Abstract:The results obtained provide the groundwork for a future clinical translation of the chemokine-based genetic modification of DCs to increase their vaccine potency.
“…The lgtB Ϫ pagL ϩ LPS can induce dose-dependent expression of the MyD88-dependent cytokine IL-10, a low level of the MyD88-dependent pro-inflammatory cytokine IL-6 and relatively higher levels of the TRIF-dependent chemokine IP-10 in human monocytic cells. The retained capacity of pentaacylated lgtB Ϫ pagL ϩ LPS to induce the secretion of the chemokine IP-10 suggests a bias toward the TRIF over the MyD88 signaling pathway after TLR4 activation, which is considered to be favorable for the development of adaptive immunity (42)(43)(44)(45). These results indicate a greater potential of the use of pagL ϩ LPS as compared with lpxL1 Ϫ LPS for immune potentiation in humans.…”
Background: LPS biosynthesis modification offers the potential to create detoxified variants with improved immunostimulatory properties. Results: Pentaacyl LPS molecules from pagL ϩ and lpxL1 Ϫ meningococcal mutants were structurally characterized and found to
“…The lgtB Ϫ pagL ϩ LPS can induce dose-dependent expression of the MyD88-dependent cytokine IL-10, a low level of the MyD88-dependent pro-inflammatory cytokine IL-6 and relatively higher levels of the TRIF-dependent chemokine IP-10 in human monocytic cells. The retained capacity of pentaacylated lgtB Ϫ pagL ϩ LPS to induce the secretion of the chemokine IP-10 suggests a bias toward the TRIF over the MyD88 signaling pathway after TLR4 activation, which is considered to be favorable for the development of adaptive immunity (42)(43)(44)(45). These results indicate a greater potential of the use of pagL ϩ LPS as compared with lpxL1 Ϫ LPS for immune potentiation in humans.…”
Background: LPS biosynthesis modification offers the potential to create detoxified variants with improved immunostimulatory properties. Results: Pentaacyl LPS molecules from pagL ϩ and lpxL1 Ϫ meningococcal mutants were structurally characterized and found to
“…S9 and S10) showing as well significant intra- and intergroup differences. IP10 is one of the most potent chemokine that induces inflammatory responses and is discussed as a factor for immunologic enhancement (Kang et al, 2009, Nakaya et al, 2011). Fig.…”
BackgroundThe recent West African Ebola epidemic led to accelerated efforts to test Ebola vaccine candidates. As part of the World Health Organisation-led VSV Ebola Consortium (VEBCON), we performed a phase I clinical trial investigating rVSV-ZEBOV (a recombinant vesicular stomatitis virus-vectored Ebola vaccine), which has recently demonstrated protection from Ebola virus disease (EVD) in phase III clinical trials and is currently in advanced stages of licensing. So far, correlates of immune protection are incompletely understood and the role of cell-mediated immune responses has not been comprehensively investigated to date.Methods: We recruited 30 healthy subjects aged 18–55 into an open-label, dose-escalation phase I trial testing three doses of rVSV-ZEBOV (3 × 105 plaque-forming units (PFU), 3 × 106 PFU, 2 × 107 PFU) (ClinicalTrials.gov; NCT02283099). Main study objectives were safety and immunogenicity, while exploratory objectives included lymphocyte dynamics, cell-mediated immunity and cytokine networks, which were assessed using flow cytometry, ELISpot and LUMINEX assay.Findings: Immunization with rVSV-ZEBOV was well tolerated without serious vaccine-related adverse events. Ebola virus-specific neutralizing antibodies were induced in nearly all individuals. Additionally, vaccinees, particularly within the highest dose cohort, generated Ebola glycoprotein (GP)-specific T cells and initiated a cascade of signaling molecules following stimulation of peripheral blood mononuclear cells with Ebola GP peptides.Interpretation: In addition to a benign safety and robust humoral immunogenicity profile, subjects immunized with 2 × 107 PFU elicited higher cellular immune responses and stronger interlocked cytokine networks compared to lower dose groups. To our knowledge these data represent the first detailed cell-mediated immuneprofile of a clinical trial testing rVSV-ZEBOV, which is of particular interest in light of its potential upcoming licensure as the first Ebola vaccine.VEBCON trial Hamburg, Germany (NCT02283099).
“…To solve this issue, Kang et al introduced the CXCL10 gene into DC2.4 cells using a retroviral system, resulting in the secretion of functionally chemoattractive CXCL10. Findings by these authors have laid the foundation for a future clinical translation of the chemokine-based genetic modification of DCs to increase their vaccine potency (62). CXCL10 has also been determined to have synergistic effects with a deoxycytidine (90) analog, gemcitabine, which inhibits the proliferation of endothelial cells, induces tumor cells apoptosis, and recruits lymphocytes to the tumor in murine models.…”
Section: Antitumor Effects Through Immunogenic Actionmentioning
Abstract. The chemokine interferon-γ inducible protein 10 kDa (CXCL10) is a member of the CXC chemokine family which binds to the CXCR3 receptor to exert its biological effects. CXCL10 is involved in chemotaxis, induction of apoptosis, regulation of cell growth and mediation of angiostatic effects. CXCL10 is associated with a variety of human diseases including infectious diseases, chronic inflammation, immune dysfuntion, tumor development, metastasis and dissemination. More importantly, CXCL10 has been identified as a major biological marker mediating disease severity and may be utilized as a prognostic indicator for various diseases. In this review, we focus on current research elucidating the emerging role of CXCL10 in the pathogenesis of cancer. Understanding the role of CXCL10 in disease initiation and progression may provide the basis for developing CXCL10 as a potential biomarker and therapeutic target for related human malignancies.
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