title: Prevention of airway allograft tolerance by polyinosinic:polycytidylic acid requires type I interferon responsiveness for mouse airway obliteration.
abstract: BACKGROUND
  Respiratory RNA viruses are associated with bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRS); however, the immune mechanisms that regulate airway obliteration remain incompletely understood.
  
  
  METHODS
  Using the mouse heterotopic tracheal transplant model of obliterative airway disease (OAD), we studied the role of double-stranded (ds)RNA using polyinosinic:polycytidylic acid (poly[I:C]), a synthetic analog of viral dsRNA, in abrogating airway allograft tolerance established with donor-specific transfusion (DST) and anti-CD154 monoclonal antibody therapy.
  
  
  RESULTS
  Wild-type (WT) B6 recipients of accepted BALB/c airway grafts demonstrated significantly reduced intragraft CD8+ T cells, with markedly impaired allospecific interferon (INF)-γ and tumor necrosis factor-α secretion, uncoupled from an activated phenotype, and evidence of proliferation. Administration of poly(I:C) to DST/anti-CD154-treated recipients restored OAD pathology and CD8+ alloeffector responses to levels observed in untreated mice. However, B6 type I IFN receptor-deficient (IFN-αβR(-/-)) recipients were resistant to the abrogation of tolerance mediated by poly(I:C) and did not develop CD8+ alloeffector responses or OAD. Further, adoptive transfers of WT CD8+ T cells or CD11c+ dendritic cells alone into B6 IFNαβR(-/-) recipients treated with poly(I:C) and DST/anti-CD154 were incapable of abrogating airway graft tolerance.
  
  
  CONCLUSIONS
  Together, these data indicate abrogation of DST/anti-CD154-induced airway allograft tolerance via dsRNA requires type-I IFN responsiveness for mouse airway obliteration.
authors: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: Hannah L
authors: HL
authors: Miller
authors: Pali D
authors: PD
authors: Shah
authors: Jonathan B
authors: JB
authors: Orens
authors: John F
authors: JF
authors: McDyer
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001989:Bronchiolitis Obliterans / Q000503:physiopathology / Q000601:surgery*; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D007369:Interferon Inducers / Q000009:adverse effects*; D007370:Interferon Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011070:Poly I-C / Q000009:adverse effects*; D012330:RNA, Double-Stranded / Q000009:adverse effects; D014132:Trachea / Q000637:transplantation*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D007369:Interferon Inducers; D007370:Interferon Type I; D012330:RNA, Double-Stranded; D023201:CD40 Ligand; D011070:Poly I-C
keywords: BOS; CD8(+) T cell; bronchiolitis obliterans syndrome; interferon; respiratory viral infection; tolerance
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