Inhibition of Th1- and Th2-mediated airway inflammation by the sphingosine 1-phosphate receptor agonist FTY720.
The sphingosine 1-phosphate receptor agonist FTY720 is a novel immunomodulator that sequesters lymphocytes in secondary lymphoid organs and thereby prevents their migration to sites of inflammation. However, there is currently no information available on whether this drug affects Th1 or Th2 cell-mediated lung-inflammatory responses. The effect of FTY720 was therefore investigated in a murine airway inflammation model using OVA-specific, in vitro differentiated, and adoptively transferred Th1 and Th2 cells. Both Th1 and Th2 cells express a similar pattern of FTY720-targeted sphingosine 1-phosphate receptors. The OVA-induced Th1-mediated airway inflammation characterized by increased numbers of lymphocytes and neutrophils in bronchoalveolar lavage fluid was significantly inhibited by oral FTY720 treatment. Similarly, FTY720 suppressed the Th2 cell-induced bronchoalveolar lavage fluid eosinophilia and the infiltration of T lymphocytes and eosinophils into the bronchial tissue. Moreover, the Ag-induced bronchial hyperresponsiveness to inhaled metacholine was almost completely blocked. The inhibitory effect of FTY720 on airway inflammation, induction of bronchial hyperresponsiveness, and goblet cell hyperplasia could be confirmed in an actively Ag-sensitized murine asthma model, clearly indicating that Th2 cell-driven allergic diseases such as asthma could benefit from such treatment.
Sawicka
Elzbieta
E
Novartis Horsham Research Centre, Horsham, U.K.
Zuany-Amorim
Claudia
C
Manlius
Corinne
C
Trifilieff
Alexandre
A
Brinkmann
Volker
V
Kemeny
David M
DM
Walker
Christoph
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000517:prevention & control; D024201:Bystander Effect / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011409:Propylene Glycols / Q000008:administration & dosage*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000096:biosynthesis; D049312:Receptors, Lysophospholipid; D013110:Sphingosine / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018984:Epitopes, T-Lymphocyte; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine