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PubMed2005

Influence of immunisation with Mycobacterium bovis bacillus Calmette-Guérin on the sensitisation to inhaled allergens after infection with respiratory syncytial virus.

Respiratory syncytial virus (RSV) may play an important role in allergic diathesis by creating a Th2-type immune response. Mycobacterium bovis bacillus Calmette-Guérin (BCG) is known to induce a Th1-type immune response, but the association of BCG vaccination and the suppression of allergy development remain controversial. We investigated the influence of BCG vaccination on the immune response to RSV in a mouse model. Balb/c mice were BCG vaccinated, RSV infected and ovalbumin (OVA) challenged. Mice were sacrificed one, two and four weeks after allergen exposure. Bronchoalveolar lavage was performed. Alveolar macrophages and lymphocytes from spleens and lung-associated lymph nodes were investigated for cytokine production and cell proliferation. Serum was tested for allergen-specific immunoglobulin-E (IgE). Lung eosinophilia was diminished by BCG immunisation. OVA-specific serum IgE was increased regardless of prior BCG vaccination. Interleukin-4 secretion of spleen lymphocytes increased in BCG-vaccinated mice only one week after allergen exposure but was comparable to non-vaccinated mice at four weeks. The reactivity of spleen lymphocytes towards concanavalin-A to secrete interferon-gamma was increased in the vaccinated group at the end of the observation period. Interleukin-6 and tumour necrosis factor-alpha secretion of alveolar macrophages as well as proliferation of stimulated thoracic lymph node cells were increased and prolonged in vaccinated mice. BCG immunisation led to a local suppression of the allergic reaction within the lung. No reduction of systemic IgE production was observed. Further studies are necessary to determine a possible time dependence of BCG immunisation.

Allergens↗

PubMed1992

Vaccination of chickens with chicken-derived Salmonella enteritidis phage type 4 aroA live oral Salmonella vaccines.

Two strains of Salmonella enteritidis phage type 4 isolated from chickens, SeLA5 and Se267, were virulent in Balb/c mice by intraperitoneal (i.p.) infection. In 18-20-day-old chickens given 10(7) c.f.u. intravenously (i.v.), both strains caused some deaths. One-day-old chicks infected orally with 10(9) c.f.u. of either strain also suffered limited mortality. Strain SeLA5 was the more virulent by the oral route. AroA mutants SeLA5 aroA and Se267 aroA were reduced in i.p. virulence by up to six logs in the Balb/c mouse model, did not kill 18-20-day-old chickens when injected i.v. and did not multiply in the tissues. Oral vaccination of chicks with either 10(9) c.f.u. at one-day-old or 10(5) c.f.u. at seven-day intervals until day 21 with vaccine strains SeLA5 aroA or Se267 aroA conferred significant protection against intravenous challenge with virulent strain Se109 NalR and reduced intestinal shedding following oral challenge. Seroconversion following oral vaccination was not seen with the lower dose regimen and was low with the higher dose. Seroconversion following oral challenge was marked in unvaccinated birds but much lower in vaccinated birds, suggesting that oral vaccination had prevented invasion by the challenge strain.

Administration, Oral↗

PubMed1996

In vitro and in vivo phenotypes resulting from deletion of the high temperature requirement A (htrA) gene from the bovine vaccine strain Brucella abortus S19.

An htrA deletion mutant was created in the bovine vaccine strain, B. abortus S19, by replacing the majority of the htrA gene with a kanamycin resistance gene. Antibiotic selection for a double crossover event yielded kanamycin-resistant, ampicillin-sensitive colonies confirmed by Southern and western blot analysis to be HtrA deficient. The B. abortus S19 htrA mutant was significantly more susceptible than the parental strain to killing by H2O2 (P < 0.001) and O(2)- generated by the redox cycling agent paraquat (P < 0.05) in disk sensitivity assays. Deletion of the htrA gene from S19 produced a bimodal effect on the spleen colonization profile of this strain in BALB/c mice. At one week post-infection, the B. abortus S19 htrA mutant colonized the spleens of experimentally infected BALB/c mice at significantly lower levels (P < 0.01) than the parental strain. Enhanced clearance (P < 0.05) was also observed at later timepoints, i.e. 4 and 7 weeks post infection, however at 2 and 3 weeks post infection, the mutant and parental strains colonized the mice at equivalent levels. The temporal development of specific delayed type hypersensitivity and antibody responses in BALB/c mice infected with the mutant or parental strain were equivalent. These results suggest that the htrA gene product contributes to successful host colonization by S19. However, deletion of this gene does not radically alter the overall, characteristic spleen colonization profile of this vaccine strain in the BALB/c mouse model, nor compromise the capacity of this strain to elicit Brucella cellular or humoral immune responses in this experimental host.

Animals↗

PubMed2004

Efficacy of the latest fluoroquinolones against experimental Yersinia pestis.

The efficacies of prophylactic and therapeutic gatifloxacin and moxifloxacin were assessed in a BALB/c mouse model of systemic and pneumonic plague and compared with ciprofloxacin. Mice were given 100 mg/kg of the antibiotic by oral administration twice daily for 7 days starting 1h prior to infection or following infection. All antibiotics offered full protection for up to 6h following systemic challenge, and for up to 30 h following an aerosol challenge. The efficacy of each of the antibiotics decreased when antibiotics were started 18 h following systemic challenge and 48 h following aerosol challenge. Fluoroquinolones may therefore be considered useful candidates for the treatment of bubonic and pneumonic plague.

Animals↗

PubMed2006

Treatment of murine pneumonic Francisella tularensis infection with gatifloxacin, moxifloxacin or ciprofloxacin.

The efficacies of gatifloxacin and moxifloxacin were assessed in a BALB/c mouse model of pneumonic tularemia and compared with the efficacy of ciprofloxacin. The rate of relapse following dexamethasone treatment was also investigated. Mice were given 100 mg/kg of the antibiotic by oral administration twice daily for 14 days following an aerosol challenge. All three fluoroquinolones prevented disease during the treatment period, but significant failure rates occurred after the cessation of therapy. Both gatifloxacin and moxifloxacin were more effective than ciprofloxacin at reducing late mortality. Fluoroquinolones may therefore be considered useful candidates for the treatment of pneumonic tularemia.

Animals↗

PubMed2004

Cysteinyl leukotriene receptor antagonist regulates vascular permeability by reducing vascular endothelial growth factor expression.

BACKGROUND: Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Cysteinyl leukotrienes (cysLTs) potently elicit increased vascular permeability in airways, leading to airway edema. Vascular endothelial growth factor (VEGF) is 1 of the most potent proangiogenic cytokines and also increases vascular permeability so that plasma proteins can leak into the extravascular space. However, the mechanisms by which cysLTs induce increased vascular permeability are not clearly understood. OBJECTIVE: An aim of the current study was to determine the role of the cysLTs, more specifically in the increase of vascular permeability. METHODS: We used a BALB/c mouse model of allergic asthma to examine effects of cysLT receptor antagonists on bronchial inflammation and airway hyperresponsiveness, more specifically on the increase of vascular permeability. RESULTS: These mice develop the following typical pathophysiological features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of VEGF. Administration of cysLT receptor antagonists markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. CONCLUSION: These results indicate that cysLT receptor antagonists modulate vascular permeability by reducing VEGF expression and suggest that cysLT receptor may regulate the VEGF expression.

Acetates↗

PubMed2006

Immunization with a low-dose replicon DNA vaccine encoding Phl p 5 effectively prevents allergic sensitization.

BACKGROUND: Replicase-based DNA vaccines stimulate T(H)1-biased immune responses at ultralow doses and induce self-removal of transfected cells through apoptosis. Both aspects are important requirements for efficient and safe DNA-based immunotherapy of type I allergies. OBJECTIVE: A Sindbis virus replicon-based DNA vaccine encoding the major timothy grass pollen allergen Phl p 5 was evaluated for its antiallergic potential compared with a conventional DNA vaccine in a BALB/c mouse model of allergy. METHODS: Mice were intradermally prevaccinated with plasmid DNA, followed by sensitization and intranasal allergen provocation with recombinant Phl p 5. In vitro proliferation and cytokine secretion was measured in splenocyte cultures. Distribution of IgG1, IgG2a, and IgE antibody subclasses was determined by means of ELISA. IgE-mediated degranulation was measured with the basophil release assay. Bronchoalveolar lavage fluid was analyzed for eosinophils, IL-4, IL-5, IL-13, and IFN-gamma. Mucus production, inflammatory infiltrates, and epithelial damage were determined in lung sections. RESULTS: Both vaccines induced T(H)1-biased immune responses, resulting in suppression of functional IgE, reduction of eosinophilia in bronchoalveolar lavage fluid, and alleviation of lung pathology. However, immunization with the replicon DNA vaccine elicited these effects at a 100-fold lower dose compared with the conventional DNA vaccine. CONCLUSIONS: The increased immunogenicity of replicon-based DNA vaccines allows for application of extremely low doses, thereby eliminating the concerns associated with conventional DNA vaccines, which have to be administered at milligram amounts to induce immune reactions in human subjects. CLINICAL IMPLICATIONS: Their high safety profile makes replicon-based DNA vaccines promising candidates for treatment of type I allergies in the clinic.

Animals↗

PubMed2004

Protection against plague afforded by immunisation with DNA vaccines optimised for expression of the Yersinia pestis V antigen.

DNA vaccine vectors were produced which were optimised for expression of the Yersinia pestis V antigen in the BALB/c mouse model. Six different eukaryotic promoters were compared, resulting in the selection of the CMV promoter with an additional translational enhancer downstream. Surprisingly, alteration of the codon usage of the lcrV gene encoding V antigen for expression in murine cells was not found to improve the antibody responses generated against V antigen. The DNA vaccine was subsequently evaluated in its delivery via intramuscular injection compared to gene-gun administration. Gene-gun delivery was found to induce significantly higher V antigen-specific antibody responses and also afforded the highest level of protection against Y. pestis challenge. In addition, the protection achieved could be increased by using a 'prime and boost' strategy, administering the DNA vaccine followed by recombinant V antigen. These results show promise for a DNA vaccine against plague.

Animals↗

PubMed2004

Oral priming of mice by recombinant spores of Bacillus subtilis.

Recombinant Bacillus subtilis spores were employed as a vaccine delivery system in a heterologous mucosal priming-parenteral boosting vaccination strategy in the mouse model. BALB/c and C57BL/6 mice were orally immunised with recombinant spores expressing tetanus toxin fragment C (TTFC) fused to the spore outer coat protein CotB, and then subcutaneously boosted with soluble TTFC (without adjuvant). Two weeks after boosting, a significantly higher serum TTFC-specific IgG response was stimulated in mice primed with recombinant spores (antibody concentration of 2600 +/- 915 in C57BL/6 and 1200 +/- 370 ng/ml in BALB/c) compared to mice inoculated with wild type spores (650 +/- 250 and 250 +/- 130 ng/ml, respectively). IgG subclass analysis showed a prevalence of IgG1 and IgG2b, indicative of a Th2 type of immune response. Oral administration of recombinant spores stimulated also a significant local TTFC-specific IgA response. These data show that recombinant spores of B. subtilis are able to prime the immune system by the oral route, and that a combined mucosal/parenteral strategy can stimulate both local and systemic antigen-specific immune responses.

Animals↗

PubMed2005

Vaccination with the divergent portion of the protein histone H2B of Leishmania protects susceptible BALB/c mice against a virulent challenge with Leishmania major.

To identify approaches for vaccination against leishmaniasis, we analyzed the protective effect of different constructions using recombinant peptides from the protein Leishmania (L.) major histone H2B. H2B sequence displays two distinct regions: an amino-terminal region divergent from mammalian H2B (27% identity) and a carboxy-terminal region highly conserved with mammalian H2B (55% identity). We tested the ability of the entire H2B protein, its divergent or conserved regions to provide protection against virulent L. major challenge. While the recombinant H2B protein adjuved with CpG induces potent cellular and antibody responses when injected to BALB/c mice, only the divergent amino-terminal region of H2B is able to confer potent protection against a virulent challenge. These findings indicate that different portions of the same parasite protein may express contrasting protective effects likely through the induction of different effector mechanisms. Due to its potent protective properties in the BALB/c mouse model, the amino-terminal region of Leishmania H2B could constitute a good vaccine candidate.

Animals↗

PubMed2006

Intramuscular immunization with a monogenic plasmid DNA tuberculosis vaccine: Enhanced immunogenicity by electroporation and co-expression of GM-CSF transgene.

Plasmid DNA vaccine has been widely explored for tuberculosis immunization but there is a need to develop the ways to improve its immunogenicity. In this study, we have constructed a plasmid DNA vaccine coding for Ag85A alone or for both Ag85A and GM-CSF and investigated the immune adjuvant effects of electroporation and GM-CSF co-expression, alone or in combination, on CD4 and CD8 T cell IFN-gamma responses, CTL activities and immune protection from pulmonary Mycobacterium tuberculosis challenge in a Balb/c mouse model. We have found that use of electroporation allows a single intramuscular (i.m.) DNA injection to be as effective as repeated i.m. DNA injections in activation of both Ag85A-specific CD4 and CD8 T cells. Co-expression of immune-enhancing cytokine GM-CSF by the same plasmid DNA TB vaccine could further enhance T cell activation including CTL activities on top of electroporation. With regard to immune protection from pulmonary M. tb challenge, use of electroporation also allows a single i.m. DNA injection to be as effective as repeated i.m. DNA injections. Co-expression of GM-CSF transgene also moderately enhances immune protection and such effect is more evident for systemic protection. However, GM-CSF expression has little added effect on immune protection by electroporation-aided immunization protocols. Our findings thus will help with the development of future DNA TB immunization strategies.

Adjuvants, Immunologic↗

PubMed2006

Equine herpesvirus 1 glycoprotein D expressed in E. coli provides partial protection against equine herpesvirus infection in mice and elicits virus-neutralizing antibodies in the horse.

The envelope glycoprotein D of EHV-1 (EHV-1 gD) is essential for virus infectivity and entry of virus into cells and is a potent inducer of virus-neutralizing antibody. In this study, truncated EHV-1 gD (gDt) was expressed with a C-terminal hexahistidine tag in E. coli using a pET vector. Western blot analysis using an anti-gD monoclonal antibody demonstrated the presence of gDt bands at 37.5, 36, 29.5 and 28 kDa. The immunogenicity and protective efficacy of partially purified gDt was compared with gD expressed in insect cells by a recombinant baculovirus (Bac gD) using a BALB/c mouse model of EHV-1 respiratory infection. The proteins were also compared in a prime-boost protocol following an initial inoculation with gD DNA. gDt elicited similar levels of gD-specific antibody and neutralizing antibody compared with Bac gD and also provided a similar level of protection against EHV-1 challenge in mice. Inoculation of horses with gDt elicited EHV-1 gD-specific antibodies including virus-neutralizing antibody, suggesting that despite the lack of glycosylation, E. coli may be a useful vehicle for large scale production of EHV-1 gD for vaccine studies.

Animals↗

PubMed2005

Role of HdeA in acid resistance and virulence in Brucella abortus 2308.

Two-dimensional gel electrophoretic analysis of cell lysates suggests that stationary phase production of wild-type levels of an ortholog of the low pH dependent chaperone HdeA in Brucella abortus 2308 during growth in a minimal medium requires the presence of the RNA binding protein Hfq. Although mutational analysis demonstrated that HdeA contributes to acid resistance in this bacterium, this protein is not required for wild-type virulence in the BALB/c mouse model. These experimental findings indicate that the brucellae rely upon additional gene products to resist the acidic conditions they encounter in the phagosomal compartment of host macrophages.

Amino Acid Sequence↗

PubMed1999

Murine B-cell and T-cell epitopes of the allergen Hev b 5 from natural rubber latex.

Hev b 5, a proline-rich acidic protein with a predominantly random secondary structure, is a major allergen in natural rubber latex and a candidate for specific immunotherapy of latex allergy. As a first step in the identification of candidate peptides for immunotherapy, we have begun to identify the B-cell and T-cell epitopes of Hev b 5 in BALB/c mice. The mice were immunized with a Hev b 5 fusion protein. The B-cell epitopes were determined by the SPOTS method using overlapping octamers or by ELISA inhibition using a series of overlapping 20-mers. The T-cell epitopes were determined by the proliferation and cytokine release of splenocytes cultured in the presence of the 20-mers. Potential antibody binding regions included residues in regions 1-38, 55-74, 109-128 and 132-151. Examination of the binding sequences for common motifs suggested enhanced antibody binding to the KXEE or KEXE sequences, where X is empty, threonine or alanine. Splenocyte stimulation and cytokine release suggest T-cell epitopes with the regions 1-20, 37-56, 73-101 and 109-146. Since they may contain major T-cell epitopes but do not exhibit significant antibody binding, peptide regions 38-48 and 75-101 are candidates for specific immunotherapy to Hev b 5 in the BALB/c mouse model.

Allergens↗

PubMed2003

Enhanced immunogenicity of SIV Gag DNA vaccines encoding chimeric proteins containing a C-terminal segment of Listeriolysin O.

We investigated the potential of the C-terminal 59-amino acid segment of Listeriolysin O (LLO) in enhancing immune responses against the SIV Gag antigen in the context of DNA immunization. Genes with codons optimized for mammalian expression were synthesized for the SIVmac239 Gag, a secreted SIV Gag protein with the tissue plasminogen antigen (tPA) signal fused to its N-terminus (tPA/Gag), as well as their corresponding chimeric proteins Gag/LLO and tPA/Gag/LLO containing the C-terminal 59 amino acids of LLO. Analysis of immune responses to these DNA constructs in a Balb/c mouse model showed that the Gag/LLO construct induced higher levels of both CD4 and CD8 T cell responses against SIV Gag, whereas the tPA/Gag construct induced higher levels of CD4 T cell responses. Moreover, immunization with the tPA/Gag/LLO construct further enhanced both CD4 and CD8 T cell responses. DNA constructs encoding secreted Gag proteins (tPA/Gag and tPA/Gag/LLO) were also more effective in eliciting antibody responses against SIV Gag. Our results demonstrate that the C-terminal segment of LLO can be effectively employed to enhance both cellular and humoral immune responses in the context of a DNA vaccine.

Animals↗

PubMed1998

Protective immunity against equine herpesvirus type-1 (EHV-1) infection in mice induced by recombinant EHV-1 gD.

The ability of recombinant preparations of equine herpesvirus type 1 (EHV-1) glycoprotein D (gD) to elicit specific antibody and T lymphocyte responses in the BALB/c mouse model of respiratory infection was investigated. Recombinant gD (rgD) expressed as a glutathione-S-transferase (GST) fusion protein in Escherichia coli elicited both high titer neutralizing antibody (nAb) and CD4 T cell proliferative responses following subcutaneous or intranasal immunization, but elicited only a weak antibody response after intraperitoneal immunization. Protection against respiratory tract infection with pathogenic EHV-1 RacL11 was observed in mice immunized subcutaneously with GST-gD. Furthermore, the degree of protection correlated to the titer of nAb and the T cell response observed. Finally, GST-gD was more effective in protecting against respiratory RacL11 infection if delivered intranasally. These results confirm that gD plays an important role in eliciting the protective immune response against EHV-1 infection, and indicate that subunit vaccines containing preparations of gD may be very effective if delivered directly to the upper respiratory tract.

Animals↗

PubMed2002

Efficiency of a myogenic DNA vaccine is strictly dependent upon cellular localization of HIV-1 Pr55(gag).

Most studies on DNA-based immunization have used viral promoters to drive antigen expression. Recently, the use of tissue-specific DNA vaccines has been favored regarding safety issues. In this study, we determined the impact of antigen localization and tissue-specific expression on the induction of humoral as well as cellular immune responses in a BALB/c mouse model. Thereby, we show that using the muscle-specific muscle creatine kinase (MCK) promoter/enhancer the efficiency of immune stimulation is strictly dependent on the ability of HIV-1 Pr55(gag) to be released from cells. By contrast, localization of Pr55(gag) and derivatives thereof plays only a minor role when antigen is constitutively expressed using the ubiquitous viral CMV promoter.

AIDS Vaccines↗

PubMed2003

Induction of murine ras oncogene peptide-specific T cell responses by immunization with plasmid DNA-based minigene vectors.

In a BALB/c mouse model, we have previously identified a ras oncogene peptide that contained both CD8(+) and CD4(+) T cell epitopes in a nested configuration. In this study, we developed several plasmid DNA minigene vectors encoding these determinants and examined whether they could induce antigen (Ag)-specific CD8(+) cytotoxic and CD4(+) lymphoproliferative responses. Furthermore, we compared two different immunization procedures, epidermal gene gun inoculation and intradermal (i.d.) injection of saline plasmid DNA, along with several approaches addressing different aspects of immune modulation. We demonstrated that each DNA plasmid induced the relevant Ag-specific cellular immune response. Gene gun inoculation was superior to that of needle injection for induction of the CTL response. Moreover, DNA plasmids containing both ras epitopes induced the highest CTL response, as compared with vector preparations containing only the CD8(+) epitope. These results suggested that a DNA plasmid expressing nested mutant ras epitope-specific CD4(+) and CD8(+) T cell epitopes can be processed in vivo to induce both subset-specific T cell responses, and that the addition of the helper epitope quantitatively improved the development of the CTL response, which may have implications for DNA-based anti-tumor immunotherapies.

Adjuvants, Immunologic↗