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Immunostimulatory Activities (immunostimulatory + activity)
Selected AbstractsThe C-terminus of viral vascular endothelial growth factor-E partially blocks binding to VEGF receptor-1FEBS JOURNAL, Issue 1 2008Marie K. Inder Vascular endothelial growth factor (VEGF) family members play important roles in embryonic development and angiogenesis during wound healing and in pathological conditions such as tumor formation. Parapoxviruses express a new member of the VEGF family which is a functional mitogen that specifically activates VEGF receptor (VEGFR)-2 but not VEGFR-1. In this study, we show that deletion from the viral VEGF of a unique C-terminal region increases both VEGFR-1 binding and VEGFR-1-mediated monocyte migration. Enzymatic removal of O -linked glycosylation from the C-terminus also increased VEGFR-1 binding and migration of THP-1 monocytes indicating that both the C-terminal residues and O -linked sugars contribute to blocking viral VEGF binding to VEGFR-1. The data suggest that conservation of the C-terminal residues throughout the viral VEGF subfamily may represent a means of reducing the immunostimulatory activities associated with VEGFR-1 activation while maintaining the ability to induce angiogenesis via VEGFR-2. [source] Modulation of dendritic cell maturation and function with mono- and bifunctional small interfering RNAs targeting indoleamine 2,3-dioxygenaseIMMUNOLOGY, Issue 1pt2 2009Gro F. Flatekval Summary Antigen-presenting cells expressing indoleamine 2,3-dioxygenase (IDO) play a critical role in maintaining peripheral tolerance. Strategies to inhibit IDO gene expression and enhance antigen-presenting cell function might improve anti-tumour immunity. Here we have designed highly effective anti-IDO small interfering (si) RNAs that function at low concentrations. When delivered to human primary immune cells such as monocytes and dendritic cells (DCs), they totally inhibited IDO gene expression without impairing DC maturation and function. Depending on the design and chemical modifications, we show that it is possible to design either monofunctional siRNAs devoid of immunostimulation or bifunctional siRNAs with gene silencing and immunostimulatory activities. The latter are able to knockdown IDO expression and induce cytokine production through either endosomal Toll-like receptor 7/8 or cytoplasmic retinoid acid-inducible gene 1 helicase. Inhibition of IDO expression with both classes of siRNAs inhibited DC immunosuppressive function on T-cell proliferation. Immature monocyte-derived DCs that had been transfected with siRNA-bearing 5,-triphosphate activated T cells, indicating that, even in the absence of external stimuli such as tumour necrosis factor-,, those DCs were sufficiently mature to initiate T-cell activation. Collectively, our data highlight the potential therapeutic applications of this new generation of siRNAs in immunotherapy. [source] Poly(,-glutamic acid) nanoparticles as an efficient antigen delivery and adjuvant system: Potential for an AIDS vaccineJOURNAL OF MEDICAL VIROLOGY, Issue 1 2008Xin Wang Abstract Antigen delivery systems using polymeric nanoparticles are of special interest as stable protein-based antigen carriers. In the present study, novel biodegradable poly(,-glutamic acid) (,-PGA) nanoparticles were examined for their antigen delivery and immunostimulatory activities in vitro and in vivo. The uptake of ovalbumin by dendritic cells was markedly enhanced by ,-PGA nanoparticles, and the ovalbumin was gradually released from ,-PGA nanoparticles into the cells. In addition, ,-PGA nanoparticles appeared to have great potential as an adjuvant, because they could induce the maturation of dendritic cells. Although not only ovalbumin-encapsulating nanoparticles (OVA-NPs) but also a simple mixture of ovalbumin and nanoparticles induced dendritic cell maturation, the only dendritic cells exposed to OVA-NPs could strongly activate antigen-specific interferon (IFN)-,-producing T cells. Subcutaneous immunization of mice with human immunodeficiency virus type 1 (HIV-1) p24-encapsulating nanoparticles activated antigen-specific IFN-,-producing T cells in spleen cells and induced p24-specific serum antibodies, as compared to immunization with p24 alone. Like ovalbumin, a mixture of p24 and nanoparticles also induced antigen-specific serum antibodies but did not activate IFN-,-producing T cells in spleen cells, suggesting that nanoparticles play a critical role in inducing cellular immune responses. Furthermore, ,-PGA nanoparticles had a capacity comparable to that of the complete Freund's adjuvant (CFA) in inducing p24-specific serum antibody. However, unlike CFA, they predominantly activated p24-specific IFN-,-producing T cells. Thus, ,-PGA nanoparticles encapsulating various antigens may have great potential as novel and efficient protein-based vaccines against infectious diseases, including HIV-1 infection. J. Med. Virol. 80:11,19, 2008. © 2007 Wiley-Liss, Inc. [source] Induction of IL-10+ CD4+ CD25+ regulatory T cells with decreased NF-,B expression during immunotherapyPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 1-Part-II 2010Yi-Giien Tsai Tsai Y-G, Chiou Y-L, Chien J-W, Wu H-P, Lin C-Y. Induction of IL-10+ CD4+ CD25+ regulatory T cells with decreased NF-,B expression during immunotherapy. Pediatr Allergy Immunol 2010: 21: e166,e173. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard MyD88 is a major toll-like receptor (TLR) adaptor to activate NF-,B, which acts as a mater switch for allergic inflammation disease. Sterile hust dust extracts have been reported with TLR-dependent immunostimulatory activities. The aim of this study was to evaluate whether Dermatophagoides pteronyssinus (Der p) immunotherapy may increase IL-10+ CD4+ CD25+ T cells with modulating MyD88 signaling proteins, to decrease NF-,B expression. Peripheral blood mononuclear cells were isolated from patients before and after 1 yr of Der p immunotherapy, and also from matched control subjects. After 2 days of Der p-2 stimulation, intracellular IL-10 and Foxp3 expression of CD4+ CD25+ T cells were measured by flow-cytometry. The expression of IL-1 receptor-associated kinase (IRAK)-1 in cytoplasm and IFN-regulator factor-3 (IRF-3) with NF-,B/p65 in nuclei was determined by Western-blot analysis. Patients undergoing immunotherapy produced more soluble CD14, IL-10, and TGF-, that correlated with FEV1improvement (p < 0.05). In the immunotherapy group, the number of Foxp3+ CD4+ Treg cells increased more than the baseline status (25.06 ± 4.19 vs. 16.08 ± 3.54, p < 0.05). Additionally, increased IL-10 production with decreased IRAK-1 and NF-,B/p65 nuclear translocation was observed in sorted-purified Treg cells. IL-10+ CD4+ CD25+ Treg cells may respond to Der p-2 and down-regulate NF-,B/p65 expression to maintain immune tolerance during immunotherapy. [source] Comparative studies on the immunomodulatory and antitumor activities of the different parts of fruiting body of Ganoderma lucidum and Ganoderma sporesPHYTOTHERAPY RESEARCH, Issue 10 2008Grace G. L. Yue Abstract Ganoderma lucidum (GL, Lingzhi) has been suggested as a candidate for immunomodulation and cancer treatment. The present study aimed at comparing the different parts of the fruiting body (whole fruiting body, pileus and stipe) of GL as well as Ganoderma spores (sporoderm-broken and -unbroken), with regard to their antitumor and immunomodulatory activities in S-180 sarcoma-bearing mice. The hot water extracts of different parts of GL or the Ganoderma spores were orally administered to the sarcoma-bearing mice. The results showed that GL whole fruiting body, stipe and sporoderm-broken spore possessed stronger inhibitory activities on sarcoma growth when compared with the pileus extract. Higher immunomodulatory activities in terms of enhancing the proliferative responses and the cytokines (IFN- ,, IL-4 and IL-6) production of spleen lymphocytes were also found in GL stipe and sporoderm-broken spore treatment groups. The sporoderm-broken spores had higher stimulatory effects on mitogen-activated spleen lymphocytes of healthy mice than those of sarcoma-bearing mice. In addition, the immunostimulatory activities of GL hot water extracts and Ganoderma spores were shown to be comparable; hence the latter did not show superiority in efficacy. This is the first comparative study on the immunomodulatory activities of Ganoderma spores and the fruiting body extracts. Copyright © 2008 John Wiley & Sons, Ltd. [source] Immunomodulatory effect of extracts of Hibiscus sabdariffa L. (Family Malvaceae) in a mouse modelPHYTOTHERAPY RESEARCH, Issue 5 2008Titilayo O. Fakeye Abstract The immunomodulatory activity of water and alcohol extracts (including its fractions) of the dried calyx of the plant was evaluated in mice. The ability of the extracts to inhibit or enhance the production of two cytokines, namely tumor necrosis factor-alpha (TNF- ,) and interleukin-10 (IL-10), respectively, implicated as proinflammatory and antiinflammatory interleukins were also evaluated. The extracts at doses of 50 mg/kg were found to possess higher immunostimulatory activities in comparison with levamisole (positive control), with significant effects when compared with the vehicle-treated group (p < 0.01). Increased activity was observed with increase in doses of the 50% ethanol and absolute ethanol extracts. The insoluble fraction exhibited a significant dose-dependent immunostimulatory activity (p < 0.05), while the residual water-soluble fraction exhibited activity at 100 mg/kg body weight. The production of tumor necrosis factor-alpha (TNF- ,), was low in all the extract groups tested, while the production of interleukin 10 (IL-10) was high compared with the control. The production of IL-10 was high in 300 mg/kg aqueous extract. The insoluble fraction exhibited a profound dose-dependent immunostimulatory activity higher than the positive control at 100 mg/kg. This study established the immunoenhancing properties of the extracts of this plant confirming that the immunomodulatory activity is cell mediated and humoral. The insoluble fraction could find use as an immunostimulatory agent in humans. Copyright © 2008 John Wiley & Sons, Ltd. [source] Combination Nonviral Interleukin-2 Gene Immunotherapy For Head and Neck Cancer: From Bench Top to BedsideTHE LARYNGOSCOPE, Issue 3 2005Bert W. O'Malley Jr MD Abstract Objective/Hypothesis: Intralesional delivery of cytokine genes has emerged as a promising therapeutic strategy for the treatment of cancer. In addition to the therapeutic effect of the delivered cytokine gene, the components of the gene delivery system also have been shown to induce beneficial immune responses. On the basis of these principles, we hypothesized that a molecular therapy could be developed that would provide synergistic antitumor activity by way of intralesional expression of interleukin (IL)-2 from a recombinant plasmid combined with induction of endogenous interferon (IFN)-, and IL-12 cytokines by immunostimulatory DNA. Our objective in these studies was to create and optimize a novel formulation of cationic lipid and DNA that generates local production of IL-2 protein within a targeted tumor environment with concomitant induction of the antitumor cytokines IFN-, and IL-12. Study Design: Prospective laboratory drug development plan that would produce human clinical trials. Materials and Methods: Engineered bacterial plasmids containing a cytomegalovirus promoter (CMV)-IL-2 expression cassette were specifically formulated with cationic lipids and optimized for antitumor effect in a floor of mouth murine tumor model. The treated tumors were assayed for local expression of IL-2 and concurrent expression of secondary cytokines IFN-, and IL-12. Established tumors in C3H/HeJ mice were treated with various IL-2 gene formulations, and clinical and immunologic responses were evaluated. Immunologic studies were performed and included cytolytic T-cell assays and cytokine expression profiles. For human clinical trials, a phase I 10 patient formulated IL-2 gene therapy study was completed. Subsequently, two large scale, phase II multi-institutional and multi-international studies were initiated comparing non-viral IL-2 gene therapy to palliative methotrexate chemotherapy or in combination with cisplatin. Results: In the preclinical stage, maximum tumor inhibition in animal models was obtained using IL-2 plasmid formulated with 1,2-dioleyloxypropyl-3-trimethyl ammonium chloride (DOTMA):cholesterol (1:1 mol:mol) at a plasmid:lipid charge ratio of 1:0.5 (,/+). Cationic lipid formulated IL-2 plasmid significantly inhibited tumor growth compared with formulated control plasmid (P < .01) or vehicle (lactose; P < .01). Consistent with previously reported studies of the immunostimulatory activity of DNA of bacterial origin, treatment of tumors with control plasmid in cationic lipid formulation induced production of endogenous IFN-, and IL-12 but not IL-2. Treatment of tumors with formulated IL-2 plasmid produced IL-2 protein levels that were 5-fold over background and increased IFN-, by 32-fold (P < .001) and IL-12 by 5.5-fold (P < .001) compared with control plasmid formulations. The phase I human trial demonstrated dose escalation safety, which was its primary objective, and there was one anecdotal reduction in tumor size. The phase II studies have been initiated and focus on either comparing the novel nonviral IL-2 gene immunotherapy formulation alone to methotrexate or comparing IL-2 gene therapy in combination with cisplatin in recurrent or unresectable patients with head and neck squamous cell carcinoma. Conclusions: The preclinical data provided proof of principle for matching a delivered IL-2 transgene with an immunostimulatory nonviral formulation to enhance intralesional production of therapeutic cytokines for the maximization of antitumor response. Human clinical trials have demonstrated this novel therapy to be safe in the human clinical setting. Phase II trials have been initiated to assess efficacy and feasibility as a single or combination therapy for head and neck cancer. [source] Strong immunostimulatory activity of AT-oligodeoxynucleotide requires a six-base loop with a self-stabilized 5,-C,G-3, stem structureCELLULAR MICROBIOLOGY, Issue 3 2006Takeshi Shimosato Summary Lactobacillus gasseri OLL2716 has recently been discovered as a probiotic that suppresses the growth of Helicobacter pylori and reduces gastric mucosal inflammation in humans. This has resulted in the development of a new type of probiotic yoghurt ,LG21' in Japan. In our previous study, we found an immunostimulatory AT5ACL oligodeoxynucleotide (AT-ODN) containing a unique core sequence (5,-ATTTTTAC-3,) in L. gasseri JCM1131T. Interestingly, although the AT-ODN does not contain any CpG sequences, it exerts mitogenic activity in B cells and augments Th-1-type immune responses via Toll-like receptor 9. These findings prompted us to identify strong immunostimulatory non-CpG AT-ODNs that contain the 5,-ATTTTTAC-3, motif in the genomic sequence of L. gasseri OLL2716. We identified 280 kinds of AT-ODNs in the L. gasseri OLL2716 genome. Mitogenicity and NF-,B gene reporting assays showed that 13 of the 280 AT-ODNs were strongly immunostimulatory when in the TLR9 transfectant. Of these, AT-ODNs LGAT-145 and LGAT-243 were the most potent. With respect to the induction of Th-1-type cytokines, LGAT-243 had the greatest activity and was more potent than the swine prototype, ODN D25. We further found that a six-base secondary loop structure containing a self-stabilized 5,-C,G-3, stem sequence is important for potent immunostimulatory activity. These results show for the first time that AT-ODNs with a specific loop and stem structure are important factors for immunostimulatory activity. Finally, we found that novel strong immunostimulatory non-CpG AT-ODNs exist in the genome of probiotic lactic acid bacteria. [source] Strong immunostimulation in murine immune cells by Lactobacillus rhamnosus GG DNA containing novel oligodeoxynucleotide patternCELLULAR MICROBIOLOGY, Issue 3 2005Iliyan D. Iliev Summary Whole cells, cell wall components and some soluble factors from Lactobacillus rhamnosus GG (LGG) are known to invoke immune responses as they interact with animal and human immune cells. In the present study, we found that chromosomal DNA from LGG is a potent inducer of splenic B cell proliferation, CD86/CD69 expression and cytokine production in mice. In the genomic DNA of LGG we discovered TTTCGTTT oligodeoxynucleotide (ODN) ID35, which has a potent activity in a number of immunostimulatory assays. Phosphorothioate backbone is not required for the activity of ID35. The ODN ID35 showed levels of activity comparable with those induced by the murine prototype ODN 1826 in B cell proliferation, CD86/CD69 expression, interleukin (IL)-6, IL-12, IL-18, interferon gamma (IFN-,) and tumour necrosis factor alpha (TNF-,) mRNA expression and IFN-,/IL-12p70 protein production assays. Additionally, ID35 appeared to be equally active in both murine and human immune cells. These stimulatory effects are due to TTTCGTTT motif located in the 5, end of ID35. In this study we demonstrate for a first time that, DNA from LGG is a factor of immunobiotic activity. Furthermore, ODN ID35 is the first ODN, with such a strong immunostimulatory activity to be found in immunobiotic bacterial DNA. [source] | |||||||||||||