Exposure to endotoxin and allergen in early life and its effect on allergen sensitization in mice

doi:10.1067/mai.2003.1646

Journal of Allergy and Clinical Immunology

Volume 112, Issue 2, August 2003, Pages 389-396

https://doi.org/10.1067/mai.2003.1646 Get rights and content

Abstract

Background: Exposure to endotoxins, allergens, or both in early life might regulate the development of tolerance to allergens later in life. Objective: We investigated whether continuous exposure of infant mice to aerosolized endotoxin, allergen, or both inhibits subsequent allergen-induced immune and inflammatory responses. Methods: Infant BALB/c mice were pre-exposed to aerosolized endotoxin, ovalbumin (OVA), or both (3 times a week for the first 4 weeks of life) before systemic sensitization (days 1-14) and repeated airway challenge (days 28-30) with OVA. Results: Compared with that seen in negative control animals, systemic sensitization and airway allergen challenges induced high serum levels of allergen-specific IgE (0.7 ± 0.09 vs 0.02 ± 0.01 OD units), predominant T_H2-type cytokine production (IL-5 by splenic mononuclear cells in vitro, 1.2 ± 0.2 vs 0.04 ± 0.06 ng/mL), airway inflammation (bronchoalveolar lavage fluid leukocytes, 125 ± 15 vs 64 ± 7/μL; eosinophils, 28 ± 5 vs 1 ± 0/μL) and development of in vivo airway hyperreactivity (maximal enhanced pause, 11 ± 1.9 vs 4 ± 0.2). Pre-exposure with LPS before sensitization increased production of specific IgG2a (67 ± 10 vs 32 ± 5 U/mL) but failed to prevent T_H2-mediated immune responses. Pre-exposure with OVA or with OVA plus LPS completely suppressed allergen sensitization, airway inflammation, and development of in vivo airway hyperreactivity; values were similar to those of negative control animals. Inhibition was due to allergen-specific T-cell anergy indicated by omitted allergen-specific T_H2 and T_H1 immune responses. In addition, combined exposure to endotoxin and allergen induced a general shift toward an unspecific T_H1 immune response. Conclusion: Exposure with endotoxins before allergen sensitization is not able to induce unresponsiveness but might decrease the susceptibility for sensitization to a variety of common allergens. (J Allergy Clin Immunol 2003;112:389-96.)

Section snippets

Experimental protocol

All experimental procedures were approved by the animal ethics committee. Pregnant BALB/c mice were purchased from Harlan Winkelmann. Offspring were placed in a Plexiglas chamber (20 × 20 × 15 cm³) and exposed for 10 minutes, 3 times per week, from birth (day 28) to day -3 to one of the following aerosolized solutions (nebulizer by Medical Assistance System): (1) LPS (1 μg/10 mL, Escherichia coli O111:B4, Sigma); (2) ovalbumin (OVA; Grade V, 100 mg/10 mL, Sigma); or (3) a combination of LPS and

Effects of aerosolized LPS exposure on LPS-mediated immune responses

In sham-sensitized mice pre-exposed to LPS, serum levels of total IgE and IgG1, but not levels of total IgG2a, were significantly decreased compared with those of negative control animals. The decrease is associated with diminished proliferative responses and IFN-γ production by splenic MNCs after culture with LPS (Table I) but not with ConA (data not shown).

. Effects of LPS pre-exposure on LPS-mediated immune responses

Pre-exposure	n	IgE (ng/mL)	IgG1 (μg/mL)	IgG2a (μg/mL)	Proliferative responses (cpm)

Discussion

Compelling data from several epidemiologic studies show that growing up in farming or rural environments with continuous exposure to high concentrations of endotoxins, allergens, or both is protective against allergen sensitization and asthma without defining a precise mechanism.6, 9 To further delineate the effects of environmental factors, such as exposure to LPS, allergen, or both in early life, on subsequent allergen-induced immunopathology, we used a mouse model of allergen sensitization

Acknowledgements

We thank Kathrin Borgwald, Petra Ellensohn, Margret Oberreit-Menesis, and Christine Seib for their excellent technical assistance.

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^☆: Supported by Deutsche Forschungsgemeinschaft (DFG Ha 2162/2-1). Kerstin Gerhold is fellow of “PINA” (German Network for Prevention and Information of Asthma und Allergy).

^☆☆: Reprint requests: Eckard Hamelmann, MD, Department of Pediatric Pneumology and Immunology, University Hospital Charité, Augustenburger Platz 1, 13353 Berlin, Germany.

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Mechanisms of AllergyExposure to endotoxin and allergen in early life and its effect on allergen sensitization in mice☆,☆☆

Abstract

Section snippets

Experimental protocol

Effects of aerosolized LPS exposure on LPS-mediated immune responses

Discussion

Acknowledgements

Lancet

Lancet

J Allergy Clin Immunol

Lancet

Immunity

J Allergy Clin Immunol

The message from the World Asthma Meeting. The Working Groups of the World Asthma Meeting, held in Barcelona, Spain, December 9-13, 1998

Eur Respir J

The burden of childhood asthma

Arch Dis Child

Respiratory health hazards in agriculture

Am J Respir Crit Care Med

Relative scarcity of asthma and atopy among rural adolescents raised on a farm

Am J Respir Crit Care Med

Exposure to endotoxin or other bacterial components might protect against the development of atopy

Clin Exp Allergy

Levels of environmental endotoxin and prevalence of atopic disease

JAMA

Environmental exposure to endotoxin and its relation to asthma in school-age children

N Engl J Med

Does early exposure to cat or dog protect against later allergy development?

Clin Exp Allergy

Antiinterleukin-5 antibody prevents airway hyperresponsiveness in a murine model of airway sensitization

Am J Respir Crit Care Med

The identification and cloning of a murine major basic protein gene expressed in eosinophils

J Immunol

Mechanisms of Allergy
Exposure to endotoxin and allergen in early life and its effect on allergen sensitization in mice☆,☆☆