title: CD28 and secretory immunoglobulin A-dependent activation of eosinophils: inhibition of mediator release by the anti-allergic drug, suplatast tosilate.
abstract: BACKGROUND
  Eosinophils are major effector cells in allergic diseases. After their recruitment to sites of inflammation, they contribute to the pathophysiology of the disease by releasing granule proteins and cytokines. Suplatast tosilate (IPD-1151T), a new anti-allergic agent, has shown beneficial effect in the treatment of asthma, associated with reduced bronchoalveolar lavage eosinophil infiltration and eosinophilic cationic protein (ECP) release in serum and sputum.
  
  
  OBJECTIVE
  We investigated whether suplatast tosilate could exert direct effects on human eosinophil activation.
  
  
  METHODS
  Eosinophils from hypereosinophilic patients or normal donors were purified by Percoll gradient and the magnetic cell separation system. Chemotaxis was studied using the Boyden chamber technique using three chemoattractants, formyl-methionine-leucine-phenylalanine (fMLP), IL-5 and eotaxin. Oxidative metabolism was determined by a luminol-dependent chemiluminescence assay after activation with eotaxin or secretory IgA (sIgA). The release of ECP and eosinophil derived neurotoxin (EDN) was measured by radioimmunoassay and cytokine production was determined by ELISA following activation with sIgA or anti-CD28.
  
  
  RESULTS
  The chemotactic response to fMLP, IL-5 and eotaxin was significantly inhibited by IPD-1151T. Suplatast tosilate was partially inhibiting the release of reactive oxygen species (ROS) induced by eotaxin and sIgA. Activation by sIgA and CD28 ligation resulted in the release of ECP and EDN, which was inhibited by IPD-1151T. Upon activation by anti-CD28, only IL-13 production was inhibited by IPD-1151T, whereas release of IL-2 and IFN-gamma was not affected. IL-10 release induced by sIgA was also inhibited by IPD-1151T. Additionally, the pro-inflammatory cytokine IL-6, which was secreted following anti-CD28 and sIgA stimulation, was strongly inhibited by IPD-1151T.
  
  
  CONCLUSIONS
  Through inhibition of chemotaxis, IPD-1151T might limit the number of eosinophils at the inflammation site. Furthermore, it could reduce the pathological potential of eosinophils by inhibiting the release of ROS and cationic proteins, main inflammatory mediators produced by eosinophils. Moreover, the inhibition of immunoregulatory cytokines released by eosinophils could locally modify the immune response.
authors.affiliation: Inserm U547-IFR17, Institut Pasteur de Lille, Lille, France.
authors.forename: G
authors.initials: G
authors.lastname: Woerly
authors.forename: V
authors.initials: V
authors.lastname: Decot
authors.forename: S
authors.initials: S
authors.lastname: Loiseau
authors.forename: M
authors.initials: M
authors.lastname: Loyens
authors.forename: J
authors.initials: J
authors.lastname: Chihara
authors.forename: N
authors.initials: N
authors.lastname: Ono
authors.forename: M
authors.initials: M
authors.lastname: Capron
mesh_terms: D018926:Anti-Allergic Agents / Q000276:immunology / Q000627:therapeutic use*; D001190:Arylsulfonates / Q000276:immunology / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000276:immunology*; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D047150:Eosinophil Cationic Protein / Q000378:metabolism; D047208:Eosinophil-Derived Neurotoxin / Q000378:metabolism; D004802:Eosinophilia / Q000276:immunology*; D004804:Eosinophils / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D007071:Immunoglobulin A, Secretory / Q000276:immunology*; D015848:Interleukin-5 / Q000276:immunology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000276:immunology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013452:Sulfonium Compounds / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D018926:Anti-Allergic Agents; D001190:Arylsulfonates; C515456:CCL11 protein, human; D018106:CD28 Antigens; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D007071:Immunoglobulin A, Secretory; D015848:Interleukin-5; D017382:Reactive Oxygen Species; D013452:Sulfonium Compounds; D009240:N-Formylmethionine Leucyl-Phenylalanine; C073028:suplatast tosilate; D047208:Eosinophil-Derived Neurotoxin; D047150:Eosinophil Cationic Protein