Persistence of bronchopulmonary hyper-reactivity and eosinophilic lung inflammation after anti-IL-5 or -IL-13 treatment in allergic BALB/c and IL-4Ralpha knockout mice.
BACKGROUND
Antigen-induced bronchopulmonary hyper-reactivity (BHR) is generally associated with eosinophilia. It involves cytokines produced by Th2 lymphocytes, including IL-4, IL-5 and IL-13, which are implicated in IgE production, eosinophil differentiation and attraction, and related events relevant to allergic inflammation, whose mechanisms remain unclear.


OBJECTIVE
To investigate the mechanisms by which Th2 cytokines mediate eosinophilia and subsequent BHR using ovalbumin (OVA)-immunized and OVA-challenged IL-4Ralpha-/- and IL-4-/- mice, which fail to transduce and/or to produce IL-4 and IgE as compared with wild type (WT) mice, and specific neutralizing antibodies.


METHODS
On days 0 and 7, mice were immunized subcutaneously (s.c.) with OVA. At day 14, anti-IL-5 or anti-IL-13 antibodies were administered intranasally and/or intravenously before allergenic challenge. Different functional and cellular parameters were studied in vivo and cytokine production was followed with a newly described ex vivo procedure using lung explants.


RESULTS
IL-4Ralpha-/- and IL-4-/- mice developed BHR and pulmonary eosinophilia, even though eosinophil recruitment to the bronchoalveolar liquid lavage (BALF) was reduced. In vivo, IL-4-/- and IL-4Ralpha-/- mice produced, respectively, no or reduced amounts of IL-5 in the BALF/serum as compared with WT mice, whereas no IL-13 in the BALF was detected. By contrast, ex vivo, surviving lung explants from WT and IL-4-/- or IL-4Ralpha-/- mice produced IL-13 and large amounts of IL-5. The neutralization of IL-5 in vivo (BALF and serum) and ex vivo (from lung explant) in IL-4Ralpha-/- and WT mice failed to suppress BHR and lung eosinophilia, and to modify IL-13 production ex vivo. In addition, neutralization of IL-13 in vivo from lung explant also failed to abrogate BHR and lung eosinophilia, whereas IL-5 was unchanged.


CONCLUSIONS
Antigen-induced BHR can develop independently from IL-4, IL-5 or IL-13 and from the IL-4alpha receptor chain, suggesting a possible novel IL-4, IL-5 and IL-13-independent pathway for the development of BHR in allergic BALB/c mice. The failure of IL-5 or IL-13 antibodies to prevent BHR in IL-4Ralpha-/- mice suggests that neither is indispensable for BHR but does not exclude a role for lung tissue eosinophilia.
Proust
B
B
Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur-INSERM, Paris, France.
Nahori
M A
MA
Ruffie
C
C
Lefort
J
J
Vargaftig
B B
BB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity; D017077:Culture Media, Conditioned; D004804:Eosinophils / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology*; D007114:Immunization; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D018793:Interleukin-13 / Q000276:immunology*; D015848:Interleukin-5 / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019948:Receptors, Interleukin-4 / Q000235:genetics*; D017211:Treatment Failure
D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D007074:Immunoglobulin G; D018793:Interleukin-13; D015848:Interleukin-5; D019948:Receptors, Interleukin-4; D007073:Immunoglobulin E