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Mechanisms preventing allergen-induced airways hyperreactivity: Role of tolerance and immune deviation,☆☆

https://doi.org/10.1067/mai.2000.108429Get rights and content

Abstract

Background: Aeroallergens continuously enter the respiratory tract of atopic individuals and provoke the development of asthma characterized by airway hyperreactivity (AHR) and inflammation. By contrast, nonatopic individuals are exposed to the same aeroallergens, but airway inflammation does not develop. However, the mechanisms that prevent allergen-induced respiratory diseases in nonatopic subjects are poorly characterized. Objective: In this study we compared the role of allergen-specific T-cell tolerance and immune deviation in conferring protection against the development of allergen-induced AHR. Methods: We exposed mice to intranasal ovalbumin (OVA) to induce T-cell tolerance and examined its effects on the subsequent development of AHR and inflammation. Results: We demonstrated that exposure of mice to intranasal OVA resulted in peripheral CD4+ T-cell unresponsiveness that very efficiently prevented not only the development of AHR but also greatly inhibited airway inflammation and OVA-specific IgE production. The induction of peripheral T-cell tolerance and protection against AHR were not dependent on the presence of IFN-γ or IL-4. The development of AHR was also prevented by an OVA-specific TH1-biased immune response induced by inhalation of OVA in the presence of IL-12. However, the OVA-specific TH1 response was associated with a significant degree of pulmonary inflammation. Conclusion: These results indicate that both allergen-specific T-cell tolerance and TH1-biased immune deviation prevent the development of AHR, but TH1 responses are associated with significantly greater inflammation in the lung than is associated with T-cell unresponsiveness. Therefore CD4+ T-cell unresponsiveness critically regulates immune responses to aeroallergens and protects against the development of allergic disease and asthma. (J Allergy Clin Immunol 2000;106:239-46.)

Section snippets

Animals

Five- to 6-week-old BALB/c or BALB/c IL-4–/– mice were purchased from Jackson Laboratories (Bar Harbor, Me) and were housed in pathogen-free conditions at the laboratory animal facilities of Stanford University in accordance with the guidelines of the National Institutes of Health.

Immunization protocol

Mice were exposed intranasally to 100 μg of OVA (grade V; Sigma Chemical Co, St Louis, Mo) in 30 μL of normal saline solution in the absence or presence of 1 μg of recombinant IL-12 (generously provided by Stanley

Results

We examined the effects of intranasal exposure to OVA on the subsequent response to intraperitoneal immunization with OVA in alum. Five days after the intraperitoneal injection, splenic T cells were isolated and cultured in vitro with OVA. Fig 1, A , shows that these T cells proliferated poorly compared with T cells from control mice, which received intranasal PBS before immunization with OVA in alum.

. A, Exposure to intranasal OVA induces antigen-specific T-cell unresponsiveness. BALB/c mice

Discussion

The respiratory mucosa of both atopic and nonatopic individuals is constantly exposed to a wide variety of environmental aeroallergens, but the clinical responses in these populations differ considerably, with TH2-biased allergic inflammation and AHR developing in the former and protective immunity developing in the latter. However, the specific mechanisms that downregulate the development of inflammation and AHR in normal nonatopic individuals have been poorly characterized. In this study we

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    Supported by National Institute of Health grants R01AI24571, R01AI26322, R01HL62348 and R. L. Blumenthal American Lung Association Research Awards (D. C. T.).

    ☆☆

    Reprint requests: Dale T. Umetsu, MD, PhD, Division of Allergy and Clinical Immunology, Department of Pediatrics, Rm G309, Stanford University Medical Center, Stanford, CA 94305-5208.

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