title: A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity.
abstract: The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyperreactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidyl-ethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of alpha-galactosylceramide (alpha-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to alpha-GalCer and competes with alpha-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the alpha-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.
authors.affiliation: Division of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lombardi
authors.forename: Philippe
authors.initials: P
authors.lastname: Stock
authors.forename: Abinav K
authors.initials: AK
authors.lastname: Singh
authors.forename: Jerome
authors.initials: J
authors.lastname: Kerzerho
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Sullivan
authors.forename: Xiangming
authors.initials: X
authors.lastname: Li
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shiratsuchi
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Hnatiuk
authors.forename: Amy R
authors.initials: AR
authors.lastname: Howell
authors.forename: Karl O A
authors.initials: KO
authors.lastname: Yu
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Moriya
authors.initials: M
authors.lastname: Tsuji
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: S Brian
authors.initials: SB
authors.lastname: Wilson
authors.forename: Omid
authors.initials: O
authors.lastname: Akbari
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism / Q000502:physiology*; D001667:Binding, Competitive / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000517:prevention & control*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D055611:Natural Killer T-Cells / Q000276:immunology*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000485:Allergens; D055610:Antigens, CD1d; C526877:CD1D protein, human; C526879:Cd1d1 protein, mouse; C102564:DPPE-PEG2000; D005699:Galactosylceramides; D007166:Immunosuppressive Agents; D010714:Phosphatidylethanolamines; C493154:alpha-galactosylceramide; D011092:Polyethylene Glycols; D010047:Ovalbumin