Am. J. Respir. Crit. Care Med., Volume 159, Number 6, June 1999, 1910-1917

Upregulation of T-Helper 1 Cytokines and Chemokine Expression in Post-transplant Airway Obliteration

ANNETTE BOEHLER, XIAO HUI BAI, MINGYAO LIU, STEPHEN CASSIVI, DEAN CHAMBERLAIN, ARTHUR S. SLUTSKY, and SHAF KESHAVJEE

Thoracic Surgery Research Laboratory, The Toronto Hospital and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Ontario, Canada

The major obstacle to long-term survival after lung transplantation is chronic graft dysfunction manifest as bronchiolitis obliterans. Since the early stages are characterized by proliferation of itinerant cells (lymphocytes and macrophages), we hypothesized that cytokines and chemokines may play a role in the development of the fibroproliferative process. In a heterotopic rat tracheal transplant model, we studied isografts and allografts 3, 7, and 21 d after transplantation as representative time points for the triphasic time course in the evolution of allograft airway obliteration. Using a semiquantitative RT-PCR technique, intragraft gene expression of T-helper 1 (Th1)- and Th2-type cytokines and of C-C and C-X-C chemokines was examined. The results of our study show a distinct pattern of cytokine and chemokine gene expression in the development of post-transplant airway obliteration. Allografts, in contrast to isografts, showed a strong and persistent Th1-type response (expression of interleukin-2 and interferon- genes), even after fibrous airway obliteration was complete, suggesting an ongoing allo-immune process until late in the fibroproliferative stage. RANTES and MCP-1 were also upregulated late after transplantation, whereas MIP-2 upregulation occurred early post-transplant and was not restricted to allografts alone, which might reflect alloantigen-independent processes after transplantation that are present in both allografts and isografts.

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