Bronchoconstriction and airway hyperresponsiveness after ovalbumin inhalation in sensitized mice

Diisocyanates are the leading cause of occupational asthma, and epidemiological evidence suggests that occupational rhinitis is a comorbid and preceding condition in patients who develop asthma. The goal of the present studies was to develop and characterize a murine model of toluene diisocyanate (TDI)-induced rhinitis. Female C57BL/6 mice were exposed to workplace-relevant concentrations of TDI vapor via inhalation for 4 h/day for 12 days with or without a 2-wk rest period and TDI challenge. Mice exposed 12 consecutive weekdays to 50 parts per billion TDI vapor showed elevated total serum IgE and increased TDI-specific IgG titers. Breathing rates were decreased corresponding with increased inspiratory time. TDI exposure elevated IL-4, IL-5, IL-13, and IFN-γ mRNA expression in the nasal mucosa, suggesting a mixed Th1/Th2 immune response. Expressions of mRNA for proinflammatory cytokines and adhesion molecules were also up-regulated. These cytokine changes corresponded with a marked influx of inflammatory cells into the nasal mucosa, eosinophils being the predominant cell type. Removal from exposure for 2 wk resulted in reduced Ab production, cytokine mRNA expression, and cellular inflammation. Subsequent challenge with 50 parts per billion TDI vapor resulted in robust up-regulation of Ab production, cytokine gene expression, as well as eosinophilic inflammation in the nasal mucosa. There were no associated changes in the lung. The present model shows that TDI inhalation induces immune-mediated allergic rhinitis, displaying the major features observed in human disease. Future studies will use this model to define disease mechanisms and examine the temporal/dose relationship between TDI-induced rhinitis and asthma.

Section: Discussionmentioning

confidence: 99%

Inhalation of Toluene Diisocyanate Vapor Induces Allergic Rhinitis in Mice

Johnson

Yücesoy

Reynolds

et al. 2007

“…In the present study, we used a murine model of allergic asthma, in which OVA-sensitized and OVA-challenged BALB/c mice display high levels of OVA-specific IgE Abs in serum, airway eosinophilia, AHR, and OVA-specific Th2 cells in lung tissue and lung-draining lymph nodes (LN), to investigate the relation between the efficacy of immunotherapy and T cell activation (17,18). Immunotherapy was performed after sensitization before challenge, by s.c. or intranasal (i.n.)…”

Section: The Efficacy Of Immunotherapy In An Experimentalmentioning

confidence: 99%

“…Previously, we described the development of an OVA-based murine model with features reminiscent of allergic asthma (17). Briefly, BALB/c mice were sensitized by seven i.p.…”

Section: Induction Of Experimental Asthma and Treatment Protocolsmentioning

confidence: 99%

The Efficacy of Immunotherapy in an Experimental Murine Model of Allergic Asthma Is Related to the Strength and Site of T Cell Activation During Immunotherapy

Janssen

Oosterhout

Nijkamp

et al. 2000

Self Cite

In the present study, the relation between the efficacy of immunotherapy, and the strength and site of T cell activation during immunotherapy was evaluated. We used a model of allergic asthma in which OVA-sensitized and OVA-challenged mice display increased airway hyperresponsiveness, airway inflammation, and Th2 cytokine production by OVA-specific T cells. In this model, different immunotherapy strategies, including different routes of administration, or treatment with entire OVA or the immunodominant T cell epitope OVA323–339, or treatment with a peptide analogue of OVA323–339 with altered T cell activation capacity were studied. To gain more insight in how immunotherapy affects allergen-specific T cells, the site of Ag-specific T cell activation and the magnitude of the T cell response induced during different immunotherapy strategies were determined using an adoptive transfer model. Our data suggest that amelioration of airway hyperresponsiveness and inflammation is associated with the induction of a strong, synchronized, and systemic T cell response, resulting in a decreased OVA-specific Th2 response. In contrast, deterioration of the disease after immunotherapy is associated with the induction of a weak nonsynchronized T cell response, resulting in the enhancement of the OVA-specific Th2 response after challenge.

“…injections of 10 g OVA (grade V, Sigma) in 0.5 ml saline on alternate days (23). Peptide treatment was performed 14 days after the last sensitization by s.c. injection of 150 l liposomes containing 300 g of peptide.…”

Section: Disease Induction and Treatment Protocolmentioning

confidence: 99%

“…We used a murine model of allergic asthma in which sensitization of BALB/c mice with OVA before OVA challenge resulted in airway hyperresponsiveness, eosinophilia, OVA-specific IgE, and production of Th2 cytokines upon OVA restimulation in vitro (23,24). The immunodominant epitope of OVA, OVA 323-339, is recognized by a population of OVA-specific Th2 cells, which produces large amounts of IL-5 upon stimulation with OVA 323-339 in vitro and which plays an important role in the development of airway symptoms in vivo (18).…”

Section: N Owadays There Is Convincing Evidence That Allergen-specifmentioning

confidence: 99%

Modulation of Th2 Responses by Peptide Analogues in a Murine Model of Allergic Asthma: Amelioration or Deterioration of the Disease Process Depends on the Th1 or Th2 Skewing Characteristics of the Therapeutic Peptide

Janssen¹,

Oosterhout²,

Rensen

et al. 2000

Self Cite

Allergen-specific CD4+ Th2 cells play an important role in the immunological processes of allergic asthma. Previously we have shown that, by using the immunodominant epitope OVA323–339, peptide immunotherapy in a murine model of OVA induced allergic asthma, stimulated OVA-specific Th2 cells, and deteriorated airway hyperresponsiveness and eosinophilia. In the present study, we defined four modulatory peptide analogues of OVA323–339 with comparable MHC class II binding affinity. These peptide analogues were used for immunotherapy by s.c. injection in OVA-sensitized mice before OVA challenge. Compared with vehicle-treated mice, treatment with the Th2-skewing wild-type peptide and a Th2-skewing partial agonistic peptide (335N-A) dramatically increased airway eosinophilia upon OVA challenge. In contrast, treatment with a Th1-skewing peptide analogue (336E-A) resulted in a significant decrease in airway eosinophilia and OVA-specific IL-4 and IL-5 production. Our data show for the first time that a Th1-skewing peptide analogue of a dominant allergen epitope can modulate allergen-specific Th2 effector cells in an allergic response in vivo. Furthermore, these data suggest that the use of Th1-skewing peptides instead of wild-type peptide may improve peptide immunotherapy and may contribute to the development of a successful and safe immunotherapy for allergic patients.