似文献
11.
Castro-Matteotti B Vera-Cabrera L Ocampo-Candiani J Rendón A Salinas-Carmona MC Welsh O 《Mycopathologia》2008,165(3):127-134
The ability of culture-filtrate proteins to induce a cellular immune response in infected mice and humans was investigated.
A crude extract culture filtrate of Nocardia brasiliensis (CFA) and five semi-purified CFA fractions (P1, P2, P3, P4, P5) were used to stimulate BALB/c mice spleen-cell cultures.
The animals were divided into three groups: the first group was infected with 1 × 107 CFU of N. brasiliensis in the footpad, the second group was immunized with heat-killed bacteria, and the third was injected with sterile saline.
IFN-γ, IL-1α, and IL-4 concentrations were determined in culture supernatants. Protein fractions eliciting IFN-γ production
in mice, as well as the CFA, were used to stimulate IFN-γ production and in vitro cell proliferation assays with peripheral
blood mononuclear cells of patients with actinomycetoma by N. brasiliensis, individuals with pulmonary tuberculosis, and healthy controls. In mice, CFA and three of the protein fractions (P3, P4 and
P5) induced significant IFN-γ production in the infected group. In humans, only the CFA-induced IFN-γ production and cell
proliferation in the group of patients with actinomycetoma. There was no stimulation in tuberculosis patients nor healthy
controls. These results suggest that some culture-filtrate antigens are recognized by patients with active actinomycetoma
and do not cross-react with M. tuberculosis antigens, being therefore potential candidates to develop a diagnostic test. 相似文献
12.
Commercially available DOTAP is a racemic mixture of two enantiomers. The adjuvanticity of each isomer was examined using
a peptide/lipid complex as a therapeutic vaccine in an established murine cervical cancer model. This simple vaccine consists
of a cationic lipid (DOTAP) and a major histocompatibility complex (MHC) class I–restricted epitope of the Human Papillomavirus
(HPV) 16 protein E7. Dose-dependent tumor regression experiments have been completed for racemic DOTAP/E7, (R)-DOTAP/E7 and
(S)-DOTAP/E7. Tumor-bearing mice treated with (R)-DOTAP/E7 complexes have shown tumor regression in a dose-dependent manner
comparable to those mice treated with a racemic DOTAP with E7 peptide. These data are supported by IFN-γ production by CD8+ splenocytes, in vivo cytotoxic T-lymphocytes (CTL) response, CD8+ tumor-infiltrating lymphocytes (TIL), and IFN-γ production by CD8+ TIL in (R)-DOTAP/E7-vaccinated mice. When (S)-DOTAP/E7 is delivered, tumor progression is delayed. While IFN-γ production
is absent from CD8+ splenocytes in mice vaccinated with (S)-DOTAP/E7, IFN-γ production by CD8+ TIL is present, supporting our hypothesis that (S)-DOTAP has limited activity. Activation of bone marrow-derived dendritic
cells by the enantiomeric formulations has also been evaluated, as well as cytokine production and toxicity with no considerable
differences between the groups. The results show the DOTAP enantiomers act differently as adjuvants in vivo, with (R)-DOTAP
being more effective at stimulating a CD8+ anti-tumor response. 相似文献
13.
Promoting effect of Antrodia camphorata as an immunomodulating adjuvant on the antitumor efficacy of HER-2/neu DNA vaccine 总被引:1,自引:0,他引:1
Chia-Hsin Huang Chia-Che Chang Chiu-Mei Lin Sin-Ting Wang Min-Tze Wu Eric I. C. Li Hsien-Chang Chang Chi-Chen Lin 《Cancer immunology, immunotherapy : CII》2010,59(8):1259-1272
It is well known that DNA vaccines induce protective humoral and cell-mediated immune responses in several animal models.
Antrodia camphorata (AC) is a unique basidiomycete fungus of the Polyporaceae family that only grows on the aromatic tree Cinnamomum kanehirai Hayata (Lauraceae) endemic to Taiwan. Importantly, AC has been shown to be highly beneficial in the treatment and prevention of cancer. The
goal of this study was to investigate whether AC is able to augment the antitumor immune properties of a HER-2/neu DNA vaccine
in a mouse model in which p185neu is overexpressed in MBT-2 tumor cells. Compared with the mice that received the HER-2/neu
DNA vaccine alone, co-treatment with AC suppressed tumor growth and extended the survival rate. This increase in the antitumor
efficacy was attributed to the enhancement of the Th1-like cellular immune response by the HER-2/neu DNA vaccine–AC combination.
Evidence for this came from the marked increase in the IFN-γ mRNA expression in CD4+ T cells in the draining inguinal lymph nodes, an increase in the number of functional HER-2/neu-specific CTLs, and the increased
tumor infiltration of both CD4+ and CD8+ T cells, depletion of which abolishes the antitumor effect of the HER-2/neu DNA vaccine–AC therapy. Our results further indicate
that the treatment of mice with AC enhanced DC activation and production of Th1-activating cytokines (e.g. IL-12, and IFN-α)
in the draining lymph nodes, which were sufficient to directly stimulate T cell proliferation and higher IFN-γ production
in response to ErbB2. Overall, these results clearly demonstrate that AC represents a promising immunomodulatory adjuvant
that could enhance the therapeutic potency of HER-2/neu DNA vaccines in cancer therapy. 相似文献
14.
Mukesh Kumar Xiaoyuan Kong Aruna K Behera Gary R Hellermann Richard F Lockey Shyam S Mohapatra 《Genetic vaccines and therapy》2003,1(1):3
Background
Allergic subjects produce relatively low amounts of IFN-γ, a pleiotropic Th-1 cytokine that downregulates Th2-associated airway inflammation and hyperresponsiveness (AHR), the hallmarks of allergic asthma. Adenovirus-mediated IFN-γ gene transfer reduces AHR, Th2 cytokine levels and lung inflammation in mice, but its use would be limited by the frequency of gene delivery required; therefore, we tested chitosan/IFN-γ pDNA nanoparticles (CIN) for in situ production of IFN-γ and its in vivo effects. 相似文献15.
Walid Abushahba Murugabaskar Balan Ismael Castaneda Yao Yuan Kenneth Reuhl Elizabeth Raveche Andrew de la Torre Ahmed Lasfar Sergei V. Kotenko 《Cancer immunology, immunotherapy : CII》2010,59(7):1059-1071
Hepatocellular carcinoma (HCC) occurs most commonly secondary to cirrhosis due to chronic hepatitis C or B virus (HCV/HBV)
infections. Type I interferon (IFN-α) treatment of chronic HCV/HBV infections reduces the incidence of HCC in cirrhotic patients.
However, IFN-α toxicity limits its tolerability and efficacy highlighting a need for better therapeutic treatments. A recently
discovered type III IFN (IFN-λ) has been shown to possess antiviral properties against HCV and HBV in vitro. In phase I clinical
trials, IFN-λ treatment did not cause significant adverse reactions. Using a gene therapy approach, we compared the antitumor
properties of IFN-α and IFN-λ in a transplantable hepatoma model of HCC. BALB/c mice were inoculated with syngeneic BNL hepatoma
cells, or BNL cells expressing IFN-λ (BNL.IFN-λ cells) or IFN-α (BNL.IFN-α cells). Despite the lack of antiproliferative activity
of IFNs on BNL cells, both BNL.IFN-λ and BNL.IFN-α cells displayed retarded growth kinetics in vivo. Depletion of NK cells
from splenocytes inhibited splenocyte-mediated cytotoxicity, demonstrating that NK cells play a role in IFN-induced antitumor
responses. However, isolated NK cells did not respond directly to IFN-λ. There was also a marked NK cell infiltration in IFN-λ
producing tumors. In addition, IFN-λ and, to a lesser extent, IFN-α enhanced immunocytotoxicity of splenocytes primed with
irradiated BNL cells. Splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN-γ, and mediated by dendritic
cells. In contrast to NK cells, isolated from spleen CD11c+ and mPDCA+ dendritic cells responded directly to IFN-λ. The antitumor
activities of IFN-λ against hepatoma, in combination with HCV and HBV antiviral activities warrant further investigation into
the clinical use of IFN-λ to prevent HCC in HCV/HBV-infected cirrhotic patients, as well as to treat liver cancer. 相似文献
16.
To determine whether interferon gamma (IFN-γ) can be used as a biomarker of exposure to viral pathogens, 12-week-old BALB/c
mice were injected intraperitoneally with coxsackievirus B3 (CVB3) or coxsackievirus B4 (CVB4) diluted in sterilized phosphate-buffered
saline (PBS). Control mice were injected with PBS only. Four months after viral infection, mouse spleen cells were harvested
and assayed for the release of IFN-γ by memory T cells after in vitro stimulation with viral antigens, phytohemagglutinin (PHA), and PBS, respectively. The level of IFN-γ was examined by an antibody-capture
enzyme-linked immunosorbent assay (ELISA). A marked increase in the level of IFN-γ was observed when memory T cells from CVB3-infected
mice were incubated with CVB3 virus, but not with CVB4 or PBS. Conversely, memory T cells from mice infected by CVB4 were
not stimulated to produce IFN-γ when they were incubated with CVB3 and PBS, but did significantly produce IFN-γ when stimulated
with CVB4. T cells from mice injected with PBS did not release IFN-γ after stimulation with CVB3 or CVB4. However, these T
cells did release IFN-γ after stimulation with PHA. Our results demonstrated that IFN-γ produced by memory T cells is virus-specific
and may have use as a biomarker in viral exposure studies. The results of this study may be extended to the study of infection
by pathogens that are capable of inducing cell-mediated immune response in humans.
Disclaimer: The United States Environmental Protection Agency through its Office of Research and Development funded and managed the
research described here. It has been subjected to Agency’s administrative review and approved for publication. 相似文献
17.
Codolo G Fassan M Munari F Volpe A Bassi P Rugge M Pagano F D'Elios MM de Bernard M 《Cancer immunology, immunotherapy : CII》2012,61(1):31-40
Intravesical Bacillus Calmette–Guérin (BCG) is the gold standard treatment for intermediate and high-risk non-muscle-invasive
bladder cancer. BCG therapy is the most successful example of immunotherapy in cancer. Unfortunately, the treatment-related
side effects are still relevant. Furthermore, non-responder patients are candidate to radical cystectomy in the absence of
valuable alternative options. These aspects have prompted the search for newer biological response modifiers (BRM) with a
better benefit/side effects ratio. The toll-like receptor (TLR) 2 ligand, Helicobacter pylori protein HP-NAP, has been shown to deserve a potential role as BRM. HP-NAP is capable of driving the differentiation of T
helper (Th) 1 cells, both in vitro and in vivo, because of its ability to create an IL-12-enriched milieu. Herein, we report
that local administration of HP-NAP decreases tumour growth by triggering tumour necrosis in a mouse model of bladder cancer
implant. The effect is accompanied by a significant accumulation of both CD4+ and CD8+ IFN-γ-secreting cells, within tumour and regional lymph nodes. Noteworthy, HP-NAP-treated tumours show also a reduced vascularization
due to the anti-angiogenic activity of IFN-γ induced by HP-NAP. Our findings strongly indicate that HP-NAP might become a
novel therapeutic “bullet” for the cure of bladder tumours. 相似文献
18.
Production of interferons and change of the lymphocyte subpopulation phenotype in peripheral blood at cervical papillomavirus infection 总被引:3,自引:0,他引:3
Lazarenko L Spivak M Lakatosh V Kryvokhatska L Mikhailenko O Rudenko A Tkáciková L Mikula I 《Folia microbiologica》2002,47(6):747-752
IFN-γ and IFN-α productionin vitro by peripheral blood cells activated by phytohemagglutinin or the Newcastle disease virus was impaired in patients with a
benign process, cervical intraepithelial neoplasm and cancerin situ associated with human papillomavirus infection. In case of IFN-γ and IFN-α production impairment following cervical papillomavirus
infection, the increased severity of disease was accompanied by remarkable IFN system suppression. The lower synthesis of
both IFN correlated with changes of some lymphocyte-subpopulation phenotype in peripheral blood. Lower CD4+ and CD3+ DR+ T cell concentrations were observed in papillomavirus-infected patients with impaired IFN production; impaired IFN-γ production
was accompanied by lower CD4/CD8 index. 相似文献
19.
Evelien L. J. M. Smits Nathalie Cools Eva Lion Kirsten Van Camp Peter Ponsaerts Zwi N. Berneman Viggo F. I. Van Tendeloo 《Cancer immunology, immunotherapy : CII》2010,59(1):35-46
Immunotherapy for leukemia is a promising targeted strategy to eradicate residual leukemic cells after standard therapy, in order to prevent relapse and to prolong the survival of leukemia patients. However, effective anti-leukemia immune responses are hampered by the weak immunogenicity of leukemic cells. Therefore, much effort is made to identify agents that could increase the immunogenicity of leukemic cells and activate the immune system. Synthetic agonists of Toll-like receptor (TLR)7 and TLR8 are already in use as anticancer treatment, because of their ability to activate several immune pathways simultaneously, resulting in effective antitumor immunity. However, for leukemic cells little is known about the expression of TLR7/8 and the direct effects of their agonists. We hypothesized that TLR7/8 agonist treatment of human acute myeloid leukemia (AML) cells would lead to an increased immunogenicity of AML cells. We observed expression of TLR7 and TLR8 in primary human AML cells and AML cell lines. Passive pulsing of primary AML cells with the TLR7/8 agonist R-848 resulted in increased expression of MHC molecules, production of proinflammatory cytokines, and enhanced allogeneic naïve T cell-stimulatory capacity. These effects were absent or suboptimal if R-848 was administered intracellularly by electroporation. Furthermore, when AML cells were cocultured with allogeneic PBMC in the presence of R-848, interferon (IFN)-γ was produced by allogeneic NK and NKT cells and AML cells were killed. In conclusion, the immunostimulatory effect of the TLR7/8 agonist R-848 on human AML cells could prove useful for the design of TLR-based immunotherapy for leukemia. 相似文献
20.
Asahi Ito Takashi Ishida Hiroki Yano Atsushi Inagaki Susumu Suzuki Fumihiko Sato Hisashi Takino Fumiko Mori Masaki Ri Shigeru Kusumoto Hirokazu Komatsu Shinsuke Iida Hiroshi Inagaki Ryuzo Ueda 《Cancer immunology, immunotherapy : CII》2009,58(8):1195-1206
Purpose There are no suitable small animal models to evaluate human antibody-dependent cellular cytotoxicity (ADCC) in vivo, due to
species incompatibilities. Thus, the first aim of this study was to establish a human tumor-bearing mouse model in which human
immune cells can engraft and mediate ADCC, but where the endogenous mouse immune cells cannot mediate ADCC. The second aim
was to evaluate ADCC mediated in these humanized mice by the defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal
antibody (mAb) which we have developed and which is now in phase I clinical trials.
Experimental design NOD/Shi-scid, IL-2Rγnull (NOG) mice were the recipients of human immune cells, and CCR4-expressing Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma
(CTCL) cell lines were used as target tumors.
Results Humanized mice have been established using NOG mice. The chimeric defucosylated anti-CCR4 mAb KM2760 showed potent antitumor
activity mediated by robust ADCC in these humanized mice bearing the HL or CTCL cell lines. KM2760 significantly increased
the number of tumor-infiltrating CD56-positive NK cells which mediate ADCC, and reduced the number of tumor-infiltrating FOXP3-positive
regulatory T (Treg) cells in HL-bearing humanized mice.
Conclusions Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill CCR4-expressing tumor
cells, but also to overcome the suppressive effect of Treg cells on the host immune response to tumor cells. In addition,
using our humanized mice, we can perform the appropriate preclinical evaluation of many types of antibody based immunotherapy. 相似文献