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Описана технология синтеза и проведена оценка адъювантных свойств олигодезоксинуклеотидов CpG. Последовательности CpG-ODN синте...
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Описана технология синтеза и проведена оценка адъювантных свойств олигодезоксинуклеотидов CpG. Последовательности CpG-ODN синтезировали в соответствии с опубликованными данными на автоматическом синтезаторе. Адьювантную активность изучали на примере комбинации CpG-ODN с рекомбинатным протективным антигеном и белком S-слоя ЕА1 сибиреязвенного микроба. Установлено, что использование синтезированного адъюванта CpG 2006 в сочетании с иммуногенными антигенами приводит к развитию у экспериментальных животных напряженного и продолжительного иммунитета. Показано преимущество в адъювантной активности у синтетического препарата CpG 2006 перед альгидрогелем. В экспериментах на различных биомоделях получены данные, подтверждающие отсутствие токсического и повреждающего действия CpG-ODN на клетки и ткани макроорганизма. Выявлена активация клеточного звена иммунного ответа (содержание CD4+ и CD8+) при иммунизации штаммом В. anthracis СТИ-1 и прототипом рекомбинантной сибиреязвенной вакцины с CpG 2006 или альгидрогелем в качестве адъюванта во всех группах экспериментальных животных.
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Background: Immunostimulating oligodeoxynucleotides containing unmethylated cytosine-guanosine motifs (CpG-ODN) have shown a promising efficacy in several cancer models when injected locally. A previous phase II study of CpG-ODN i...
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Background: Immunostimulating oligodeoxynucleotides containing unmethylated cytosine-guanosine motifs (CpG-ODN) have shown a promising efficacy in several cancer models when injected locally. A previous phase II study of CpG-ODN in patients with recurrent glioblastoma (GBM) has suggested some activity and has shown a limited toxicity. This multicentre single-blinded randomised phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with de novo glioblastomas.
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In this study, we investigated the immunostimulatory and protective effects of CpG motif oligonucleotides (CpG-ODNs) against Edwardsiella tarda infection in olive flounder (Paralichthys olivaceus). Groups of fish injected with CpG...
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In this study, we investigated the immunostimulatory and protective effects of CpG motif oligonucleotides (CpG-ODNs) against Edwardsiella tarda infection in olive flounder (Paralichthys olivaceus). Groups of fish injected with CpG-ODNs (1585, 1668, and 2007) or PBS (control) showed varying mortality rates in response to challenge with E. tarda. The survival rates of fish treated with CpG-ODN 1668 and 2007, which belonged to the same class type B, were 45% and 60%, respectively, with CpG-ODN 2007 showing the highest survival rate. Further analysis showed that the respiratory burst and bactericidal activities induced by CpG-ODN 2007 were higher than those in the control group (induced by non-CpG-ODNs) or in the group of fish induced by CpG-ODN 1585, which belonged to class type A. Additionally, the respiratory burst activity induced by CpG-ODN 2007 was higher than that induced by CpG-ODN 1668, despite similar bactericidal activity titers. In vivo experiments showed that CpG-ODN 2007 stimulation resulted in higher survival rates than CpG-ODN 1668 stimulation, possibly owing to differences in respiratory burst activity. In summary, we demonstrated that differences in CpG-motif or class type altered respiratory burst and bactericidal activities, resulting in differences in survival rates against E. tarda challenge in the olive flounder. Therefore, it is necessary to use CpG-ODNs optimized against E. tarda infection in olive flounder, because different CpG motifs belonging to the same class type have different effects. (C) 2017 Elsevier Ltd. All rights reserved.
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In this study, we investigated the immunostimulatory and protective effects of CpG motif oligonucleotides (CpG-ODNs) against Edwardsiella tarda infection in olive flounder (Paralichthys olivaceus). Groups of fish injected with CpG...
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In this study, we investigated the immunostimulatory and protective effects of CpG motif oligonucleotides (CpG-ODNs) against Edwardsiella tarda infection in olive flounder (Paralichthys olivaceus). Groups of fish injected with CpG-ODNs (1585, 1668, and 2007) or PBS (control) showed varying mortality rates in response to challenge with E. tarda. The survival rates of fish treated with CpG-ODN 1668 and 2007, which belonged to the same class type B, were 45% and 60%, respectively, with CpG-ODN 2007 showing the highest survival rate. Further analysis showed that the respiratory burst and bactericidal activities induced by CpG-ODN 2007 were higher than those in the control group (induced by non-CpG-ODNs) or in the group of fish induced by CpG-ODN 1585, which belonged to class type A. Additionally, the respiratory burst activity induced by CpG-ODN 2007 was higher than that induced by CpG-ODN 1668, despite similar bactericidal activity titers. In vivo experiments showed that CpG-ODN 2007 stimulation resulted in higher survival rates than CpG-ODN 1668 stimulation, possibly owing to differences in respiratory burst activity. In summary, we demonstrated that differences in CpG-motif or class type altered respiratory burst and bactericidal activities, resulting in differences in survival rates against E. tarda challenge in the olive flounder. Therefore, it is necessary to use CpG-ODNs optimized against E. tarda infection in olive flounder, because different CpG motifs belonging to the same class type have different effects. (C) 2017 Elsevier Ltd. All rights reserved.
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Toll-like receptors 7 (TLR7) and 9 (TLR9) are important mediators of innate immune responses. Both receptors are located in endosomal compartments, recognize nucleic acids, and signal via Myeloid differentiation factor 88 (MyD88)....
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Toll-like receptors 7 (TLR7) and 9 (TLR9) are important mediators of innate immune responses. Both receptors are located in endosomal compartments, recognize nucleic acids, and signal via Myeloid differentiation factor 88 (MyD88). In the current study, we analyzed TLR7 and TLR9 induced activation of astrocytes and microglia, two cell types that contribute to innate immune responses in the CNS. TLR7 and TLR9 agonists induced similar cytokine profiles within each cell type. However, there were notable differences in the cytokine profile between astrocytes and microglia, including the production of the anti-inflammatory cytokine IL-10 and antiapoptotic cytokines G-CSF and IL-9 by microglia but not astrocytes. Costimulation studies demonstrated that the TLR7 agonist, imiquimod, could inhibit TLR9 agonist-induced innate immune responses, in both cell types, in a concentration-dependent manner. Surprisingly, this inhibition was not mediated by TLR7, as deficiency in TLR7 did not alter suppression of the TLR9 agonist-induced responses. The suppression of innate immune responses was also not due to an inhibition of TLR9 agonist uptake. This suggested that imiquimod suppression may be a direct effect, possibly by blocking CpG-ODN binding and/or signaling with TLR9, thus limiting cell activation. An antagonistic relationship was also observed between the two receptors in microglia, with TLR7 deficiency resulting in enhanced cytokine responses to CpG-ODN stimulation. Thus, both TLR7 and its agonist can have inhibitory effects on TLR9-induced cytokine responses in glial cells.
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A beta-1,3-D-glucan called Schizophyllan (SPG) can form a novel complex with homo oligodeoxynucleotides (ODNs) via the combination of hydrogen bonding and hydrophobic interactions. Dectin-1 is a major receptor involved in the reco...
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A beta-1,3-D-glucan called Schizophyllan (SPG) can form a novel complex with homo oligodeoxynucleotides (ODNs) via the combination of hydrogen bonding and hydrophobic interactions. Dectin-1 is a major receptor involved in the recognition of beta-1,3-D-glucans and expressed on antigen presenting cells (APCs) including macrophages, dendritic cells, monocytes, neutrophils, and a subset of T cells. Therefore, the SPG/ODN complex can be used as APCs cell-specific delivery of antisense ODNs (ASODNs) or unmethylated CpG sequences (CpG-ODNs). In fact, AS-ODN/SPG complex protected mice from LPS-induced hepatitis and CpG-ODN/SPG complex induced high antibody titers when it was administered to cynomolgus monkeys as adjutant of influenza vaccine. These results indicate that SPG can be an excellent drug delivery system carrier targeting APCs.
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The maturation of dendritic cells into more-immunostimulatory dendritic cells by stimulation with different combinations of immunologic agents is expected to provide efficient, adoptive immunotherapy against cancer. Soluble beta-g...
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The maturation of dendritic cells into more-immunostimulatory dendritic cells by stimulation with different combinations of immunologic agents is expected to provide efficient, adoptive immunotherapy against cancer. Soluble beta-glucan maitake D-fraction, extracted from the maitake mushroom Grifola frondosa, acts as a potent immunotherapeutic agent, eliciting innate and adoptive immune responses, thereby contributing to its antitumor activity. Here, we evaluated the efficacy of maitake D-fraction, in combination with a Toll-like receptor agonist, to treat tumors in a murine model. Our results showed that maitake D-fraction, in combination with the Toll-like receptor 9 agonist, cytosine-phosphate-guanine oligodeoxynucleotide, synergistically increased the expression of dendritic cell maturation markers and interleukin-12 production in dendritic cells, but it did not increase interleukin-10 production, generating strong effector dendritic cells with an augmented capacity for efficiently priming an antigen-specific, T helper 1-type T cell response. Maitake D-fraction enhances cytosine-phosphate-guanine oligodeoxynucleotide-induced dendritic cell maturation and cytokine responses in a dectin-1-dependent pathway. We further showed that a combination therapy using cytosine-phosphate-guanine oligodeoxynucleotide and maitake D-fraction was highly effective, either as adjuvants for dendritic cell vaccination or by direct administration against murine tumor. Therapeutic responses to direct administration were associated with increased CD11c(+) dendritic cells in the tumor site and the induction of interferon-gamma-producing CD4(+) and CD8(+) T cells. Our results indicate that maitake D-fraction and cytosine-phosphate-guanine oligodeoxynucleotide synergistically activated dendritic cells, resulting in tumor regression via an antitumor T helper cell 1-type response. Our findings provide the basis for a potent antitumor therapy using a novel combination of immunologic agents for future clinical immunotherapy studies in patients.
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The maturation of dendritic cells into more-immunostimulatory dendritic cells by stimulation with different combinations of immunologic agents is expected to provide efficient, adoptive immunotherapy against cancer. Soluble beta-g...
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The maturation of dendritic cells into more-immunostimulatory dendritic cells by stimulation with different combinations of immunologic agents is expected to provide efficient, adoptive immunotherapy against cancer. Soluble beta-glucan maitake D-fraction, extracted from the maitake mushroom Grifola frondosa, acts as a potent immunotherapeutic agent, eliciting innate and adoptive immune responses, thereby contributing to its antitumor activity. Here, we evaluated the efficacy of maitake D-fraction, in combination with a Toll-like receptor agonist, to treat tumors in a murine model. Our results showed that maitake D-fraction, in combination with the Toll-like receptor 9 agonist, cytosine-phosphate-guanine oligodeoxynucleotide, synergistically increased the expression of dendritic cell maturation markers and interleukin-12 production in dendritic cells, but it did not increase interleukin-10 production, generating strong effector dendritic cells with an augmented capacity for efficiently priming an antigen-specific, T helper 1-type T cell response. Maitake D-fraction enhances cytosine-phosphate-guanine oligodeoxynucleotide-induced dendritic cell maturation and cytokine responses in a dectin-1-dependent pathway. We further showed that a combination therapy using cytosine-phosphate-guanine oligodeoxynucleotide and maitake D-fraction was highly effective, either as adjuvants for dendritic cell vaccination or by direct administration against murine tumor. Therapeutic responses to direct administration were associated with increased CD11c(+) dendritic cells in the tumor site and the induction of interferon-gamma-producing CD4(+) and CD8(+) T cells. Our results indicate that maitake D-fraction and cytosine-phosphate-guanine oligodeoxynucleotide synergistically activated dendritic cells, resulting in tumor regression via an antitumor T helper cell 1-type response. Our findings provide the basis for a potent antitumor therapy using a novel combination of immunologic agents for future clinical immunotherapy studies in patients.
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Numerous studies have focused on the treatment of melanoma, but the current therapies for melanoma have limited therapeutic effects. To find a more effective therapy for melanoma, we combined artificially designed CpG ODN (cytosin...
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Numerous studies have focused on the treatment of melanoma, but the current therapies for melanoma have limited therapeutic effects. To find a more effective therapy for melanoma, we combined artificially designed CpG ODN (cytosine-phosphate-guanine oligodeoxynucleotides) and siRNAs (small-interfering ribonucleic acids) targeting PD-1 (programmed cell death protein 1), which were delivered by attenuated Salmonella to treat melanoma in mice, and explored the underlying antitumor mechanisms. We found that mice receiving the combination therapy had the smallest tumor size and the longest survival time. The possible mechanisms underlying this phenomenon include pathways mediated by cyclin D1, p-STAT3 (phosphorylated signal transducers and activators of transcription protein 3), MMP2 (matrix metallopeptidase 2) and cleaved caspase 3, since after treatment, the expression of cyclin D1, p-STAT3, and MMP2 decreased but that of cleaved caspase 3 increased; additional mechanisms include increases in the recruitment of immune cells to tumor sites and in the number of immune cells in mouse spleens and the upregulation of TNF-alpha (tumor necrosis factor) and IL-6 (interleukin 6). We demonstrated that the combination therapy composed of CpG ODN and PD-1-siRNA delivered by attenuated Salmonella exhibited a strong ability to inhibit melanoma and improve the antitumor immune responses of tumor-bearing mice.
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