Genetic Analysis of Antigen-Induced Airway Manifestations of Asthma Using Recombinant Congenic Mouse Strains* (original) (raw)
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Mouse genetic model for antigen-induced airway manifestations of asthma
Genes and Immunity, 2007
Allergic asthma is a genetically complex disease characterized by allergen-specific immunoglobulin (Ig)E, eosinophilic inflammation of the lungs and airway hyper-responsiveness to bronchospasmogenic stimuli. In this study, we compared 13 recombinant congenic (RC) mouse strains in an ovalbumin model of allergic asthma. Different intensities and types of responses are observed throughout the RC strains. Intensities range from resistance to asthma in CcS05, to a very severe bronchoconstrictive reaction upon methacholine challenge for the parental STS strain. All strains show a 'modified' Th2 response except CcS14, which shows a 'true' Th2 response. When data from all strains are pooled, airway reactivity shows significant correlations with the serum Ig levels and the levels of interleukin (IL)-4, IL-5 and IL-13 in the broncho-alveolar lavage (BAL), at low dosage of methacholine (below 25 mg/ml), whereas at high dosage airway reactivity only correlates with BAL neutrophil levels. This indicates that at least two different mechanisms are involved in the airway reactivity to methacholine. None of these correlations can be found in every individual strain, which demonstrates that the asthma traits in this mouse model are genetically dissociated and that the loci can be genetically mapped.
Allergen-induced airway disease is mouse strain dependent
American journal of physiology. Lung cellular and molecular physiology, 2003
We investigated the development of airway hyperreactivity (AHR) and inflammation in the lungs of nine genetically diverse inbred strains of mice [129/SvIm, A/J, BALB/cJ, BTBR+(T)/tf/tf, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ] after sensitization and challenge with ovalbumin (OVA). At 24, 48, and 72 h post-OVA exposure, the severity of AHR and eosinophilic inflammation of the mouse strains ranged from relatively unresponsive to responsive. The severity of the airway eosinophilia of some strains did not clearly correlate with the development of AHR. The temporal presence of T helper type 2 cytokines in lung lavage fluid also varied markedly among the strains. The levels of IL-4 and IL-13 were generally increased in the strains with the highest airway eosinophilia at 24 and 72 h postexposure, respectively; the levels of IL-5 were significantly increased in most of the strains with airway inflammation over the 72-h time period. The differences of physiological and biological res...
Quantitative Trait Loci Controlling Allergen-Induced Airway Hyperresponsiveness in Inbred Mice
American Journal of Respiratory Cell and Molecular Biology, 2000
Identification of the genetic loci underlying asthma in humans has been hampered by variability in clinical phenotype, uncontrolled environmental influences, and genetic heterogeneity. To circumvent these complications, the genetic regulation of asthma-associated phenotypes was studied in a murine model. We characterized the strain distribution patterns for the asthma-related phenotypes airway hyperresponsiveness (AHR), lung eosinophils, and ovalbumin (OVA)-specific serum immunoglobulin (Ig) E induced by allergen exposure protocols in A/J, AKR/J, BALB/cJ, C3H/HeJ, and C57BL/6J inbred strains and in (C3H/HeJ ϫ A/J)F1 mice. Expression of AHR differed between strains and was sometimes discordant with lung eosinophils or serum IgE. Furthermore, we identified two distinct quantitative trait loci (QTL) for susceptibility to allergeninduced AHR, Abhr1 (allergen-induced bronchial hyperresponsiveness) (lod ϭ 4.2) and Abhr2 (lod ϭ 3.7), on chromosome 2 in backcross progeny from A/J and C3H/HeJ mice. In addition, a QTL on chromosome 7 was suggestive of linkage to this trait. These QTL differ from those we have previously found to control noninflammatory AHR in the same crosses. Elucidation of the genes underlying these QTL will facilitate the identification of biochemical pathways regulating AHR in animal models of asthma and may provide insights into the pathogenesis of human disease. Materials and Methods Animals Studies were performed in age-matched, virus-free, male mice obtained from Jackson Laboratory (Bar Harbor, ME) at 4 wk of age and allowed to acclimate for 1 to 2 wk before experimentation. A/J (n ϭ 94), AKR/J (n ϭ 5), BALB/cJ (n ϭ 5), C57BL/6J (n ϭ 7), C3H/HeJ (n ϭ 99), (C3H/HeJ ϫ A/J)F1 (n ϭ 39), (A/J ϫ C3H/ HeJ)F1 (n ϭ 5), [A/J ϫ (C3H/HeJ ϫ A/J)F1] backcross (n ϭ 780), [(C3H/HeJ ϫ A/J)F1 ϫ A/J] backcross (n ϭ 58), [C3H/HeJ ϫ (C3H/HeJ ϫ A/J)F1] backcross (n ϭ 124), and [(C3H/HeJ ϫ A/J)F1 ϫ (C3H/HeJ ϫ A/J)F1]F2 (n ϭ 128) mice were studied. No differences in the range or trends of allergen-induced AHR were seen between [A/J ϫ (C3H/HeJ ϫ A/J)F1] and [(C3H/HeJ ϫ A/J)F1 ϫ A/J] backcross mice, so these groups were combined and are referred to collectively as A/J backcross mice. Animals were housed under high-efficiency particulate absolute (HEPA) laminar flow hoods in an environmentally controlled facility and allowed free access to ovalbumin (OVA)-free rodent chow and water.
International Immunology, 2003
Histamine is an important mediator released from activated mast cells provoked by allergen and has a substantial role in the pathophysiology of asthma. However, several lines of evidence indicate that histamine could also have important functions in the regulation of basic cell biological processes. We have used histidine decarboxylase gene-targeted (HDC-KO) mice, lacking histamine, to investigate the effect of histamine de®ciency in an animal model of asthma. Our previous investigations revealed that HDC-KO mice had fewer mast cells with reduced granular content and defective degranulation characteristics. Ovalbumin (OVA)-sensitized and challenged HDC-KO mice had signi®cantly reduced airway hyper-responsiveness, lung in¯ammation, bronchoalveolar lavage eosinophilia, and OVA-speci®c IgE compared with congenic wild-type littermates treated in the same way. Comparing the expression pro®les of cytokines, the levels of IL-1a, IL-1b, IL-4, IL-5, IL-6 and IFN-g were signi®cantly lower in the HDC-KO mice in asthmatic late phase, indicating a signi®cantly altered immune response to OVA provocation and challenge. Evaluation of chemokine gene expression revealed that OVA treatment caused elevation of both T h 1-and T h 2-type chemokines in wild-type mice, while the chemokine expression was polarized toward a T h 1 response in HDC-KO mice. According to our results we can suggest that the possible causes of the reduced asthma symptoms in the HDC-KO mice may be the imperfect mast and eosinophil cell system, and an altered immune response to OVA provocation and challenge.
American Journal of Respiratory Cell and Molecular Biology, 1999
Nonspecific airway hyperresponsiveness (AHR) is a hallmark of human asthma. Both airway eosinophilia and high serum levels of total and antigen-specific immunoglobulin E (IgE) are associated with AHR. It is unclear, however, whether either eosinophilia or increased IgE levels contribute directly to, or predict, the development of AHR. Investigations conducted with various murine models of asthma and different mouse strains have resulted in conflicting evidence about the roles that IgE and airway eosinophilia play in the manifestation of AHR. We show that systemic priming with ovalbumin (OVA) in alum, followed by a single day of OVA aerosol challenge, is sufficient to induce AHR, as measured by increased pulmonary resistance in response to intravenously delivered methacholine in BALB/c, but not C57BL/6 or B 6 D 2 F1, mice. This was observed despite the fact that OVA-challenged BALB/c mice had less airway eosinophilia and smaller increases in total IgE than either C57BL/6 or B 6 D 2 F1 mice, and had less pulmonary inflammation and OVA-specific IgE than B 6 D 2 F1 mice. We conclude that airway eosinophilia, pulmonary inflammation, and high serum levels of total or OVA-specific IgE are all insufficient to induce AHR in C57BL/6 and B 6 D 2 F1 mice, whereas BALB/c mice demonstrate AHR in the absence of airway eosinophilia. These data confirm that the development of AHR is genetically determined, not only in naive mice, but also in actively immunized ones, and cannot be predicted by levels of airway eosinophilia, pulmonary inflammation, total IgE, or antigen-specific IgE. . 1999. Dissociation of airway hyperresponsiveness from immunoglobulin E and airway eosinophilia in a murine model of allergic asthma. Am. J. Respir. Cell Mol.
Respiratory medicine, 2000
Brown-Norway (BN) rats develop airway hyper-responsiveness and lung eosinophilia 18-24 h after ovalbumin (OA) challenge. We hypothesized therefore that allergen-induced airway inflammation would further enhance airway responses to a subsequent antigen challenge. Animals were sensitized to both OA and bovine serum albumin (BSA) and, 14 days later, challenged by aerosols with both antigens 24 h apart. Measurements of pulmonary resistance (RL) were made for 8 h after the second antigen challenge and bronchoalveolar lavage (BAL) was performed. Animals were divided into three groups and received two challenges as follows: saline-BSA (n=9), OA-saline (n=8) and OA-BSA (n=10). Sensitization was confirmed by measurements of specific OA-IgE and BSA-IgE. Early responses [determined as the highest value of RL within the first 30 min after the challenge] were absent in all study groups. The late responses [determined from the area under the RL versus time curve from 120 to 480 min after the chal...
Immunogenetics, 2009
Murine models of allergic lung disease have many similar traits to asthma in humans and can be used to investigate mechanisms of allergic sensitization and susceptibility factors associated with disease severity. The purpose of this study was to determine strain differences in allergic airway inflammation, immunoglobulin production, and changes in respiratory responses between systemic and mucosal sensitization routes in BALB/cJ, FVB/NJ, and C57BL/6J, and to provide correlations between immune and pathophysiological endpoints. After a single intranasal ovalbumin (OVA) challenge, all three strains of mice systemically sensitized with OVA and adjuvant exhibited higher airflow limitation than non-sensitized mice. No changes were seen in mice that were pre-sensitized via the nose with OVA. Systemic sensitization resulted in an elevated response to methacholine (MCH) in BALB/cJ and FVB/NJ mice and elevated total and OVA-specific IgE levels and pulmonary eosinophils in all three strains. The mucosal sensitization and challenge produced weaker responses in the same general pattern with the C57BL/6J strain producing less serum IgE, IL5, IL13, and eosinophils in lung fluid than the other two strains. The converse was found for IL6 where the C57BL/6J mice had more than twice the amount of this cytokine. The results show that the FVB/NJ and BALB/cJ mice are higher Th2-responders than the C57BL/6J mice and that the levels of pulmonary eosinophilia and cytokines did not fully track with MCH responsiveness. These differences illustrate the need to assess multiple endpoints to provide clearer associations between immune responses and type and severity of allergic lung disease.