Citations

Different strains of mice exhibit different degrees of airway hyperresponsiveness after sensitization to and airway challenge with ovalbumin. Antibody responses in BALB/c mice far exceeded those in C57BL/6 mice; in contrast, although responsiveness to methacholine was much higher in the BALB/c mice, the number of eosinophils in the bronchoalveolar lavage fluid was higher in C57BL/6 animals. Sensitized and challenged BALB/c mice developed increases in lung resistance and decreases in dynamic compliance after methacholine or 5-hydroxytryptamine inhalation. C57BL/6 mice only exhibited significant levels of responsiveness when dynamic compliance was monitored in response to inhaled 5-hydroxytryptamine. Eosinophils accumulated in the peribronchial and peripheral lung tissue in BALB/c mice but were distributed diffusely in the peripheral lung tissue of C57BL/6 mice. Thus, in addition to differences in antibody responses and cholinergic agonist reactivity, differences in the responses of large and small airways may reflect the selective distribution of eosinophils in lung tissue.

Abstract The effects of an anti-CD23 monoclonal antibody (B3B4) in CD23-deficient and CD23-overexpressing mice were compared in a murine model of allergic sensitization. After sensitization and challenge with OA, mice developed increased serum levels of OA-specific IgE and IgG1 with airway eosinophilia and AHR when compared with nonsensitized animals. Anti-CD23 treatment was studied under two protocols: 10-d OA aerosol exposure and intraperitoneal sensitization followed by aerosol challenge. In both protocols anti-CD23 significantly reduced IgE and IgG1 levels, abolished eosinophilia, and normalized AHR in BALB/c and wild-type CD23+ / + mice but not in CD23− / − mice. These changes were associated with increases in IFN- γ and decreases in IL-4 production, suggesting that CD23 binding may affect not only IgE production but also the Th1/Th2 imbalance during the development of allergic AHR. Absence of CD23 in gene-deficient mice significantly enhanced OA-specific IgE and IgG1 levels, airway eosinophilia, and AHR when compared with CD23+ / + wild-type littermates after sensitization and airway challenge. Sensitized and challenged CD23 transgenic mice also developed eosinophilic airway inflammation and methacholine hyperresponsiveness. However, the extent of AHR, BAL, and tissue eosinophilia in these animals showed a significant negative correlation with levels of CD23 expression on splenic T and B cells, demonstrating a limiting role of CD23 in the development of allergic AHR. Haczku A, Takeda K, Hamelmann E, Loader J, Joetham A, Redai I, Irvin CG, Lee JJ, Kikutani H, Conrad D, Gelfand EW. CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperresponsiveness.

Abstract Allergic sensitization in asthma develops as a consequence of complex interactions between T cells and antigen-presenting cells. We have developed several in vivo models to study allergen-specific T cell and B cell function and their relevance to allergic airway hyperresponsiveness (AHR), focusing on the role of the costimulatory molecules CD80 and CD86. Treatment of mice with anti-CD86, but not anti-CD80, significantly inhibited increased serum levels of ovalbumin (OA)-specific IgE and IgG1, airway eosinophilia, and AHR both after 10 d of OA aerosol exposure (in the absence of adjuvant) and after intraperitoneal sensitization followed by repeated airway challenges. Inhibition of AHR was associated with decreased IL-4 and IL-5 levels in the BAL fluid of sensitized mice, suggesting impaired Th2 function in anti-CD86-treated animals. This effect was not seen when mice received treatment only before allergen challenge, indicating that anti-CD86 acts through inhibition of allergic sensitization and not simply by inhibiting the influx of inflammatory cells. These data suggest that the CD86 costimulatory ligand plays a major role in the development of allergic inflammation and AHR in allergen-challenged mice. Further, this study demonstrates that T–B cell interactions during allergic sensitization are amenable to therapeutic manipulation and that selective blockade of accessory signals can be an effective means for modulating distinct T cell functions.

In a mouse model of the human disease pulmonary lymphangioleiomyomatosis, treatment with rapamycin plus simvastatin prevented alveolar space enlargement and growth of TSC2-null lesions.

We have generated transgenic mice that constitutively express murine interleukin (IL)-5 in the lung epithelium. Airway expression of this cytokine resulted in a dramatic accumulation of peribronchial eosinophils and striking pathologic changes including the expansion of bronchusassociated lymphoid tissue (BALT), goblet cell hyperplasia, epithelial hypertrophy, and focal collagen deposition. These changes were also accompanied by eosinophil infiltration of the airway lumen. In addition, transgenic animals displayed airway hyperresponsiveness to methacholine in the absence of aerosolized antigen challenge. These findings demonstrate that lung-specific IL-5 expression can induce pathologic changes characteristic of asthma and may provide useful models to evaluate the efficacy of potential respiratory disease therapies or pharmaceuticals.