Combined donor specific transfusion and anti-CD154 therapy achieves airway allograft tolerance

Abstract

Objective To define the molecular mechanism of obliterative bronchiolitis (OB) following heterotopic tracheal transplantation during the early stages of tolerance induction by donor specific transfusion and anti-CD154.Methods Tolerance induction was achieved in tracheal allografts from BALB/C to C57BL/6 mice by donor specific transfusion of splenocytes intravenously and intraperitoneal injection of anti-CD154 mAbs.The differential gene expression was detected in tolerant murine heterotopic tracheal allografts by means of gene microarrays.Differential expression of selected genes was confirmed bv real-time fluorescent quantitative reverse transcription ( RT-qPCR).Results Comparative analysis between DST/anti-CD154 protocol-induced tolerant and rejected grafts revealed many genes were specifically downregulated in the tolerant allografts,including RAP1 pathway,CD40/CD40L concerned T cell surface molecules and many profibrotic genes,which were upregulated in the rejected allografts.In the tolerant allografts there was also marked expression of a number of genes for proinflammatory factors.Conclusion These results suggest a vital role for RAP1 pathway,CD40/CD40L concerned T cell surface molecules and many profibrotic genes in inducing airway transplant tolerance in this model. Key words: Lung transplantation; Obliterative bronchiolitis; Immunological tolerance