CpG oligodeoxynucleotides do not require TH1 cytokines to prevent eosinophilic airway inflammation in a murine model of asthma.
BACKGROUND
Oligodeoxynucleotides (ODNs) containing the dinucleotide CpG in a specific sequence context (CpG-ODNs) have the ability to prevent the development of eosinophilic airway inflammation and bronchial hyperreactivity in a murine model of asthma. We have previously demonstrated that CpG-ODNs stimulate expression of the T(H1)-inducing cytokines IFN-gamma and IL-12 in a murine model of asthma and that this stimulation is associated with the protection against asthmatic inflammation.


OBJECTIVE
The purpose of this study was to examine whether the protection conferred by CpG-ODNs in a schistosome egg-egg antigen murine model of asthma is dependent on the induction of IFN-gamma, IL-12, or both.


METHODS
C57BL/6 mice were sensitized to schistosome eggs in the presence or absence of CpG-ODNs or control ODNs and then stimulated with soluble egg antigen in the airway. The protection offered by CpG-ODNs in these mice was compared with the protection induced by CpG-ODNs in IL-12 and IFN-gamma knockout mice and in mice treated with anticytokine blocking antibodies. Double-knockout mice (IL-12/IFN-gamma) were also generated and used in these studies. Determinations included airway eosinophilic inflammation and bronchial hyperreactivity to inhaled methacholine.


RESULTS
We found that CpG-ODNs confer protection against both airway eosinophilia and bronchial hyperreactivity in the absence of IFN-gamma or IL-12 or in the presence of both cytokines together. However, in the absence of either IL-12 or IFN-gamma, mice require 10 times as much CpG-ODNs to be protected against the induction of airway eosinophilia. The T(H2) cytokines IL-4 and IL-5 were reduced in all of the CpG-treated mice, although less in the absence of IL-12 and IFN-gamma.


CONCLUSIONS
These data indicate that CpG-ODNs prevent the generation of T(H2)-like immune responses by multiple mechanisms, which involve, but do not require, IL-12 and IFN-gamma. A direct suppressive effect of CpG-ODNs on T(H2) responses is suggested by their reduction in IFN-gamma and IL-12 knockout mice.
Kline
J N
JN
Departments of Medicine and Pathology, University of Iowa College of Medicine, Iowa City, USA.
Krieg
A M
AM
Waldschmidt
T J
TJ
Ballas
Z K
ZK
Jain
V
V
Businga
T R
TR
D000818:Animals; D001249:Asthma / Q000503:physiopathology / Q000517:prevention & control; D016535:Bronchial Hyperreactivity / Q000517:prevention & control; D018899:CpG Islands / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000517:prevention & control; D005260:Female; D007249:Inflammation / Q000517:prevention & control; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012140:Respiratory Tract Diseases / Q000517:prevention & control; D018417:Th1 Cells / Q000737:chemistry; D018418:Th2 Cells / Q000737:chemistry
D016207:Cytokines; D018664:Interleukin-12; D007371:Interferon-gamma