| 1. |
- Blodörn, Krister
(författare)
-
Development and evaluation of new generation vaccines against bovine respiratory syncytial virus
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bovine respiratory syncytial virus (BRSV) is a major cause of respiratory disease in cattle worldwide. Improved BRSV vaccines are needed, with better efficacy and longer duration of protection, in particular when used in calves with specific maternally derived antibodies (MDA). New generation BRSV vaccines should also be DIVA compliant, and thus allow continued seromonitoring in vaccinated herds, including continuous evaluation of vaccine safety and efficacy. In this thesis work, classic BRSV immunostimulating complexes (BRSV-ISCOMs) were shown to overcome inhibition by specific MDA, and induce a high level of protection, probably mediated by strong humoral and Th1 type T cell responses. Characterization of proteins in BRSV-ISCOMs was performed to facilitate future standardization or improvement of BRSV-ISCOMs, and to serve as a basis to design efficient subunit vaccines (SU). SU consisted of recombinant human RSV (HRSV) proteins P, M2-1 and N nanorings with epitopes from BRSV proteins F and G. Three DIVA-compatible vaccines, all omitting the SH protein, were evaluated: two vaccines formulated using SU, adjuvanted by either Montanide ISA71VG (SUMont) or AbISCO-300 (SUAbis); and ΔSHrBRSV, a live recombinant BRSV with deleted SH gene. The safety, immunogenicity and protective efficacy of SUMont, SUAbis and ΔSHrBRSV were compared in calves with specific MDA in a BRSV infection model with high clinical expression, which was also developed in this thesis work. Both ΔSHrBRSV and SUMont induced protection against BRSV infection, seemingly by activating different immunological pathways. ΔSHrBRSV induced almost complete clinical and virological protection, which appeared to rely mainly on mucosal IgA and systemic neutralizing antibodies directed against viral surface proteins, and T cell priming in the airways. SUMont induced a good level of protection, which appeared to be mediated by HRSV/BRSV cross-reactive specific T cells. SUAbis induced limited protection from BRSV challenge. The three vaccines BRSV-ISCOMs, ΔSHrBRSV and SUMont, individually identified as promising vaccine candidates, are described and discussed in this thesis, including possibilities to improve their immunogenicity and protective efficacy, and to further investigate induced immunity and DIVA compliancy.
|
|
| 2. |
- Blodörn, Krister, et al.
(författare)
-
Vaccine Safety and Efficacy Evaluation of a Recombinant Bovine Respiratory Syncytial Virus (BRSV) with Deletion of the SH Gene and Subunit Vaccines Based On Recombinant Human RSV Proteins: N-nanorings, P and M2-1, in Calves with Maternal Antibodies
- 2014
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9, s. 1-17
-
Tidskriftsartikel (refereegranskat)abstract
- The development of safe and effective vaccines against both bovine and human respiratory syncytial viruses (BRSV, HRSV) to be used in the presence of RSV-specific maternally-derived antibodies (MDA) remains a high priority in human and veterinary medicine. Herein, we present safety and efficacy results from a virulent BRSV challenge of calves with MDA, which were immunized with one of three vaccine candidates that allow serological differentiation of infected from vaccinated animals (DIVA): an SH gene-deleted recombinant BRSV (Delta SHrBRSV), and two subunit (SU) formulations based on HRSV-P, -M2- 1, and -N recombinant proteins displaying BRSV-F and -G epitopes, adjuvanted by either oil emulsion (Montanide ISA71(VG), SUMont) or immunostimulating complex matrices (AbISCO-300, SUAbis). Whereas all control animals developed severe respiratory disease and shed high levels of virus following BRSV challenge, Delta SHrBRSV-immunized calves demonstrated almost complete clinical and virological protection five weeks after a single intranasal vaccination. Although mucosal vaccination with DSHrBRSV failed to induce a detectable immunological response, there was a rapid and strong anamnestic mucosal BRSV-specific IgA, virus neutralizing antibody and local T cell response following challenge with virulent BRSV. Calves immunized twice intramuscularly, three weeks apart with SUMont were also well protected two weeks after boost. The protection was not as pronounced as that in Delta SHrBRSV-immunized animals, but superior to those immunized twice subcutaneously three weeks apart with SUAbis. Antibody responses induced by the subunit vaccines were non-neutralizing and not directed against BRSV F or G proteins. When formulated as SUMont but not as SUAbis, the HRSV N, P and M2-1 proteins induced strong systemic cross-protective cell-mediated immune responses detectable already after priming. Delta SHrBRSV and SUMont are two promising DIVA-compatible vaccines, apparently inducing protection by different immune responses that were influenced by vaccine-composition, immunization route and regimen.
|
|
| 3. |
- Fall, Tove, et al.
(författare)
-
Early Exposure to Dogs and Farm Animals and the Risk of Childhood Asthma
- 2015
-
Ingår i: JAMA pediatrics. - Stockholm : American Medical Association. - 2168-6203 .- 2168-6211. ; 169:11
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The association between early exposure to animals and childhood asthma is not clear, and previous studies have yielded contradictory results.OBJECTIVE: To determine whether exposure to dogs and farm animals confers a risk of asthma.DESIGN, SETTING AND PARTICIPANTS: In a nationwide cohort study, the association between early exposure to dogs and farm animals and the risk of asthma was evaluated and included all children born in Sweden from January 1, 2001, to December 31, 2010 (N = 1 011 051), using registry data on dog and farm registration, asthma medication, diagnosis, and confounders for parents and their children. The association was assessed as the odds ratio (OR) for a current diagnosis of asthma at age 6 years for school-aged children and as the hazard ratio (HR) for incident asthma at ages 1 to 5 years for preschool-aged children. Data were analyzed from January 1, 2007, to September 30, 2012.EXPOSURES: Living with a dog or farm animal.MAIN OUTCOMES AND MEASURES: Childhood asthma diagnosis and medication used.RESULTS: Of the 1 011 051 children born during the study period, 376 638 preschool-aged (53 460 [14.2%] exposed to dogs and 1729 [0.5%] exposed to farm animals) and 276 298 school-aged children (22 629 [8.2%] exposed to dogs and 958 [0.3%] exposed to farm animals) were included in the analyses. Of these, 18 799 children (5.0%) in the preschool-aged children's cohort experienced an asthmatic event before baseline, and 28 511 cases of asthma and 906 071 years at risk were recorded during follow-up (incidence rate, 3.1 cases per 1000 years at risk). In the school-aged children's cohort, 11 585 children (4.2%) experienced an asthmatic event during the seventh year of life. Dog exposure during the first year of life was associated with a decreased risk of asthma in school-aged children (OR, 0.87; 95% CI, 0.81-0.93) and in preschool-aged children 3 years or older (HR, 0.90; 95% CI, 0.83-0.99) but not in children younger than 3 years (HR, 1.03; 95% CI, 1.00-1.07). Results were comparable when analyzing only first-born children. Farm animal exposure was associated with a reduced risk of asthma in both school-aged children and preschool-aged children (OR, 0.48; 95% CI, 0.31-0.76, and HR, 0.69; 95% CI, 0.56-0.84), respectively.CONCLUSIONS AND RELEVANCE: In this study, the data support the hypothesis that exposure to dogs and farm animals during the first year of life reduces the risk of asthma in children at age 6 years. This information might be helpful in decision making for families and physicians on the appropriateness and timing of early animal exposure.
|
|
| 4. |
- Ahlström, J. Zebialowicz, et al.
(författare)
-
Synthetic surfactant with a recombinant surfactant protein C analogue improves lung function and attenuates inflammation in a model of acute respiratory distress syndrome in adult rabbits
- 2019
-
Ingår i: Respiratory Research. - : BMC. - 1465-9921 .- 1465-993X. ; 20
-
Tidskriftsartikel (refereegranskat)abstract
- AimIn acute respiratory distress syndrome (ARDS) damaged alveolar epithelium, leakage of plasma proteins into the alveolar space and inactivation of pulmonary surfactant lead to respiratory dysfunction. Lung function could potentially be restored with exogenous surfactant therapy, but clinical trials have so far been disappointing. These negative results may be explained by inactivation and/or too low doses of the administered surfactant. Surfactant based on a recombinant surfactant protein C analogue (rSP-C33Leu) is easy to produce and in this study we compared its effects on lung function and inflammation with a commercial surfactant preparation in an adult rabbit model of ARDS.MethodsARDS was induced in adult New Zealand rabbits by mild lung-lavages followed by injurious ventilation (V-T 20m/kg body weight) until P/F ratio<26.7kPa. The animals were treated with two intratracheal boluses of 2.5mL/kg of 2% rSP-C33Leu in DPPC/egg PC/POPG, 50:40:10 or poractant alfa (Curosurf (R)), both surfactants containing 80mg phospholipids/mL, or air as control. The animals were subsequently ventilated (V-T 8-9m/kg body weight) for an additional 3h and lung function parameters were recorded. Histological appearance of the lungs, degree of lung oedema and levels of the cytokines TNF alpha IL-6 and IL-8 in lung homogenates were evaluated.ResultsBoth surfactant preparations improved lung function vs. the control group and also reduced inflammation scores, production of pro-inflammatory cytokines, and formation of lung oedema to similar degrees. Poractant alfa improved compliance at 1h, P/F ratio and PaO2 at 1.5h compared to rSP-C33Leu surfactant.ConclusionThis study indicates that treatment of experimental ARDS with synthetic lung surfactant based on rSP-C33Leu improves lung function and attenuates inflammation.
|
|
| 5. |
- Akula, Srinivas, et al.
(författare)
-
Quantitative Transcriptome Analysis of Purified Equine Mast Cells Identifies a Dominant Mucosal Mast Cell Population with Possible Inflammatory Functions in Airways of Asthmatic Horses
- 2022
-
Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:22
-
Tidskriftsartikel (refereegranskat)abstract
- Asthma is a chronic inflammatory airway disease and a serious health problem in horses as well as in humans. In humans and mice, mast cells (MCs) are known to be directly involved in asthma pathology and subtypes of MCs accumulate in different lung and airway compartments. The role and phenotype of MCs in equine asthma has not been well documented, although an accumulation of MCs in bronchoalveolar lavage fluid (BALF) is frequently seen. To characterize the phenotype of airway MCs in equine asthma we here developed a protocol, based on MACS Tyto sorting, resulting in the isolation of 92.9% pure MCs from horse BALF. We then used quantitative transcriptome analyses to determine the gene expression profile of the purified MCs compared with total BALF cells. We found that the MCs exhibited a protease profile typical for the classical mucosal MC subtype, as demonstrated by the expression of tryptase (TPSB2) alone, with no expression of chymase (CMA1) or carboxypeptidase A3 (CPA3). Moreover, the expression of genes involved in antigen presentation and complement activation strongly implicates an inflammatory role for these MCs. This study provides a first insight into the phenotype of equine MCs in BALF and their potential role in the airways of asthmatic horses.
|
|
| 6. |
- Allam, Venkata, et al.
(författare)
-
Nafamostat has anti-asthmatic effects associated with suppressed pro-inflammatory gene expression, eosinophil infiltration and airway hyperreactivity
- 2023
-
Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- IntroductionAsthma is characterized by an imbalance between proteases and their inhibitors. Hence, an attractive therapeutic option could be to interfere with asthma-associated proteases. Here we exploited this option by assessing the impact of nafamostat, a serine protease inhibitor known to neutralize mast cell tryptase. MethodsNafamostat was administered in a mouse model for asthma based on sensitization by house dust mite (HDM) extract, followed by the assessment of effects on airway hyperreactivity, inflammatory parameters and gene expression. ResultsWe show that nafamostat efficiently suppressed the airway hyperreactivity in HDM-sensitized mice. This was accompanied by reduced infiltration of eosinophils and lymphocytes to the airways, and by lower levels of pro-inflammatory compounds within the airway lumen. Further, nafamostat had a dampening impact on goblet cell hyperplasia and smooth muscle layer thickening in the lungs of HDM-sensitized animals. To obtain deeper insight into the underlying mechanisms, a transcriptomic analysis was conducted. This revealed, as expected, that the HDM sensitization caused an upregulated expression of numerous pro-inflammatory genes. Further, the transcriptomic analysis showed that nafamostat suppressed the levels of multiple pro-inflammatory genes, with a particular impact on genes related to asthma. DiscussionTaken together, this study provides extensive insight into the ameliorating effect of nafamostat on experimental asthma, and our findings can thereby provide a basis for the further evaluation of nafamostat as a potential therapeutic agent in human asthma.
|
|
| 7. |
- Allam, Venkata, et al.
(författare)
-
Treatment of chronic airway diseases using nutraceuticals : Mechanistic insight
- 2022
-
Ingår i: Critical reviews in food science and nutrition. - : Taylor & Francis. - 1040-8398 .- 1549-7852. ; 62:27, s. 7576-7590
-
Forskningsöversikt (refereegranskat)abstract
- Respiratory diseases, both acute and chronic, are reported to be the leading cause of morbidity and mortality, affecting millions of people globally, leading to high socio-economic burden for the society in the recent decades. Chronic inflammation and decline in lung function are the common symptoms of respiratory diseases. The current treatment strategies revolve around using appropriate anti-inflammatory agents and bronchodilators. A range of anti-inflammatory agents and bronchodilators are currently available in the market; however, the usage of such medications is limited due to the potential for various adverse effects. To cope with this issue, researchers have been exploring various novel, alternative therapeutic strategies that are safe and effective to treat respiratory diseases. Several studies have been reported on the possible links between food and food-derived products in combating various chronic inflammatory diseases. Nutraceuticals are examples of such food-derived products which are gaining much interest in terms of its usage for the well-being and better human health. As a consequence, intensive research is currently aimed at identifying novel nutraceuticals, and there is an emerging notion that nutraceuticals can have a positive impact in various respiratory diseases. In this review, we discuss the efficacy of nutraceuticals in altering the various cellular and molecular mechanisms involved in mitigating the symptoms of respiratory diseases.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
|
|
