Animal Models: Antigen Challenge

One intriguing question is the extent to which virus-specific IgE might contribute to airway dysfunction. Dakhama and colleagues provide some evidence that it might by showing that lung infection with RSV in mice was associated with increased mRNA for IgE and for IgE high- and low-affinity receptors. Moreover, RSV induced mast cell degranulation in vitro. Passive sensitization with virus-specific IgE was associated with an exaggerated airway response to RSV infection. The extent to which RSV-specific IgE contributes to human disease needs further study.

In examining the events associated with allergen-induced airway reactions, Abraham and colleagues explored the role of the integrin ${alpha}$ 1ß1 (very late antigen-1, CD49a/CD29) in early and late airway reactions to antigen in allergic sheep. An aerosolized antibody to the ${alpha}$ 1 chain administered 30 minutes before allergen inhalation challenge blocked the allergen-induced late airway response (but not the early airway response) and the associated airway hyperresponsiveness, as well as the recruitment of lymphocytes, neutrophils, and eosinophils induced by segmental allergen challenge. These data suggest the importance of this receptor in allergen-induced airway inflammatory reactions.

Leigh and coworkers reported that, whereas IL-13 appeared to be important in airway hyperresponsiveness in mice who underwent acute antigen sensitization and challenge, it appeared to be unimportant in the increase in airway wall remodeling (increase in goblet cells, subepithelial collagen deposition, and ${alpha}$ -smooth muscle actin staining) in mice that had chronic (4-week) antigen exposure. This report stresses, yet again, important differences in acute versus chronic animal models of antigen exposure and "asthma."

The lung collectin, surfactant protein D, is an important component of the innate immune response. Takeda and coworkers investigated the role of surfactant protein in the development of allergic inflammation and airway hyperresponsiveness in mice exposed to ovalbumin. Allergen challenge of sensitized mice produced a progressive increase in surfactant protein D over 48 hours followed by a subsequent decrease. The levels of surfactant protein D paralleled the development of airway eosinophilia and airway hyperresponsiveness. Intratracheal administration of rat surfactant protein D to sensitized mice before the allergen challenge induced dose-dependent decreases in airway hyperresponsiveness and eosinophilia. Levels of interleukin-10, interleukin-12, and interferon- ${gamma}$ in bronchoalveolar fluid were increased, and goblet cell hyperplasia was decreased. Administration of a mutant form of the surfactant had no effect. Culture of alveolar macrophages combined with surfactant protein-D and allergen resulted in increased production of interleukin-10, interleukin-12, and interferon- ${gamma}$ . The authors conclude that surfactant protein-D decreases airway inflammation and airway hyperresponsiveness after airway challenge in sensitized mice and that the effects are mediated in part by alveolar macrophages.

To determine whether strains of mice differ in their susceptibility to asthmatic-type responses, Shinagawa and Kojima screened four strains of mice (A/J, BALB/c, C57BL/6, and C3H/HeJ) by giving antigen into the nose and assessing the evoked response. Continuous eosinophilic inflammation was observed only in A/J mice, and not in the other three strains. Twelve weeks after antigen exposure, the A/J mice exhibited features characteristic of airway remodeling (airway wall thickening and increased collagen deposition). The A/J mice exhibited persistent airway hyperresponsiveness after chronic exposure to the antigen. The BALB/c mice exhibited less eosinophilic inflammation, collagen deposition, and airway wall thickening than did the A/J mice, and airway hyperresponsiveness was absent. The C57BL/6 and C3H/HeJ mice exhibited no eosinophilic inflammation, airway wall thickening, or airway hyperresponsiveness; deposition of collagen was slightly increased. In the A/J mice, antigen challenge by inhalation (after ovalbumin/alum immunization) led to only a transient increase in eosinophils and less airway wall thickening, indicating the importance of the protocol used. The authors conclude that use of the A/J strain of mice and delivering antigen by nasal instillation is the preferred mouse model for studying mechanisms underlying asthma. An editorial commentary by Shore accompanies this article.

Long-term exposure to allergen can attenuate inflammation and revert airway hyperreactivity to normal responsiveness. Cui and coworkers developed a model of this reversal by administering multiple daily airway challenges to ovalbumin-sensitized and challenged mice. The reversal in inflammation and airway hyperresponsiveness was associated with a transition from Th2 to Th1 cytokine profile in bronchoalveolar fluid. Transfer of cells from mice exposed to long-term allergen challenges into hyperreactive mice induced normal airway responsiveness, indicating that active suppression was responsible for the reversal of the hyperresponsiveness; the transfer of cells did not affect eosinophil airway inflammation. After suppression of airway responsiveness (by long-term allergen challenge), hyperresponsiveness could be reestablished by depleting ${gamma}$ ${delta}$ T cells, especially V ${gamma}$ 4⁺ cells. Antigen-specific tolerance of ${alpha}$ ß T cells or suppression by non- ${gamma}$ ${delta}$ T cells did not contribute to normalization of airway hyperresponsiveness; and ${gamma}$ ${delta}$ T cells were not involved in the regulation of the allergic inflammatory response. The authors conclude that the normalization of airway hyperresponsiveness through use of long-term allergen challenge in previously hyperreactive mice is based on several independent regulatory mechanisms, including active suppression of airway responsiveness that requires ${gamma}$ ${delta}$ T cells.

Because complement anaphylatoxins (C3a and C5a) are thought to contribute to the development of allergic asthma in mice, Taube and coworkers investigated the effects of inhibiting complement activation after sensitization (but before allergen challenge) on the development of allergic airway inflammation and airway hyperresponsiveness. Complement activation was prevented with complement receptor–related gene y (Crry) fused to the IgG1 hinge, CH2 and CH3 domains (Crry-Ig), which accelerates decay in both the classic and alternative pathways of complement, and is also a cofactor for the cleavage of C3b and C4b mediated by factor I. After mice had been sensitized with ovalbumin (Days 1 and 14), Crry-Ig was administered. When the mice were subsequently challenged with ovalbumin, Crry-Ig prevented the development of airway hyperresponsiveness, decreased airway and lung eosinophilia, decreased lung lymphocytes, decreased interleukin-4, interleukin-5, and interleukin-13 in bronchoalveolar fluid, and decreased serum-specific IgE and IgG1. The authors conclude that inhibition of the classic and alternative pathways of complement decreases airway inflammation and prevents the development of airway hyperreactivity when sensitized mice are challenged with ovalbumin.

Citations 1-7 of 7 total displayed.

The Role of Virus-specific Immunoglobulin E in Airway Hyperresponsiveness

Azzeddine Dakhama, Jung-Won Park, Christian Taube, Kosuke Chayama, Annette Balhorn, Anthony Joetham, Xu-Dong Wei, Rhi-Hua Fan, Christina Swasey, Nobuaki Miyahara, Taku Kodama, Alberto Alvarez, Katsuyuki Takeda, and Erwin W. Gelfand
Am. J. Respir. Crit. Care Med. 170: 952 -959. First published online as doi:10.1164/rccm.200311-1610OC [Abstract] [Full text]

Is Interleukin-13 Critical in Maintaining Airway Hyperresposiveness in Allergen-challenged Mice?

Richard Leigh, Russ Ellis, Jennifer Wattie, Debra D. Donaldson, and Mark D. Inman
Am. J. Respir. Crit. Care Med. 170: 851 -856. First published online as doi:10.1164/rccm.200311-1488OC [Abstract] [Full text]

A Monoclonal Antibody to ${alpha}$ 1ß1 Blocks Antigen-induced Airway Responses in Sheep

William M. Abraham, Ashfaq Ahmed, Irakli Serebriakov, Amie N. Carmillo, Janine Ferrant, Antonin R. de Fougerolles, Ellen A. Garber, Philip J. Gotwals, Victor E. Koteliansky, Fred Taylor, and Roy R. Lobb
Am. J. Respir. Crit. Care Med. 169: 97 -104. First published online as doi:10.1164/rccm.200304-543OC [Abstract] [Full text]

Inhibition of Complement Activation Decreases Airway Inflammation and Hyperresponsiveness

Christian Taube, Yeong-Ho Rha, Katsuyuki Takeda, Jung-Won Park, Anthony Joetham, Annette Balhorn, Azzeddine Dakhama, Patricia C. Giclas, V. Michael Holers, and Erwin W. Gelfand
Am. J. Respir. Crit. Care Med. 168: 1333 -1341. First published online as doi:10.1164/rccm.200306-739OC [Abstract] [Full text]

Modeling Airway Remodeling: The Winner by a Nose?

Stephanie A. Shore
Am. J. Respir. Crit. Care Med. 168: 910-911. [Full text]

Mouse Model of Airway Remodeling: Strain Differences

Kazuhiko Shinagawa and Masami Kojima
Am. J. Respir. Crit. Care Med. 168: 959 -967. First published online as doi:10.1164/rccm.200210-1188OC [Abstract] [Full text]

Surfactant Protein D Regulates Airway Function and Allergic Inflammation through Modulation of Macrophage Function

Katsuyuki Takeda, Nobuaki Miyahara, Yeong-Ho Rha, Christian Taube, Eun-Seok Yang, Anthony Joetham, Taku Kodama, Annette M. Balhorn, Azzeddine Dakhama, Catherine Duez, Amanda J. Evans, Dennis R. Voelker, and Erwin W. Gelfand
Am. J. Respir. Crit. Care Med. 168: 783 -789. First published online as doi:10.1164/rccm.200304-548OC [Abstract] [Full text]

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