Active vaccination against IL-5 bypasses immunological tolerance and ameliorates experimental asthma.
Current therapeutic approaches to asthma have had limited impact on the clinical management and resolution of this disorder. By using a novel vaccine strategy targeting the inflammatory cytokine IL-5, we have ameliorated hallmark features of asthma in mouse models. Delivery of a DNA vaccine encoding murine IL-5 modified to contain a promiscuous foreign Th epitope bypasses B cell tolerance to IL-5 and induces neutralizing polyclonal anti-IL-5 Abs. Active vaccination against IL-5 reduces airways inflammation and prevents the development of eosinophilia, both hallmark features of asthma in animal models and humans. The reduced numbers of inflammatory T cells and eosinophils in the lung also result in a marked reduction of Th2 cytokine levels. Th-modified IL-5 DNA vaccination reduces the expression of IL-5 and IL-4 by approximately 50% in the airways of allergen-challenged mice. Most importantly, Th-modified IL-5 DNA vaccination restores normal bronchial hyperresponsiveness to beta-methacholine. Active vaccination against IL-5 reduces key pathological events associated with asthma, such as Th2 cytokine production, airways inflammation, and hyperresponsiveness, and thus represents a novel therapeutic approach for the treatment of asthma and other allergic conditions.
Hertz
M
M
Pharmexa A/S, DK-2970 Hørsholm, Denmark.
Mahalingam
S
S
Dalum
I
I
Klysner
S
S
Mattes
J
J
Neisig
A
A
Mouritsen
S
S
Foster
P S
PS
Gautam
A
A
D000818:Animals; D001249:Asthma / Q000276:immunology / Q000628:therapy*; D001402:B-Lymphocytes / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000628:therapy; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D007136:Immunoglobulins / Q000096:biosynthesis; D007249:Inflammation / Q000628:therapy; D015848:Interleukin-5 / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D010047:Ovalbumin / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000628:therapy; D017634:Self Tolerance; D018418:Th2 Cells / Q000276:immunology; D019444:Vaccines, DNA / Q000627:therapeutic use*
D016207:Cytokines; D007136:Immunoglobulins; D015848:Interleukin-5; D019444:Vaccines, DNA; D010047:Ovalbumin