Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice.

BACKGROUND: New preventive strategies against the development of allergic diseases focus on potentially immunomodulatory components, such as bacterial LPSs. Optimal time frames for initiating immunomodulation to receive a sufficient effect against allergen sensitization are still unclear. OBJECTIVE: Using a mouse model, we investigated the influence of prenatal LPS exposure on later allergen-mediated sensitization and airway inflammation in the offspring. METHODS: Pregnant BALB/c mice were repeatedly exposed to aerosolized LPS (LPS Escherichia coli; 3x per week, day 7 of gestation time up to delivery). Some of the offspring were further exposed to aerosolized LPS before allergen sensitization with ovalbumin (OVA; administered intraperitoneally day 28 up to day 42) and OVA airway challenges (days 56-58). Positive control animals were placebo exposed to PBS instead of LPS, and negative control animals were first placebo exposed and later placebo sensitized with PBS instead of OVA. RESULTS: Compared with positive control animals, prenatal LPS exposure suppressed (1) allergen-specific sensitization (IgE production), (2) eosinophilic airway inflammation (reduced numbers of eosinophils in bronchoalveolar lavage fluids), and (3) in vivo airway reactivity in response to methacholine. These effects occurred only when prenatal was combined with further postnatal LPS exposure. Suppression of allergen-mediated inflammatory responses was associated with increased Toll-like receptor and T-bet expression by lung tissues and a shift toward predominantly T(H)1 immune responses in spleen cells cultured with OVA in vitro. CONCLUSION: Prenatal initiated and postnatal sustained LPS exposure increased endotoxin susceptibility and prevented later allergen sensitization in offspring through inhibition of T(H)2 immune responses. CLINICAL IMPLICATIONS: Immunomodulation with bacterial compounds during gestation time might be an effective mode for first-step primary prevention against allergic diseases.

Endotoxins prevent murine IgE production, T(H)2 immune responses, and development of airway eosinophilia but not airway hyperreactivity.

BACKGROUND: Contact with immunomodulatory factors, such as LPS, in early infancy is associated with decreased allergen sensitization. OBJECTIVE: We sought to study the effects of systemic or airway exposure with LPS on the development of allergen sensitization, eosinophilic airway inflammation, and increased in vivo airway reactivity (AR) in a mouse model. METHODS: BALB/c mice were systemically sensitized with ovalbumin (OVA) plus adjuvant on days 1 and 14 and challenged through the airways with allergen on days 34 to 36. We performed measurement of OVA-specific IgE serum levels, in vitro T(H)2 cytokine production, differential cell counts in bronchoalveolar lavage fluids, and assessment of in vivo AR to inhaled methacholine by means of barometric whole-body plethysmography. RESULTS: Systemic LPS administration before OVA sensitization reduced OVA-specific IgE serum levels (426 +/- 76 vs 880 +/- 104 U/mL, P <.01), T(H)2 cytokine production by splenic mononuclear cells (IL-4: 0.08 +/- 0.01 vs 0.17 +/- 0.01 ng/mL; IL-5: 1.98 +/- 0.52 vs 4.11 +/- 0.54 ng/mL; P <.01), and extent of airway eosinophilia (total cell counts: 93 vs 376 x 10(3)/mL; eosinophils: 23% vs 51%; P <.01) compared with that in OVA-sensitized mice. Local LPS administration to sensitized mice before airway allergen challenges particularly induced IFN-gamma production by peribronchial lymph node cells in vitro (1718 +/- 315 vs 483 +/- 103 ng/mL, P <.01) associated with reduced airway eosinophilia compared with that seen in OVA-sensitized mice. Development of increased AR was not affected by systemic or local LPS exposure. Inhibitory effects of LPS on allergen sensitization and eosinophilic airway inflammation were inhibited by administration of anti-IL-12 antibodies before LPS exposure. CONCLUSION: These data indicate that local and systemic application of LPS modulates systemic and local T(H)1/T(H)2 immune responses in a distinct but similarly IL-12-dependent mode.