title: A soluble thymic stromal lymphopoietin (TSLP) antagonist, TSLPR-immunoglobulin, reduces the severity of allergic disease by regulating pulmonary dendritic cells.
abstract: Recent studies show that thymic stromal lymphopoietin (TSLP) plays a critical role in the upstream phase of the allergic cascade to induce T helper type 2 cell (Th2)-dominant allergic diseases. However, the effect of blocking TSLP signalling with the soluble TSLP receptor (TSLPR), TSLPR-immunoglobulin (Ig), on asthma development needs further investigation. Here, we examined the effects of TSLPR-Ig on asthmatic airway inflammation and dendritic cell (DC) function. TSLPR-Ig (comprising the extracellular domain of murine TSLPR and an IgG2a Fc tail) purified from transfected COS-7 cells reduced the expression of CD40, CD80 and CD86 on TSLP-activated DCs in vitro. We also investigated the mechanisms underlying TSLPR-Ig-mediated amelioration of allergic airway inflammation in a murine asthma model. When TSLP signalling was blocked by intratracheal administration of TSLPR-Ig prior to sensitization, allergen-specific serum IgE levels, airway tissue inflammation, inflammatory cell infiltration and Th2 cytokine levels in the bronchiolar lavage fluid (BALF) were reduced significantly. This was because of the TSLP-Ig-mediated down-regulation of co-stimulatory molecule expression on pulmonary DCs. We also transferred bone marrow-derived mature DCs (mDCs) into the airways of asthmatic mice. Intratracheal administration of TSLPR-Ig prior to the transfer of mDCs reduced eosinophilic airway inflammation and Th2 differentiation significantly. Collectively, these data suggest that local use of TSLPR-Ig prevents airway inflammation, at least in part, by regulating DC function, and that blocking TSLP signalling using TSLPR-Ig may be a novel strategy for the treatment of asthma bronchiale.
authors.affiliation: Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, China. zhangfanglab@yahoo.com.cn
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Huang
authors.forename: B
authors.initials: B
authors.lastname: Hu
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000235:genetics; D019013:CD40 Antigens / Q000096:biosynthesis / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D004195:Disease Models, Animal; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D007136:Immunoglobulins / Q000235:genetics / Q000627:therapeutic use*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology / Q000633:toxicity; D017434:Protein Structure, Tertiary; D018121:Receptors, Cytokine / Q000235:genetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D007136:Immunoglobulins; D018121:Receptors, Cytokine; D011993:Recombinant Fusion Proteins; C410591:Tslpr protein, mouse; D007073:Immunoglobulin E; D010047:Ovalbumin