15 results
Search Results
2. Correction to: Mast cell proliferation in the cerebrospinal fluid after intraventricular administration of anti‑B7H3 immunotherapy.
- Author
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Kramer, Kim, Donzelli, Maria A., and Pessin, Melissa S.
- Subjects
- *
CEREBROSPINAL fluid , *MAST cells , *CELL proliferation , *IMMUNOTHERAPY - Abstract
A correction to this paper has been published: https://doi.org/10.1007/s00262-021-02942-3 [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
3. Cryptotanshinone has curative dual anti-proliferative and immunotherapeutic effects on mouse Lewis lung carcinoma
- Author
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Joost J. Oppenheim, Hongsheng Lin, Sean Hannifin, Shuo Liu, Zhen Han, De Yang, and Anna L. Trivett
- Subjects
CD4-Positive T-Lymphocytes ,Cancer Research ,Immunology ,Cryptotanshinone ,CD8-Positive T-Lymphocytes ,Salvia miltiorrhiza ,Cell-cycle arrest ,B7-H1 Antigen ,Carcinoma, Lewis Lung ,Mice ,Downregulation and upregulation ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,Lung cancer ,Cell Proliferation ,A549 cell ,business.industry ,Lewis lung carcinoma ,Dendritic Cells ,Phenanthrenes ,medicine.disease ,In vitro ,Cancer therapeutic ,Mice, Inbred C57BL ,Treatment Outcome ,Oncology ,A549 Cells ,Cancer research ,Tumor necrosis factor alpha ,Original Article ,Female ,Immunotherapy ,business - Abstract
Lung cancer is currently the leading cause of cancer-related mortality with very limited effective therapy. Screening of a variety of traditional Chinese medicines (TCMs) for their capacity to inhibit the proliferation of human lung cancer A549 cells and to induce the in vitro maturation of human DCs led to the identification of cryptotanshinone (CT), a compound purified from the TCM Salvia miltiorrhiza Bunge. Here, CT was shown to inhibit the proliferation of mouse Lewis lung carcinoma (LLC) cells by upregulating p53, downregulating cyclin B1 and Cdc2, and, consequently, inducing G2/M cell-cycle arrest of LLC cells. In addition, CT promoted maturation of mouse and human DCs with upregulation of costimulatory and MHC molecules and stimulated DCs to produce TNFα, IL-1β, and IL-12p70, but not IL-10 in vitro. CT-induced maturation of DCs depended on MyD88 and also involved the activation of NF-κB, p38, and JNK. CT was effective in the treatment of LLC tumors and, when used in combination with low doses of anti-PD-L1, cured LLC-bearing mice with the induction of subsequent anti-LLC long-term specific immunity. CT treatment promoted T-cell infiltration and elevated the expression of genes typical of Th1 polarization in LLC tumor tissue. The therapeutic effect of CT and low doses of anti-PD-L1 was reduced by depletion of CD4 and CD8 T cells. This paper provides the first report that CT induces immunological antitumor activities and may provide a new promising antitumor immunotherapeutic. Electronic supplementary material The online version of this article (10.1007/s00262-019-02326-8) contains supplementary material, which is available to authorized users.
- Published
- 2019
4. Recombinant IgE antibody engineering to target EGFR.
- Author
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Spillner, Edzard, Plum, Melanie, Blank, Simon, Miehe, Michaela, Singer, Josef, and Braren, Ingke
- Subjects
IMMUNOGLOBULIN E ,RECOMBINANT antibodies ,EPIDERMAL growth factor receptors ,TARGETED drug delivery ,MONOCLONAL antibodies ,IMMUNOTECHNOLOGY ,CELL-mediated cytotoxicity ,CELL proliferation - Abstract
Monoclonal antibodies have become a mainstay for the targeted treatment of cancer today. Some of the most successful targets of monoclonal antibodies are constituted by the epidermal growth factor receptor family spearheaded by the epidermal growth factor receptor (EGFR). Prompted by studies indicating that IgE compared to IgG may harness alternate effector functions to eradicate malignant cells, we addressed the establishment, engineering, and the potential tumoricidal effects of recombinant anti-EGFR IgE. Therefore, two different therapeutic EGFR-specific antibodies, 225 and 425, were chosen for re-cloning into different chimeric IgE and IgG formats and produced in human cells. Simultaneous antibody binding to the sEGFR demonstrated accessibility of both epitopes for recombinant IgE. Proliferation and cytotoxicity assays demonstrated signal blocking and effector mediating capability of IgE isotypes. Pronounced degranulation in the presence of sEGFR upon activation exclusively with two IgE antibodies verified the epitope proximity and provides evidence that tumor-targeting by anti-EGFR IgE is safe with regard to soluble target structures. Degranulation mediated by tumor cells expressing EGFR could be demonstrated for singular and combined IgE antibodies; however, use of two IgE specificities was not superior to use of one IgE alone. The data suggest that the surface distribution of EGFR is optimally suited to mount a robust effector cell trigger and corroborate the potential and specificity of the IgE/IgE receptor network to react to xenobiotic or pathogenic patterns for targeting malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
5. Long-term proliferation of functional human NK cells, with conversion of CD56 NK cells to a CD56 phenotype, induced by carcinoma cells co-expressing 4-1BBL and IL-12.
- Author
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Dowell, Alexander, Oldham, Kimberley, Bhatt, Rupesh, Lee, Steven, and Searle, Peter
- Subjects
OVARIAN cancer treatment ,CELL proliferation ,CANCER cells ,GENE expression ,KILLER cells ,IMMUNOGLOBULINS ,LABORATORY mice - Abstract
4-1BB ligation co-stimulates T cell activation, and agonistic antibodies have entered clinical trials. Natural killer (NK) cells also express 4-1BB following activation and are implicated in the anti-tumour efficacy of 4-1BB stimulation in mice; however, the response of human NK cells to 4-1BB stimulation is not clearly defined. Stimulation of non-adherent PBMC with OVCAR-3 cells expressing 4-1BB ligand (4-1BBL) or IL-12 resulted in preferential expansion of the NK cell population, while the combination 4-1BBL + IL-12 was superior for the activation and proliferation of functional NK cells from healthy donors and patients with renal cell or ovarian carcinoma, supporting long-term (21 day) NK cell proliferation. The expanded NK cells are predominantly CD56, and we show that isolated CD56CD16 NK cells can switch to a CD56CD16 phenotype and proliferate in response to 4-1BBL + IL-12. Whereas 4-1BB upregulation on NK cells in response to 4-1BBL required 'help' from other PBMC, it could be induced on isolated NK cells by IL-12, but only in the presence of target (OVCAR-3) cells. Following primary stimulation with OVCAR-3 cells expressing 4-1BBL + IL-12 and subsequent resting until day 21, NK cells remained predominantly CD56 and retained both high cytotoxic capability against K562 targets and enhanced ability to produce IFNγ relative to NK cells in PBMC. These data support the concept that NK cells could contribute to anti-tumour activity of 4-1BB agonists in humans and suggest that combining 4-1BB-stimulation with IL-12 could be beneficial for ex vivo or in vivo expansion and activation of NK cells for cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
6. MHC-based detection of antigen-specific CD8+ T cell responses.
- Author
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Hadrup, Sine Reker and Schumacher, Ton N.
- Subjects
IMMUNITY ,ANTIGENS ,T cells ,CYTOLOGY ,CELL proliferation - Abstract
The hallmark of adaptive immunity is its ability to recognise a wide range of antigens and technologies that capture this diversity are therefore of substantial interest. New methods have recently been developed that allow the parallel analysis of T cell reactivity against vast numbers of different epitopes in limited biological material. These technologies are based on the joint binding of differentially labelled MHC multimers on the T cell surface, thereby providing each antigen-specific T cell population with a unique multicolour code. This strategy of ‘combinatorial encoding’ enables detection of many (at least 25) different T cell populations per sample and should be of broad value for both T cell epitope identification and immunomonitoring. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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7. Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice.
- Author
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Carrio, Roberto, Altman, Norman H., and Lopez, Diana M.
- Subjects
CARCINOGENESIS ,T cell differentiation ,TUMOR growth ,VASCULAR endothelial growth factors ,CELL proliferation - Abstract
During mammary tumorigenesis, there is a profound thymic involution associated with severe depletion of the most abundant subset of thymocytes, CD4
+ CD8+ immature cells, and an early arrest in at least two steps of T cell differentiation. Thymic atrophy that is normally related with aging has been observed in other model systems, including graft-vs-host disease (GVHD) and tumor development. However, the mechanisms involved in this phenomenon remain to be elucidated. Vascular endothelial growth factor (VEGF) has been associated with thymic involution, when expressed at high levels systemically. In thymuses of D1-DMBA-3 tumor-bearing mice, this growth factor is diminished relative to the level of normal thymuses. Interestingly, the expression of hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesis and B-cell differentiation, is profoundly down-regulated in thymuses of tumor bearers. In parallel, IL-7 and IL-15 mRNA, crucial cytokines involved in thymocytes development and cellular homeostasis, respectively, are also down-regulated in the thymuses of tumor hosts as compared to those of normal mice. Injection of HGF into mice implanted with mammary tumors resulted in normalization of thymic volume and levels of VEGF, IL-7 and IL-15. While, injections of IL-7 partially restored the thymic involution observed in the thymuses of tumor-bearing mice, injection of IL-15 did not have any significant effects. Our data suggest that the downregulation of HGF and IL-7 may play an important role in the thymic involution observed in tumor-bearing hosts. [ABSTRACT FROM AUTHOR]- Published
- 2009
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8. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells.
- Author
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Galustian, Christine, Meyer, Brendan, Labarthe, Marie-Christine, Dredge, Keith, Klaschka, Deborah, Henry, Jake, Todryk, Stephen, Chen, Roger, Muller, George, Stirling, David, Schafer, Peter, Bartlett, J. Blake, and Dalgleish, Angus G.
- Subjects
T cells ,CELL proliferation ,CELL growth ,MULTIPLE myeloma ,LYMPHOCYTES - Abstract
Lenalidomide (Revlimid
® ; CC-5013) and pomalidomide (CC-4047) are IMiDs® proprietary drugs having immunomodulatory properties that have both shown activity in cancer clinical trials; lenalidomide is approved in the United States for a subset of MDS patients and for treatment of patients with multiple myeloma when used in combination with dexamethasone. These drugs exhibit a range of interesting clinical properties, including anti-angiogenic, anti-proliferative, and pro-erythropoietic activities although exact cellular target(s) remain unclear. Also, anti-inflammatory effects on LPS-stimulated monocytes (TNF-α is decreased) and costimulatory effects on anti-CD3 stimulated T cells, (enhanced T cell proliferation and proinflammatory cytokine production) are observed These drugs also cause augmentation of NK-cell cytotoxic activity against tumour-cell targets. Having shown that pomalidomide confers T cell-dependant adjuvant-like protection in a preclinical whole tumour-cell vaccine-model, we now show that lenalidomide and pomalidomide strongly inhibit T-regulatory cell proliferation and suppressor-function. Both drugs inhibit IL-2-mediated generation of FOXP3 positive CTLA-4 positive CD25high CD4+ T regulatory cells from PBMCs by upto 50%. Furthermore, suppressor function of pre-treated T regulatory cells against autologous responder-cells is abolished or markedly inhibited without drug related cytotoxicity. Also, Balb/C mice exhibit 25% reduction of lymph-node T regulatory cells after pomalidomide treatment. Inhibition of T regulatory cell function was not due to changes in TGF-β or IL-10 production but was associated with decreased T regulatory cell FOXP3 expression. In conclusion, our data provide one explanation for adjuvant properties of lenalidomide and pomalidomide and suggest that they may help overcome an important barrier to tumour-specific immunity in cancer patients. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
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9. Efficient inhibition of EGFR signalling and of tumour growth by antagonistic anti-EGFR Nanobodies.
- Author
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Roovers, Rob, Laeremans, Toon, Huang, Lieven, Taeye, Severine, Verkleij, Arie, Revets, Hilde, Haard, Hans, and Bergen en Henegouwen, Paul M.
- Subjects
EPIDERMAL growth factor ,TUMOR growth ,PROTEIN-tyrosine kinases ,CELL proliferation ,T cell receptors ,DRUG therapy ,ANTIGEN-antibody reactions - Abstract
The development of a number of different solid tumours is associated with over-expression of ErbB1, or the epidermal growth factor receptor (EGFR), and this over-expression is often correlated with poor prognosis of patients. Therefore, this receptor tyrosine kinase is considered to be an attractive target for antibody-based therapy. Indeed, antibodies to the EGFR have already proven their value for the treatment of several solid tumours, especially in combination with chemotherapeutic treatment regimens. Variable domains of camelid heavy chain-only antibodies (called Nanobodies
™ ) have superior properties compared with classical antibodies in that they are small, very stable, easy to produce in large quantities and easy to re-format into multi-valent or multi-specific proteins. Furthermore, they can specifically be selected for a desired function by phage antibody display. In this report, we describe the successful selection and the characterisation of antagonistic anti-EGFR Nanobodies. By using a functional selection strategy, Nanobodies that specifically competed for EGF binding to the EGFR were isolated from ‘immune’ phage Nanobody repertoires. The selected antibody fragments were found to efficiently inhibit EGF binding to the EGFR without acting as receptor agonists themselves. In addition, they blocked EGF-mediated signalling and EGF-induced cell proliferation. In an in vivo murine xenograft model, the Nanobodies were effective in delaying the outgrowth of A431-derived solid tumours. This is the first report describing the successful use of untagged Nanobodies for the in vivo treatment of solid tumours. The results show that functional phage antibody selection, coupled to the rational design of Nanobodies, permits the rapid development of novel anti-cancer antibody-based therapeutics. [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
- View/download PDF
10. Synergy between interleukin-2 and prothymosin α for the increased generation of cytotoxic T lymphocytes against autologous human carcinomas.
- Author
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Voutsas, Ioannis F., Baxevanis, Constantin N., Gritzapis, Angelos D., Missitzis, Ioannis, Stathopoulos, George P., Archodakis, George, Banis, Constantin, Voelter, Wolfgang, and Papamichail, Michael
- Subjects
INTERLEUKIN-2 ,CANCER ,T cells ,ANTINEOPLASTIC antibiotics ,MONOCLONAL antibodies ,IMMUNOGLOBULINS ,CELL proliferation - Abstract
Peripheral blood mononuclear cells (PBMC) from cancer patients were cultured in vitro with irradiated autologous tumor cells isolated from malignant effusions (mixed lymphocyte tumor cultures, MLTC) and low-dose (50 IU/ml) recombinant interleukin-2 (IL-2). The combination of IL-2 and prothymosin α (ProTα) resulted in a greater PBMC-induced response to the autologous tumor than that brought about by IL-2 alone. In particular, ProTα specifically enhanced the CD4
+ T-cell-mediated proliferation against the autologous tumor. CD4+ T cells seemed to recognize tumor antigens presented by HLA-DR molecules expressed on the autologous monocytes, since preincubation of the latter with an anti-HLA-DR monoclonal antibody (mAb) abrogated the response. In addition, MLTC set up with IL-2 and ProTα also generated more MHC-class-I-restricted cytotoxic T lymphocytes (CTL) against the autologous tumor than did MLTC set up with IL-2 alone. The MLTC-induced CTL contained high levels of cytoplasmic perforin and their development was strictly dependent on the presence of both autologous CD4+ T cells and monocytes. In the absence of either population there was a strong impairment of both proliferative and cytotoxic responses which was not restored by the presence of ProTα. In contrast, when both cell populations were present, ProTα exerted optimal enhancement of CD4+ T cell proliferation, which was associated with potentiated CTL responses. Our data emphasize the role of ProTα for the enhancement of IL-2-induced CTL responses against autologous tumor cells. Such responses require collaborative interactions between CD4+ , CD8+ T cells and monocytes as antigen-presenting cells. Our data are relevant for adoptive immunotherapeutic settings utilizing IL-2 and ProTα-induced autologous-tumor-specific CTL. [ABSTRACT FROM AUTHOR]- Published
- 2000
- Full Text
- View/download PDF
11. Antigen-presenting cells containing multiple costimulatory molecules promote activation and expansion of human antigen-specific memory CD8+ T cells
- Author
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Yang, Sixun and Schlom, Jeffrey
- Published
- 2009
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12. The immunologically active site of prothymosin α is located at the carboxy-terminus of the polypeptide. Evaluation of its in vitro effects in cancer patients
- Author
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Skopeliti, Margarita, Voutsas, Ioannis F., Klimentzou, Persefoni, Tsiatas, Marinos L., Beck, Alexander, Bamias, Aristotelis, Moraki, Maria, Livaniou, Evangelia, Neagu, Monica, Voelter, Wolfgang, and Tsitsilonis, Ourania E.
- Published
- 2006
- Full Text
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13. Effect of essential fatty acids on circulating T cell subsets in patients with colorectal cancer
- Author
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Purasiri, P., Ashby, J., Heys, S. D., and Eremin, O.
- Published
- 1994
- Full Text
- View/download PDF
14. Bioactivity and pharmacokinetics of two human serum albumin–thymosin α1-fusion proteins, rHSA-Tα1 and rHSA-L-Tα1, expressed in recombinant Pichia pastoris
- Author
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Jing Chen, Yi-Wei Yin, Luying Yan, Li Tang, Xin-Guo Zhang, Dai-Shuang Cheng, Jianhua Chen, Yu-tao Jiang, and Min Wang
- Subjects
Cancer Research ,Thymalfasin ,Recombinant Fusion Proteins ,T-Lymphocytes ,Immunology ,Serum albumin ,Apoptosis ,Protein Engineering ,Pichia ,Pichia pastoris ,Rats, Sprague-Dawley ,Fusion gene ,Mice ,Affinity chromatography ,T-Lymphocyte Subsets ,In vivo ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cells, Cultured ,Serum Albumin ,Cell Proliferation ,Aldehydes ,Mice, Inbred BALB C ,Mice, Inbred ICR ,biology ,Superoxide Dismutase ,Body Weight ,Human serum albumin ,biology.organism_classification ,Molecular biology ,Fusion protein ,In vitro ,Rats ,Thymosin ,Oncology ,Biochemistry ,biology.protein ,Female ,Immunization ,medicine.drug - Abstract
Thymosin-alpha1 (Talpha1) is indicated for the treatment of certain viral infections, including hepatitis B and C, and cancers, such as melanoma. In this paper, the fusion genes encoding human serum albumin (HSA) and Talpha1 with (rHSA-L-Talpha1) and without a linker peptide (rHSA-Talpha1) were constructed and overexpressed in P. pastoris. Through the process of ion interaction chromatography (Q-Sepharose F.F), hydrophobic interaction chromatography (Phenyl Sepharose HP) and affinity chromatography (Blue Sepharose F.F), the purity of fusion proteins was greater than 97%. In contrast to the reactivity of normal spleen cells to Con A, the data of in vitro murine spleen lymphocytes proliferation experiment suggested that spleen cells achieved a higher degree of T cell maturation after rHSA-L-Talpha1, rHSA-Talpha1 and Talpha1 treatments, respectively. Moreover, rHSA-L-Talpha1, rHSA-Talpha1 and Talpha1 can also antagonize dexamethasone-induced apoptosis of thymocyte sub-populations. In hydrocortisone-induced immunosuppression mice (in vivo experiments), after subcutaneous injections with two fusion proteins and Talpha1 for seven consecutive days, the net increment of body weight, the spleen index and the thymus index were significantly improved. Simultaneously, the increase in SOD level and the decrease in MDA level in plasma were observed. The pharmacokinetic data of rHSA-L-Talpha1 and rHSA-Talpha1 administered in rats showed an improved pharmacokinetic profile with a conspicuous prolonged half life. The analysis of bioactivity and pharmacokinetics suggested that fusion proteins rHSA-L-Talpha1 and rHSA-Talpha1 were new drug candidates.
- Published
- 2010
15. Inhibition of nuclear factor kappa B (NFκB) activity in oral tumor cells prevents depletion of NK cells and increases their functional activation
- Author
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Anahid Jewett, Marcela Romero, Meiying Wang, Marjan Rashedi, Antonia Teruel, Nicholas A. Cacalano, and Hiromi Nakamura
- Subjects
Antigens, Differentiation, T-Lymphocyte ,Cancer Research ,medicine.medical_specialty ,Cell Survival ,Immunology ,Biology ,Lymphocyte Activation ,CD49b ,Natural killer cell ,Interferon-gamma ,Interleukin 21 ,Antigens, CD ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Lectins, C-Type ,Antigen-presenting cell ,Laryngeal Neoplasms ,Cell Proliferation ,CD40 ,Lymphokine-activated killer cell ,Interleukin-6 ,Janus kinase 3 ,Gene Transfer Techniques ,NF-kappa B ,Coculture Techniques ,Up-Regulation ,Killer Cells, Natural ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Interleukin 12 ,biology.protein ,Cancer research ,I-kappa B Proteins ,Mouth Neoplasms ,Signal Transduction - Abstract
The aim of this study is to identify candidate factors which may be responsible for the functional inactivation and depletion of NK cells by tumor cells. Inhibition of NFkappaB activity by an IkappaB super-repressor in HEp2 cells, a cell line commonly used as an oral tumor model, blocked tumor-induced NK cell death, and increased the function of NK cells significantly. Increased expression of CD69 early activation antigen on NK cells as well as augmented proliferation and secretion of IFN-gamma by NK cells were observed when these cells were co-incubated with IkappaB super-repressor transfected HEp2 cells (HEp2-IkappaB((S32AS36A))). More importantly, the secretion of IL-6 was significantly inhibited when NK cells were co-cultured with HEp2-IkappaB((S32AS36A)) cells. In addition, the survival and function of cytotoxic effector cells remained significantly elevated in the presence of IFN-gamma-treated HEp2-IkappaB((S32AS36A)) cells when compared to either untreated or IFN-gamma-treated vector-alone transfected HEp2 cells. Similar findings to those obtained using purified peripheral blood NK cells were also observed when non-fractionated peripheral blood mononuclear cells were used in the co-cultures of immune effectors with HEp2 cell transfectants. Addition of recombinant human IL-6 to the co-cultures of immune effectors with the NFkappaB knockdown HEp2 tumor cells substantially decreased the levels of secreted IFN-gamma. Thus, the results presented in this paper suggest that the inhibition of NFkappaB function in oral tumors may serve to activate and expand the function and numbers of NK cells. Moreover, NFkappaB-mediated increase in IL-6 secretion by oral tumors may in part be responsible for the observed inactivation and death of the immune effectors.
- Published
- 2005
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