Aluminum-based adjuvants (aluminum salts or alum) are widely used in human vaccination, although their mechanisms of action are poorly understood. Here we report that, in mice, alum causes cell death ...and the subsequent release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production after alum-adjuvanted immunization. We suggest that, on the one hand, host DNA induces primary B cell responses, including IgG1 production, through interferon response factor 3 (Irf3)-independent mechanisms. On the other hand, we suggest that host DNA also stimulates 'canonical' T helper type 2 (T(H)2) responses, associated with IgE isotype switching and peripheral effector responses, through Irf3-dependent mechanisms. The finding that host DNA released from dying cells acts as a damage-associated molecular pattern that mediates alum adjuvant activity may increase our understanding of the mechanisms of action of current vaccines and help in the design of new adjuvants.
The oxidant/antioxidant equilibrium in horses Kirschvink, Nathalie; Moffarts, Brieuc de; Lekeux, Pierre
The veterinary journal (1997),
08/2008, Letnik:
177, Številka:
2
Journal Article, Web Resource
Recenzirano
Since “free radical research” started in 1954, understanding the role of oxidants and antioxidants in physiological and pathological conditions has increased continuously. Oxidants are essentially ...generated by metabolic enzymes, inflammatory cells and mitochondrial electron leakage; they are indispensable for the cellular redox regulation and may, under certain conditions, have a pro-inflammatory stimulatory role. Endogenous and exogenous antioxidants counterbalance the oxidative processes and so maintain the oxidant/antioxidant equilibrium. Excessive oxidant generation or antioxidant insufficiency can lead to oxidative stress. The aims of this review are: (1) to provide an insight into the concept of the oxidant/antioxidant equilibrium by briefly introducing the oxidant and the antioxidant systems; (2) to describe how the oxidant/antioxidant equilibrium or oxidative stress can be evaluated in horses, and (3) to summarise current knowledge about oxidative stress in equine medicine and equine exercise physiology.
Any disorder impairing a performance horse’s ability to ventilate its lungs and exchange oxygen compromises exercise performance in any discipline. Since bronchoalveolar lavage was described in ...horses in the early 1980s, laboratory evaluation of respiratory fluids, along with clinical and functional assessment of the respiratory system, has become a relevant step in the diagnosis of respiratory disease affecting performance. The aim of this review is to provide objective information to assist clinicians in interpreting laboratory findings by (1) summarising published cytological references values in both clinically healthy horses and those with various airway diseases, (2) assessing the influence of physiological circumstances, such as exercise, on the cytological evaluation, (3) discussing the relationship between cytological and microbiological analyses, clinical signs and respiratory function, and (4) suggesting how this latter relationship may affect performance.
Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway ...sensitization. Here, we systematically assessed the respective pro-allergic potential of individually sorted lung DC subsets isolated from house dust mite antigen (HDM)-treated donor mice, following transfer to naïve recipients. Transfer of lung CD11c(+)CD11b(+) DCs, but not CD11c(+)CD11b(-)CD103(+) DCs, was sufficient to prime airway allergy. The CD11c(+)CD11b(+) DC subpopulation was composed of CD11c(+)CD11b(+)Ly6C(+) inflammatory monocyte-derived cells, whose numbers increase in the lungs following HDM exposure, and of CD11c(+)CD11b(+)Ly6C(-) DCs, which remain stable. Counterintuitively, only CD11c(+)CD11b(+)Ly6C(-) DCs, and not CD11c(+)CD11b(+)Ly6C(+) DCs, were able to convey antigen to the lymph nodes and induce adaptive T cell responses and subsequent airway allergy. Our results thus support that lung resident non-inflammatory CD11c(+)CD11b(+)Ly6C(-) DCs are the essential inducers of allergic airway sensitization to the common aeroallergen HDM in mice.
Background Pattern-recognition receptors (PRRs) are critically involved in the pathophysiology of airway allergy, yet most of the signaling pathways downstream of PRRs implicated in allergic airway ...sensitization remain unknown. Objective We sought to study the effects of genetic depletion of interferon response factor (IRF) 3 and IRF7, important transcription factors downstream of various PRRs, in a murine model of house dust mite (HDM)–induced allergic asthma. Methods We compared HDM-induced allergic immune responses in IRF3-deficient (IRF3−/− ), IRF7−/− , and wild-type mice. Results Parameters of airway allergy caused by HDM exposure were strongly attenuated in IRF3−/− , but not IRF7−/− , mice compared with those in wild-type mice. Indeed, in HDM-exposed IRF3−/− mice HDM-specific TH 2 cell responses did not develop. This correlated with impaired maturation and migration of IRF3−/− lung dendritic cells (DCs) on HDM treatment. Furthermore, adoptive transfer of HDM-loaded DCs indicated that IRF3−/− DCs had an intrinsic defect rendering them unable to migrate and to prime HDM-specific TH 2 responses. Intriguingly, we also show that DC function and allergic airway sensitization in response to HDM were independent of signaling by type I interferons, the main target genes of IRF3. Conclusion Through its role in DC function, IRF3, mainly known as a central activator of antiviral immunity, is essential for the development of TH 2-type responses to airway allergens.
Introduction
Progress testing in education is an assessment principle for the measurement of students’ progress over time, e.g., from start to graduation. Progress testing offers valid longitudinal ...formative measurement of the growth in the cognitive skills of the individual students within the subjects of the test as well as a tool for educators to monitor potential educational gaps and mismatches within the curriculum in relation to the basic veterinary learning outcomes.
Methods
Six veterinary educational establishments in Denmark, Finland, Germany (Hannover), the Netherlands, Norway, and Sweden established in cooperation with the European Association of Establishments for Veterinary Education (EAEVE) a common veterinary item repository that can be used for progress testing in European Veterinary Education Establishments (VEEs), linear as well as computer adaptive, covering the EAEVE veterinary subjects and theoretical “Day One Competencies.” First, a blueprint was created, suitable item formats were identified, and a quality assurance process for reviewing and approving items was established. The items were trialed to create a database of validated and calibrated items, and the responses were subsequently psychometrically analyzed according to Modern Test Theory.
Results
In total, 1,836 items were submitted of which 1,342 were approved by the reviewers for trial testing. 1,119 students from all study years and all partners VEEs participated in one or more of six item trials, and 1,948 responses were collected. Responses were analyzed using Rasch Modeling (analysis of item-fit, differential item function, item-response characteristics). A total of 821 calibrated items of various difficulty levels matching the veterinary students’ abilities and covering the veterinary knowledge domains have been banked.
Discussion
The item bank is now ready to be used for formative progress testing in European veterinary education. This paper presents and discusses possible pitfalls, problems, and solutions when establishing an international veterinary progress test.
The objectives of this study were to determine the prevalence of sub-clinical diseases in poorly-performing Standardbred horses, compare their physiological response to exercise with control horses, ...and identify predictive parameters of poor-performance. Fifty horses underwent thorough clinical and ancillary examinations, including haematological and biochemical evaluation, Doppler echocardiography, standardised exercise tests (SETs) on both treadmill and racetrack, treadmill video-endoscopy and collection of respiratory fluids.
Most of the poorly-performing horses exhibited many concomitant diseases. The most frequently diagnosed problems involved the lower and upper respiratory tract and the musculoskeletal system. Poor-performers had lower speeds at a blood lactate (LA) concentration of 4
mmol/L (V
LA4) and a heart rate (HR) of 200
bpm (V
200) on treadmill and racetrack, as well as lower values for haematological parameters, plasma angiotensin-converting enzyme and antioxidants, compared to control horses. Problems of the respiratory system were the most frequently diagnosed sub-clinical diseases affecting performance. SETs, together with some blood markers, may be useful as a non-specific diagnostic tool for early detection of diseases that may affect performance.
Dendritic cells (DCs) are professional APCs that have a unique capacity to initiate primary immune responses, including tolerogenic responses. We have genetically engineered bone marrow-derived DCs ...to express the immunosuppressive cytokine IL-10 and tested the ability of these cells to control experimental asthma. A single intratracheal injection of OVA-pulsed IL-10-transduced DCs (OVA-IL-10-DCs) to naive mice before OVA sensitization and challenge prevented all of the cardinal features of airway allergy, namely, eosinophilic airway inflammation, airway hyperreactivity, and production of mucus, Ag-specific Igs, and IL-4. OVA-IL-10-DCs also reversed established experimental asthma and had long-lasting and Ag-specific effects. We furthermore showed, by using IL-10-deficient mice, that host IL-10 is required for mediating the immunomodulatory effects of OVA-IL-10-DCs and demonstrated a significant increase in the percentage of OVA-specific CD4(+)CD25(+)Foxp3(+)IL-10(+) regulatory T cells in the mediastinal lymph nodes of OVA-IL-10-DC-injected mice. Finally, adoptive transfer of CD4(+) mediastinal lymph node T cells from mice injected with OVA-IL-10-DCs protected OVA-sensitized recipients from airway eosinophilia upon OVA provocation. Our study describes a promising strategy to induce long-lasting Ag-specific tolerance in airway allergy.
Neutrophils rapidly undergo spontaneous apoptosis following their release from the bone marrow. Although central to leukocyte homeostasis, the mechanisms that regulate neutrophil apoptosis remain ...poorly understood. We show here that apoptosis of cultured neutrophils is preceded by a substantial increase in the intracellular levels of 16 and 24 carbon atom (C16‐ and C24)‐ceramides, which are lipid second messengers of apoptosis and stress signaling. Treatment of neutrophils with fumonisin B2, a selective inhibitor of the de novo pathway of ceramide synthesis, prevented accumulation of C16‐ and C24‐ceramides. Moreover, fumonisin B2 significantly reduced caspase‐3, ‐8, and ‐9 activation and apoptosis in these cells. Conversely, 3‐O‐methylsphingomyelin and fantofarone, which are specific inhibitors of neutral and acid sphingomyelinases, respectively, neither inhibited C16‐ and C24‐ceramide production nor decreased the apoptosis rate in neutrophils, indicating that in these cells, ceramides are not generated from membrane sphingomyelin. Further experiments showed that increasing endogenous C16‐ and C24‐ceramide levels by using DL‐threo‐1‐phenyl‐2‐palmitoylamino‐3‐morpholino‐1‐propanol and (1S,2R)‐D‐erythro‐2‐(N‐myristoylamino)‐1‐phenyl‐1‐propanol, two inhibitors of ceramide metabolism, enhances caspase‐3, ‐8, and ‐9 activity and increases neutrophil apoptosis. Similarly, apoptosis was induced rapidly when synthetic C16‐ and/or C24‐ceramides were added to neutrophil cultures. Finally, GM‐CSF, a cytokine that delays neutrophil apoptosis, abrogated C16‐ and C24‐ceramide accumulation totally in cultured neutrophils, whereas Fas ligation accelerated apoptosis in these cells without affecting de novo ceramide production. We conclude that de novo generation of C16‐ and C24‐ceramides contributes to spontaneous neutrophil apoptosis via caspase activation and that GM‐CSF exerts its antiapoptotic effects on neutrophils, at least partly through inhibition of ceramide accumulation.
Cadmium (Cd) induces centrilobular emphysema and is suspected to contribute to tobacco related lung diseases as chronic obstructive pulmonary disease (COPD). This study aimed to check whether the ...inflammatory process observed in rats exposed to nebulised Cd is resistant to betamethasone as observed in COPD and to determine the influence of this drug on airspace enlargement together with the MMP-2-9/TIMP-1-2 imbalance. Our results showed that betamethasone induced emphysema by itself in healthy rats. Moreover, pre-treatment of rats with betamethasone could only partially modulate the increase in bronchoalveolar lavage fluid cell counts and the absence of preventive effect of this compound against emphysema development is associated with its inability to rebalance the MMP-2-9/TIMP-1-2 ratio.
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