title: Innate and adaptive immune responses in obliterative airway disease in rat tracheal allografts.
abstract: BACKGROUND
  We assessed cellular innate and adaptive immune responses in a rat heterotopic tracheal allograft model during the development of obliterative airway disease.
  
  
  METHODS
  Syngeneic tracheal grafts were transplanted heterotopically from DA to DA rats and fully MHC-mismatched allografts from DA to WF rats. The recipients received either no immunosuppression or two different doses of cyclosporine and were euthanized at 3, 10 and 30 days. Non-transplanted DA tracheas served as controls. Histologic, immunohistochemical and real-time RT-PCR analyses were performed.
  
  
  RESULTS
  The syngrafts had normal epithelium at 10 days and no tracheal occlusion was seen at 30 days. In non-immunosuppressed allografts, almost total loss of epithelium was observed at 10 days, culminating in tracheal occlusion at 30 days. The activation of innate immune response was observed during the ischemic period at 3 days in both groups. Influx of the infiltrating inflammatory cells was more prominent in the allografts. In syngrafts, mRNA expression of pro-inflammatory, but also tolerogenic, cytokines was significantly upregulated, whereas Th1 and Th17 priming factors were significantly downregulated. In allografts, prominent mRNA expression of pro-inflammatory cytokines was seen and adaptive Th1 and Th17 alloresponses were increased. Cyclosporine treatment reduced tracheal occlusion and inhibited both tolerogenic and pro-inflammatory T-cell responses in allografts.
  
  
  CONCLUSIONS
  Ischemia induced a self-limiting, alloantigen-independent innate immune response in syngrafts. In allografts, the predominant pro-inflammatory milieu and alloantigen-dependent Th1 and Th17 responses were linked to the development of obliterative airway disease and were inhibited by cyclosporine treatment.
authors.affiliation: Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. jussi.o.ropponen@helsinki.fi
authors.forename: Jussi O
authors.initials: JO
authors.lastname: Ropponen
authors.forename: Simo O
authors.initials: SO
authors.lastname: Syrjälä
authors.forename: Rainer
authors.initials: R
authors.lastname: Krebs
authors.forename: Antti
authors.initials: A
authors.lastname: Nykänen
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Tikkanen
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000276:immunology*; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000517:prevention & control*; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014132:Trachea / Q000637:transplantation*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine