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1.  A Nonintegrative Lentiviral Vector-Based Vaccine Provides Long-Term Sterile Protection against Malaria 
PLoS ONE  2012;7(11):e48644.
Trials testing the RTS,S candidate malaria vaccine and radiation-attenuated sporozoites (RAS) have shown that protective immunity against malaria can be induced and that an effective vaccine is not out of reach. However, longer-term protection and higher protection rates are required to eradicate malaria from the endemic regions. It implies that there is still a need to explore new vaccine strategies. Lentiviral vectors are very potent at inducing strong immunological memory. However their integrative status challenges their safety profile. Eliminating the integration step obviates the risk of insertional oncogenesis. Providing they confer sterile immunity, nonintegrative lentiviral vectors (NILV) hold promise as mass pediatric vaccine by meeting high safety standards. In this study, we have assessed the protective efficacy of NILV against malaria in a robust pre-clinical model. Mice were immunized with NILV encoding Plasmodium yoelii Circumsporozoite Protein (Py CSP) and challenged with sporozoites one month later. In two independent protective efficacy studies, 50% (37.5–62.5) of the animals were fully protected (p = 0.0072 and p = 0.0008 respectively when compared to naive mice). The remaining mice with detectable parasitized red blood cells exhibited a prolonged patency and reduced parasitemia. Moreover, protection was long-lasting with 42.8% sterile protection six months after the last immunization (p = 0.0042). Post-challenge CD8+ T cells to CSP, in contrast to anti-CSP antibodies, were associated with protection (r = −0.6615 and p = 0.0004 between the frequency of IFN-g secreting specific T cells in spleen and parasitemia). However, while NILV and RAS immunizations elicited comparable immunity to CSP, only RAS conferred 100% of sterile protection. Given that a better protection can be anticipated from a multi-antigen vaccine and an optimized vector design, NILV appear as a promising malaria vaccine.
PMCID: PMC3487763  PMID: 23133649
2.  Lentiviral Vector-Based Prime/Boost Vaccination against AIDS: Pilot Study Shows Protection against Simian Immunodeficiency Virus SIVmac251 Challenge in Macaques ▿  
Journal of Virology  2009;83(21):10963-10974.
AIDS vaccination has a pressing need for more potent vaccination vectors capable of eliciting strong, diversified, and long-lasting cellular immune responses against human immunodeficiency virus (HIV). Lentiviral vectors have demonstrated efficiency not only as gene delivery vehicles for gene therapy applications but also as vaccination tools. This is likely due to their ability to transduce nondividing cells, including dendritic cells, enabling sustained endogenous antigen presentation and thus the induction of high proportions of specific cytotoxic T cells and long-lasting memory T cells. We show in a first proof-of-concept pilot study that a prime/boost vaccination strategy using lentiviral vectors pseudotyped with a glycoprotein G from two non-cross-reactive vesicular stomatitis virus serotypes elicited robust and broad cellular immune responses against the vector-encoded antigen, simian immunodeficiency virus (SIV) GAG, in cynomolgus macaques. Vaccination conferred strong protection against a massive intrarectal challenge with SIVmac251, as evidenced both by the reduction of viremia at the peak of acute infection (a mean of over 2 log10 fold reduction) and by the full preservation of the CD28+ CD95+ memory CD4+ T cells during the acute phase, a strong correlate of protection against pathogenesis. Although vaccinees continued to display lower viremia than control macaques during the early chronic phase, these differences were not statistically significant by day 50 postchallenge. A not-optimized SIV GAG antigen was chosen to show the strong potential of the lentiviral vector system for vaccination. Given that a stronger protection can be anticipated from a modern HIV-1 antigen design, gene transfer vectors derived from HIV-1 appear as promising candidates for vaccination against HIV-1 infection.
PMCID: PMC2772810  PMID: 19706700
3.  Secretory phospholipase A2 induces dendritic cell maturation 
European Journal of Immunology  2004;34(8):2293-2302.
High level of phospholipase A2 (PLA2) activity is found in serum and biological fluids during the acute phase response (APR). Extracellular PLA2 in fluids of patients with inflammatory diseases such as sepsis, acute pancreatitis or rheumatoid arthritis is also associated with propagation of inflammation. PLA2 activity is involved in the release of both pro- and anti-inflammatory lipid mediators from phospholipids of cellular membranes or circulating lipoproteins. PLA2 may thus generate signals that influence immune responses. Here, group III secretory PLA2s were tested for their ability to promote generation of functionally mature human dendritic cells (DC). PLA2 treatment of differentiating monocytes in the presence of GM-CSF and IL-4 yielded cells with phenotypical and functional characteristics of mature DC. This maturation was dependent on the dose of PLA2 and PLA2-generated DC stimulated interferon gamma secretion by allogeneic T cells. The effects of PLA2 on DC maturation was mainly dependent on enzyme activity and correlated with the activation of NF-κB, AP-1 and NFAT. The data suggest that transient increase in PLA2 activity generates signals that promote transition of innate to adaptive immunity during the APR.
PMCID: PMC2755771  PMID: 15259027
Catalytic Domain; Cell Differentiation; immunology; physiology; Dendritic Cells; enzymology; immunology; physiology; Humans; Phenotype; Phospholipases A; metabolism; Phospholipases A2; Transcription Factors; metabolism; dendritic cells; acute-phase reactants; lipid mediators; inflammation; immunomodulators
4.  Protective Antiviral Immunity Conferred by a Nonintegrative Lentiviral Vector-Based Vaccine 
PLoS ONE  2008;3(12):e3973.
Lentiviral vectors are under intense scrutiny as unique candidate viral vector vaccines against tumor and aggressive pathogens because of their ability to initiate potent and durable specific immune responses. Strategies that alleviate safety concerns will facilitate the clinical developments involving lentiviral vectors. In this respect, the development of integration deficient lentiviral vectors circumvents the safety concerns relative to insertional mutagenesis and might pave the way for clinical applications in which gene transfer is targeted to non-dividing cells. We thus evaluated the potential use of nonintegrative lentiviral vectors as vaccination tools since the main targeted cell in vaccination procedures is the non-dividing dendritic cell (DC). In this study, we demonstrated that a single administration of nonintegrative vectors encoding a secreted form of the envelope of a virulent strain of West Nile Virus (WNV) induces a robust B cell response. Remarkably, nonintegrative lentiviral vectors fully protected mice from a challenge with a lethal dose of WNV and a single immunization was sufficient to induce early and long-lasting protective immunity. Thus, nonintegrative lentiviral vectors might represent a safe and efficacious vaccination platform for the development of prophylactic vaccines against infectious agents.
PMCID: PMC2600612  PMID: 19096527
5.  1-Methyl-tryptophan can interfere with TLR signaling in dendritic cells independently of IDO activity 
1-methyl-tryptophan (1-MT) is a competitive inhibitor of indoleamine 2,3-dioxygenase that can break tolerance and induce fetus, graft and tumor rejection. Because of its broad effect on immune-related mechanisms, the direct action of 1-MT on human monocyte-derived dendritic cells (DC) was analyzed. It is shown here that 1-MT effect on DC is dependent on the maturation pathway. 1-MT had no effect on DC stimulated by the TLR3 ligand polyI:C but strongly enhanced the Th1 profile of DC stimulated with TLR2/1 or TLR2/6 ligands. 1-MT induced drastic changes in the function of DC stimulated by the TLR4 ligand LPS. These cells could still activate allogeneic and syngeneic T cells but stimulation yielded T cells secreting IL-5 and IL-13 rather than IFNγ. This action of 1-MT correlated with an increased phosphorylation of p38 and ERK MAP-kinases and sustained activation of the transcription factor c-Fos. Inhibiting p38 and ERK phosphorylation with synthetic inhibitors blocked the effect of 1-MT on LPS-stimulated DC. Thus, 1-MT can modulate DC function depending on the maturation signal and independently of its action on IDO. This is consistent with previous observations and will help further understanding the mechanisms of DC polarization.
PMCID: PMC2377404  PMID: 16887964
Cell Differentiation; drug effects; immunology; Cells; Cultured; Dendritic Cells; cytology; enzymology; metabolism; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; metabolism; physiology; Signal Transduction; drug effects; immunology; Toll-Like Receptors; antagonists & inhibitors; physiology; Tryptophan; analogs & derivatives; pharmacology; Dendritic cells; Protein kinases; Th1/Th2 cells; Toll-like receptor; 1-methyltryptophan
6.  Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death 
The Journal of Experimental Medicine  2005;202(12):1691-1701.
Systemic anticancer chemotherapy is immunosuppressive and mostly induces nonimmunogenic tumor cell death. Here, we show that even in the absence of any adjuvant, tumor cells dying in response to anthracyclins can elicit an effective antitumor immune response that suppresses the growth of inoculated tumors or leads to the regression of established neoplasia. Although both antracyclins and mitomycin C induced apoptosis with caspase activation, only anthracyclin-induced immunogenic cell death was immunogenic. Caspase inhibition by Z-VAD-fmk or transfection with the baculovirus inhibitor p35 did not inhibit doxorubicin (DX)-induced cell death, yet suppressed the immunogenicity of dying tumor cells in several rodent models of neoplasia. Depletion of dendritic cells (DCs) or CD8+T cells abolished the immune response against DX-treated apoptotic tumor cells in vivo. Caspase inhibition suppressed the capacity of DX-killed cells to be phagocytosed by DCs, yet had no effect on their capacity to elicit DC maturation. Freshly excised tumors became immunogenic upon DX treatment in vitro, and intratumoral inoculation of DX could trigger the regression of established tumors in immunocompetent mice. These results delineate a procedure for the generation of cancer vaccines and the stimulation of anti-neoplastic immune responses in vivo.
PMCID: PMC2212968  PMID: 16365148

Results 1-6 (6)