title: Treatment with a sphingosine analog after the inception of house dust mite-induced airway inflammation alleviates key features of experimental asthma.
abstract: BACKGROUND
  In vivo phosphorylation of sphingosine analogs with their ensuing binding and activation of their cell-surface sphingosine-1-phosphate receptors is regarded as the main immunomodulatory mechanism of this new class of drugs. Prophylactic treatment with sphingosine analogs interferes with experimental asthma by impeding the migration of dendritic cells to draining lymph nodes. However, whether these drugs can also alleviate allergic airway inflammation after its onset remains to be determined. Herein, we investigated to which extent and by which mechanisms the sphingosine analog AAL-R interferes with key features of asthma in a murine model during ongoing allergic inflammation induced by Dermatophagoides pteronyssinus.
  
  
  METHODS
  BALB/c mice were exposed to either D. pteronyssinus or saline, intranasally, once-daily for 10 consecutive days. Mice were treated intratracheally with either AAL-R, its pre-phosphorylated form AFD-R, or the vehicle before every allergen challenge over the last four days, i.e. after the onset of allergic airway inflammation. On day 11, airway responsiveness to methacholine was measured; inflammatory cells and cytokines were quantified in the airways; and the numbers and/or viability of T cells, B cells and dendritic cells were assessed in the lungs and draining lymph nodes.
  
  
  RESULTS
  AAL-R decreased airway hyperresponsiveness induced by D. pteronyssinus by nearly 70%. This was associated with a strong reduction of IL-5 and IL-13 levels in the airways and with a decreased eosinophilic response. Notably, the lung CD4(+) T cells were almost entirely eliminated by AAL-R, which concurred with enhanced apoptosis/necrosis in that cell population. This inhibition occurred in the absence of dendritic cell number modulation in draining lymph nodes. On the other hand, the pre-phosphorylated form AFD-R, which preferentially acts on cell-surface sphingosine-1-phosphate receptors, was relatively impotent at enhancing cell death, which led to a less efficient control of T cell and eosinophil responses in the lungs.
  
  
  CONCLUSIONS
  Airway delivery of the non-phosphorylated sphingosine analog, but not its pre-phosphorylated counterpart, is highly efficient at controlling the local T cell response after the onset of allergic airway inflammation. The mechanism appears to involve local induction of lymphocyte apoptosis/necrosis, while mildly affecting dendritic cell and T cell accumulation in draining lymph nodes.
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. david.gendron@criucpq.ulaval.ca.
authors: David
authors: D
authors: Gendron
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. anne-marie.lemay@criucpq.ulaval.ca.
authors: Anne-Marie
authors: AM
authors: Lemay
authors: Laboratoires Charles River, Services Précliniques, Montréal, Canada. tremc@hotmail.com.
authors: Claudine
authors: C
authors: Tremblay
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. laetitia.lai@gmail.com.
authors: Laetitia Ja
authors: LJ
authors: Lai
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. Anick.Langlois@criucpq.ulaval.ca.
authors: Anick
authors: A
authors: Langlois
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. embernatchez@gmail.com.
authors: Émilie
authors: É
authors: Bernatchez
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. Nicolas.Flamand@criucpq.ulaval.ca.|Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada. Nicolas.Flamand@criucpq.ulaval.ca.
authors: Nicolas
authors: N
authors: Flamand
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. Marie-Renee.Blanchet@criucpq.ulaval.ca.|Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada. Marie-Renee.Blanchet@criucpq.ulaval.ca.
authors: Marie-Renée
authors: MR
authors: Blanchet
authors: Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, 2052, NSW, Australia. anthonyd@unsw.edu.au.
authors: Anthony S
authors: AS
authors: Don
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. ynuk.bosse@criucpq.ulaval.ca.|Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada. ynuk.bosse@criucpq.ulaval.ca.
authors: Ynuk
authors: Y
authors: Bossé
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. Elyse.Bissonnette@fmed.ulaval.ca.|Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada. Elyse.Bissonnette@fmed.ulaval.ca.
authors: Élyse
authors: É
authors: Bissonnette
authors: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ), Québec, QC, Canada. David.Marsolais@criucpq.ulaval.ca.|Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada. David.Marsolais@criucpq.ulaval.ca.
authors: David
authors: D
authors: Marsolais
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D040002:Dermatophagoides pteronyssinus; D004195:Disease Models, Animal; D005260:Female; D018793:Interleukin-13 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010766:Phosphorylation; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D018926:Anti-Allergic Agents; D018793:Interleukin-13; D015848:Interleukin-5; D013110:Sphingosine
references: Curr Opin Allergy Clin Immunol. 2012 Feb;12(1):39-41
references: 22157151
references: J Med Chem. 2000 Jul 27;43(15):2946-61
references: 10956203
references: Toxicol Pathol. 2012 Jun;40(4 Suppl):7S-13S
references: 22637736
references: J Allergy Clin Immunol. 2013 Feb;131(2):501-11.e1
references: 22939756
references: Nat Med. 2013 Feb;19(2):232-7
references: 23334847
references: Immunopharmacology. 2000 Jun;48(1):75-85
references: 10822091
references: J Physiol. 2014 Jul 15;592(14):2999-3012
references: 24687581
references: Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1939-47
references: 11734450
references: Toxicol Pathol. 2002 Jan-Feb;30(1):93-6
references: 11890482
references: Science. 2002 Apr 12;296(5566):346-9
references: 11923495
references: Eur Respir J. 2003 Feb;21(2):225-31
references: 12608434
references: Ann Intern Med. 1996 Jan 15;124(2):223-7
references: 8533997
references: Bioorg Med Chem Lett. 1998 Jan 6;8(1):101-6
references: 9925439
references: J Clin Invest. 2005 Jun;115(6):1580-9
references: 15902312
references: N Engl J Med. 2006 Sep 14;355(11):1124-40
references: 16971719
references: J Clin Invest. 2006 Nov;116(11):2935-44
references: 17080194
references: Int Immunopharmacol. 2006 Dec 20;6(13-14):1902-10
references: 17161343
references: Eur J Immunol. 2007 Jan;37(1):271-81
references: 17154260
references: Blood. 2007 Feb 1;109(3):1077-85
references: 17008548
references: J Biol Chem. 2007 May 25;282(21):15833-42
references: 17400555
references: Contrib Microbiol. 2007;14:42-67
references: 17684332
references: Blood. 2007 Sep 15;110(6):2005-12
references: 17557898
references: J Allergy Clin Immunol. 2007 Dec;120(6):1360-7
references: 17981317
references: Int Immunol. 2008 Jul;20(7):911-23
references: 18495625
references: Mol Pharmacol. 2008 Sep;74(3):896-903
references: 18577684
references: Clin Exp Immunol. 2009 Jan;155(1):107-16
references: 19076834
references: Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1560-5
references: 19164548
references: Nat Rev Drug Discov. 2009 Apr;8(4):297-307
references: 19300460
references: Lancet. 2009 May 30;373(9678):1905-17
references: 19482216
references: Mol Pharmacol. 2010 Oct;78(4):685-92
references: 20610734
references: Mol Pharmacol. 2011 Jan;79(1):61-8
references: 20935081
references: Immunol Rev. 2011 Jul;242(1):205-19
references: 21682747
references: PLoS One. 2012;7(5):e34830
references: 22693544
references: Allergy. 2013 Feb;68(2):204-12
references: 23253209
references: Drug Discov Today. 2011 Aug;16(15-16):659-70
references: 21723955
references: PLoS One. 2011;6(8):e23326
references: 21858070
references: PLoS One. 2013;8(3):e58033
references: 23533579
references: Curr Allergy Asthma Rep. 2013 Jun;13(3):262-70
references: 23585216
references: Am J Physiol Lung Cell Mol Physiol. 2012 Apr 15;302(8):L736-45
references: 22287614