Early lung leukocyte infiltration, HLA and adhesion molecule expression predict chronic rejection

Obliterative bronchiolitis remains the main cause of graft dysfunction and death after 1 year. Defined by an irreversible airway obstruction, bronchiolitis obliterans syndrome is usually recognized in the advanced stage of the disease, with histological evidence of fibrotic damage. Fibrosis represents the end-stage of an inflammatory process, leading to the postulate that chronic lung graft dysfunction is preceded by cellular and molecular events. This study was performed during the first year following lung transplantation, in the absence of histological or functional criteria of chronic rejection. Transbronchial biopsies from eight lung allografts were examined. Four developed a bronchiolitis obliterans syndrome (Group I), and 4 had good outcomes (Group II) at 2 years. Using immunohistochemistry, the aim of the study was to correlate early immunological events with graft outcomes at 2 years. An up-regulation of HLA class I antigen (P = 0.0001), an overexpression of Ki-67 (P = 0.006) on bronchial epithelium, and graft infiltration by CD45+, CD25+ cells (P = 0.003) were significantly associated with the development of chronic rejection. An overexpression of numerous adhesion molecules was observed. However, only very late antigen-4 had a discriminative value (P = 0.04), preceding chronic graft dysfunction. Our results suggest that graft dysfunction is associated with early molecular and cellular events, and raises the possibility that a fibroproliferative disorder is initiated shortly after transplantation. The recognition of such early immunological markers might facilitate improved graft management and prognosis.