A hallmark of asthma is mucin overproduction, a condition that contributes to airway obstruction. The events responsible for mucin overproduction are not known but are thought to be associated with mediators of chronic inflammation. Others have shown that T-helper 2 (Th2) lymphocytes are required for mucous cell metaplasia, which then leads to mucin overproduction in animal models of allergy. We hypothesized that Th2 cell mediators are present in asthmatic airway fluid and directly stimulate mucin synthesis in airway epithelial cells. Results in cultured airway epithelial cells showed that samples of asthmatic fluid stimulated mucin (MUC5AC) synthesis severalfold more potently than non-asthmatic fluid. Consistent with this, lavage fluid from the airways of allergen-challenged dogs stimulated mucin synthesis severalfold more potently than that from non-allergen-challenged dogs. Fractionation of dog samples revealed 2 active fractions at <10 kDa and 30-100 kDa. Th2 cytokines in these molecular weight ranges are IL-9 (36 kDa), IL-5 (56 kDa), and IL-13 (10 kDa). Antibody blockade of ligand-receptor interaction for IL-9 (but not IL-5 or IL-13) inhibited mucin stimulation by dog airway fluid. Furthermore, recombinant IL-9, but not IL-5 or IL-13, stimulated mucin synthesis. These results indicate that IL-9 may account for as much as 50-60% of the mucin-stimulating activity of lung fluids in allergic airway disease.
To create an allergy model in the dog, allergic Beagles with high levels of serum immunoglobulin E (IgE) and eosinophilia were bred; resulting puppies were sensitized to ragweed by intraperitoneal (IP) injection within 24 hours of birth through 22 weeks of age. At least 50% of the puppies developed high levels of serum IgE and eosinophilia. As young adults, 6 of these dogs, and 6 control age-matched, nonallergic, nonimmunized dogs were exposed by inhalation to ragweed twice at 13-day intervals, and a third time 45 days later. Total and ragweed-specific serum IgE and ragweed-specific serum IgG were increased significantly in allergic dogs relative to baseline. Allergic dogs had significantly greater levels of antibody specific for ragweed, as well as higher eosinophil counts in the bronchoalveolar lavage fluid, compared to nonallergic dogs. Airway reactivity to histamine in allergic, but not nonallergic dogs, increased significantly after aerosol exposure to ragweed. After a third exposure to ragweed, airway responses to histamine were elevated in the allergic dogs and remained high for at least 5 months. These results demonstrate the potential of the allergic dog model for investigating the underlying pulmonary immune mechanisms and therapeutic treatment of allergic asthma.
An attenuated, recombinant Salmonella typhimurium mutant, 4072(pYA2905), expressing the surface protein antigen A (SpaA) of Streptococcus sobrinus was investigated for its effectiveness in inducing protective immune responses against S. sobrinus-induced dental caries in an experimental caries model. Fischer rats were orally immunized with either 10 8 or 10 9 CFU of S. typhimurium 4072(pYA2905). Persistence of salmonellae in Peyer's patches and spleens and the induction of immune responses were determined. Maximum numbers of salmonellae were recovered from Peyer's patches of rats within the first week of immunization, with higher numbers recovered from rats given 10 9 CFU than from those given 10 8 CFU. Serum anti-Salmonella and anti-SpaA responses increased more rapidly in rats given 10 9 CFU than in rats given 10 8 CFU. The salivary antibody response to SpaA increased with time, but the response varied in the two groups. In a separate study, rats were orally immunized with the recombinant Salmonella mutant and then challenged with cariogenic S. sobrinus 6715. The levels of serum and salivary antibody and caries activity were assessed at the termination of the experiment. Higher levels of salivary immunoglobulin A antibody to SpaA and Salmonella carrier were detected in rats given 10 9 CFU than in those given 10 8 CFU, and these responses were higher than those in nonimmunized controls. Mandibular molars from immunized rats had lower numbers of recoverable streptococci and less extensive carious lesions than those from nonimmunized, control rats. These data indicate that oral immunization with an attenuated recombinant S. typhimurium expressing SpaA of S. sobrinus induces the production of antigen-specific mucosal antibody and confers protection against dental caries.
To elucidate the role of mucosal macrophages in intestinal human cytomegalovirus (HCMV) disease, primary lamina propria macrophages (LPM) were isolated from normal human jejunum, infected with HCMV, and studied for their cytokine responses. HCMV infection of LPM was confirmed by the presence of HCMV IE72 (UL123), pp65 (UL83), and glycoprotein B (UL55) proteins, which were detected by immunofluorescence, beginning at postinfection (pi) day 3, and were sustained through pi day 12 in 0.1%-0.5% of LPM. The late protein pp28 (UL99) was also detected up to pi day 12, consistent with productive infection. HCMV infection in LPM was characterized by quantitative competitive polymerase chain reaction, with maximum levels of HCMV DNA detected at pi day 7. HCMV infection of the LPM augmented lipopolysaccharide-inducible chemokine (interleukin [IL]-8 and macrophage inflammatory protein-1alpha) and cytokine (IL-6) production. These findings suggest that mucosal macrophages, via enhanced mediator production, play an important role in intestinal inflammation associated with HCMV infection.
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