title: Targeting ST2L potentiates CpG-mediated therapeutic effects in a chronic fungal asthma model.
abstract: IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors.forename: Hemanth
authors.initials: H
authors.lastname: Ramaprakash
authors.forename: Takehiko
authors.initials: T
authors.lastname: Shibata
authors.forename: Karen E
authors.initials: KE
authors.lastname: Duffy
authors.forename: Ugur B
authors.initials: UB
authors.lastname: Ismailoglu
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Bredernitz
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Moreira
authors.forename: Ana L
authors.initials: AL
authors.lastname: Coelho
authors.forename: Anuk M
authors.initials: AM
authors.lastname: Das
authors.forename: Natalie
authors.initials: N
authors.lastname: Fursov
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Chupp
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D001232:Aspergillus fumigatus / Q000276:immunology / Q000378:metabolism; D001249:Asthma / Q000382:microbiology / Q000517:prevention & control*; D015153:Blotting, Western; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D016022:Case-Control Studies; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005355:Fibrosis / Q000517:prevention & control; D006801:Humans; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C408982:CPG-oligonucleotide; D054370:Chemokine CXCL9; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; C530318:ST2L protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9