Inhibition of antigen-induced eosinophilia and late phase airway hyperresponsiveness by an IL-5 antisense oligonucleotide in mouse models of asthma.
Chronic airway eosinophilia is associated with allergic asthma and is mediated in part by secretion of IL-5 from allergen-specific Th2 lymphocytes. IL-5 is a known maturation and antiapoptotic factor for eosinophils and stimulates release of nascent eosinophils from bone marrow into the peripheral circulation. An antisense oligonucleotide found to specifically inhibit IL-5 expression in vitro was observed to significantly reduce experimentally induced eosinophilia in vivo, in both the murine OVA lung challenge and allergic peritonitis models. Intravenous administration resulted in sequence-dependent inhibition of eosinophilia coincident with reduction of IL-5 protein levels, supporting an antisense mechanism of action. Potent suppression of lung eosinophilia was observed up to 17 days after cessation of oligonucleotide dosing, indicating achievement of prolonged protection with this strategy. Furthermore, sequence-specific, antisense oligonucleotide-mediated inhibition of Ag-mediated late phase airway hyperresponsiveness was also observed. These data underscore the potential utility of an antisense approach targeting IL-5 for the treatment of asthma and eosinophilic diseases.
Karras
J G
JG
Departments of Molecular and Cellular Pharmacology and Pharmacology, Isis Pharmaceuticals, Carlsbad, CA 92008, USA. jkarras@isisph.com
McGraw
K
K
McKay
R A
RA
Cooper
S R
SR
Lerner
D
D
Lu
T
T
Walker
C
C
Dean
N M
NM
Monia
B P
BP
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000941:Antigens / Q000008:administration & dosage*; D001249:Asthma / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000276:immunology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000941:Antigens; D015848:Interleukin-5; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D010047:Ovalbumin