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.

Keywords: BOS; CD8(+) T cell; bronchiolitis obliterans syndrome; interferon; respiratory viral infection; tolerance.