David E. Bice

Ovalbumin aerosols induce airway hyperreactivity in naïve DO11.10 T cell receptor transgenic mice without pulmonary eosinophilia or OVA-specific antibody.

The pathobiology of allergic asthma is being studied using murine models, most of which use systemic priming followed by pulmonary challenges with the immunizing antigen. In general, mice develop eosinophilic pulmonary inflammation, increased antigen‐specific immunoglobulins, and airway hyperreactivity (AHR), all of which are dependent on antigen‐specific T cell activation. To establish a model of allergic asthma, which did not require systemic priming, we exposed DO11.10 T cell receptor transgenic mice, which have an expanded repertoire of ovalbumin (OVA), peptide‐specific T cells, to limited aerosols of OVA protein. DO11.10 +/− mice developed AHR in the absence of increases in total serum IgE, OVA‐specific IgG, or eosinophilia. The AHR was accompanied by pulmonary recruitment of antigen‐specific T cells with decreased expression of CD62L and CD45RB and increased expression of CD69, a phenotype indicative of T cell activation. Our results support recent hypotheses that T cells mediate AHR directly.

Parental allergic status influences the risk of developing allergic sensitization and an asthmatic‐like phenotype in canine offspring

Increasing evidence suggests that parental allergic status, especially that of the mother, may play a unique and important role in influencing the development of fetal infant immune responses to inhaled allergens, independently of genetic predisposition. We have developed an experimental model in dogs where the offspring from allergic parents, when exposed to inhaled allergen, develop allergic sensitization and an asthmatic phenotype, whereas the offspring from non‐allergic parents do not. Offspring from ragweed‐sensitized (two litters, nu2003=u200310) or non‐sensitized (two litters, nu2003=u200311) Beagle dogs were exposed repeatedly, by inhalation, to ragweed or filtered air (negative control) beginning within 1u2003week after birth. Serum levels of total immunoglobulin (Ig)E, and ragweed‐specific IgE and IgG, were measured at specific time‐points up to 40u2003weeks after birth. Cell differentials in the bronchoalveolar lavage were determined on days 1 and 4 following ragweed instillation into the offsprings lungs at 26u2003weeks of age. Changes in pulmonary resistance following challenge with histamine and ragweed (five breaths) were measured at 40u2003weeks after birth. Offspring from sensitized parents exposed to ragweed developed elevated serum total IgE and ragweed‐specific IgE and IgG, and showed an increased pulmonary resistance to histamine and ragweed, and increased numbers of eosinophils in bronchoalveolar lavage. In contrast, offspring from non‐sensitized parents did not exhibit this immune response. These results suggest that parental allergic sensitivity is important in the development of allergic sensitization and an asthmatic phenotype in the offspring.

Effect of Inhaled Ultrafine Carbon Particles on the Allergic Airway Response in Ragweed-Sensitized Dogs

Episodic increases in air pollution have been associated with the exacerbation of asthma symptoms. Ultrafine particles are a component of air pollution and may be involved in causing the adverse health effects associated with high air pollution. We evaluated the effects of ultrafine particle inhalation on immune and airway responses in a beagle dog model of allergic asthma. Six allergic (ragweed sensitive) and six nonallergic dogs were exposed to ultrafine carbon particles (232.3 ± 2.5 µg/m 3, 35.2 ± 0.3 nm) for 1 h, followed by a challenge with vehicle (water) as a negative control. Airway resistance was measured during particle exposure and after vehicle challenge. Immune responses 3 days before and after (1 h and 1, 4, 7, and 11 days) particle exposure were assessed by measuring total immunoglobulin E (IgE) and ragweed-specific IgE and IgG in serum and bronchoalveolar lavage fluid (BALF), and cell differentials in BALF. Each dog was exposed a second time to ultrafine carbon particles (251.4 ± 5.3 µg/m 3, 34.9 ± 0.5 nm) for 1 h followed by a challenge with ragweed and the same measurements. Airway resistance did not change during particle exposure in any of the dogs, and ragweed-induced airway reactivity was not altered by particle exposure. Total and ragweed-specific serum IgE and total IgE in BALF were higher in allergic dogs at all time points. Particle exposure did not affect antibody levels in serum or BALF in allergic dogs. Nonallergic dogs developed specific IgG in response to multiple inhalation exposures to ragweed, but this was not associated with particle exposure. Neutrophils were elevated in BALF for all groups 1 day after particle exposure. In conclusion, despite the induction of low level inflammation in the lungs of allergic and nonallergic dogs, exposure to ultrafine carbon particles did not alter airway reactivity or immune responses.

Local T‐cell activation after segmental allergen challenge in the lungs of allergic dogs

Dogs with immunoglobulin E (IgE) allergy for ragweed that are sensitized by intrapulmonary exposure to ragweed can be used to study the pulmonary immune response that is important in allergic asthma. Using this model, we tested the hypothesis that T lymphocytes are activated locally in the airways shortly after allergen exposure of the lungs. The airways of six allergic dogs and three non‐allergic dogs were exposed to ragweed by segmental allergen challenge (SAC). T‐cell subsets and T‐cell activation in blood and bronchoalveolar lavage (BAL) fluid were measured by flow cytometry before SAC and at 4, 24 and 72u2003hr thereafter. SAC caused a statistically significant increase in the percentage of major histocompatibility complex (MHC) class II‐positive CD4 and CD8 T cells in BAL fluid and a significant increase in the mean fluorescent activity of MHC class II from 4u2003hr after SAC onward. This activation was significantly different from that found in cells from lung lobes challenged with saline, or from lung lobes in non‐allergic dogs challenged with ragweed. The percentage of CD45RAbrightu2003CD8 cells increased significantly in allergic dogs after both ragweed and saline challenges. This was significantly higher than in non‐allergic dogs. We conclude that T‐cell activation in the airways of dogs can be measured after in vivo activation of the cells by measuring MHC class II and CD45RA expression in BAL fluid T cells. Furthermore, in allergic dogs, T cells are activated locally in the lungs within 4u2003hr after exposure to ragweed allergen. These results suggest a role for T lymphocytes in the development of late‐phase allergic reactions in the airways.

A model of allergic nasal congestion in dogs sensitized to ragweed

Background Acoustic rhinometry is a noninvasive method that uses sound waves to measure dimensions of the nasal cavity. Methods In this study, nasal patency was measured by acoustic rhinometry in allergic Beagle dogs sensitized to ragweed allergen. Ragweed (0.03–0.3%) or vehicle were administered intranasally in isoflurane-anesthetized dogs. Results The instillation of ragweed caused a dose-related decrease in nasal cavity volume and minimal cross-sectional area (Am in) without adverse systemic effects. Nasal cavity volume and Am in decreased within 30 minutes after instillation of the highest ragweed dose by 35.1 ± 6.0% and 66.4 ± 13.8%, respectively, and persisted for at least 90 minutes. Oral administration of α-adrenergic agonist, d-pseudoephedrine (3 mg/kg), or histamine H1 antagonist chlorpheniramine (10 mg/kg) blocked the ragweed-induced nasal congestion. Conclusion These results suggest that the canine model may be used to study upper-airway diseases such as allergic rhinitis and to evaluate the pharmacologic activity of nasal decongestants.

Nedocromil Sodium Inhibits Canine Adenovirus Bronchiolitis in Beagle Puppies

Nedocromil sodium is a nonsteroidal anti-inflammatory drug used to control asthmatic attacks. Our hypothesis is that nedocromil sodium inhibits virus-induced airway inflammation, a common trigger of asthma. We nebulized nedocromil sodium into beagle dogs (n = 10, mean ± SEM ages: 149 ± 13 days) before and after inoculation with canine adenovirus type 2 (CAV2). Control dogs (n = 10) received saline aerosols and were either infected with CAV2 (Sa1/CAV2, n = 7, mean ± SEM ages: 140 ± 11 days) or were not infected (Sal/Sal, n = 3, ages: 143 ± 0 days). All dogs were anesthetized with choralose (80 mg/kg IV), intubated, and mechanically ventilated. Pulmonary function tests and bronchoalveolar lavage (BAL) were performed using standard techniques. Pulmonary function tests revealed no significant change between the nedocromil sodium and non-nedocromil-treated groups. The percentage of infected bronchioles was quantitated as the number of inflamed airways of 40 bronchioles examined times 100 for each dog. Nedocromil-treated dogs had significantly (p < 0.05) less mucosal inflammation (mean ± SEM, 39% ± 5%), epithelial denudation (36% ± 5%), and BAL neutrophilia (11 ± 3) than did Sal/CAV2 dogs (51% ± 6%, 57% ± 4%, and 33% ± 8%, respectively). We concluded that pretreatment with nedocromil sodium aerosols attenuated CAV2-induced airway inflammation in these beagle puppies.