DEVELOPMENT OF OBLITERATIVE AIRWAY DISEASE AFTER HETEROTOPIC TRACHEAL TRANSPLANTATION IS ABROGATED IN TUMOR NECROSIS FACTOR DEFICIENCY IN EITHER DONOR OR RECIPIENT.

1.1
#5
DEVELOPMENT OF OBLITERATIVE AIRWAY DISEASE AFTER HETEROTOPIC TRACHEAL TRANSPLANTATION IS ABROGATED IN TUMOR NECROSIS FACTOR DEFICIENCY IN EITHER DONOR OR RECIPIENT.
F. Fernandez MD , A. Jaramillo PhD , D. Liu BS , C. Chen MD and T. Mohanakumar PhD . St. Louis MO, Washington University, 63110, Surgery .

Background: Murine heterotopic tracheal allografts develop obliterative airway disease (OAD), which is a suitable model of obliterative bronchiolitis folowing human lung transplantation. Administration of anti-TNF mAb abrogates development of OAD in a single MHC antigen mismatched system. We hypothesize that knockout of the TNF receptor (TNF R) gene in the allograft can abrogate the development of OAD in a fully allogeneic system.
Methods: BALB/c tracheal allografts were heterotopically transplanted subcutaneously into C57BL/6 TNF R-knockout (KO) mice and vice versa. Controls included Balb/c tracheas heterotopically transplanted into C57BL/6 mice and vice versa. Grafts were harvested at day 10, 20, and 30 post-transplant for histological examination of OAD.
Results: OAD development is significantly inhibited in both TNF R-KO recipients of BALB/c tracheal allografts and BALB/c recipients of TNF R-KO allografts. These allografts exhibited mild epithelial damage without evidence of substantial cellular infiltration or fibroproliferation at 10 days which did not progress at 30 days. Control mice develop cellular infiltration and epithelial damage by day 10, fibroproliferation by day 20, and luminal obliteration by 30 days post-transplant.
Conclusion: The fact that OAD is abrogated when TNF R-KO mice are either donor or recipient indicates that TNF plays an essential role early in development of OAD. TNF may propagate an immunologic response by activating tracheal parenchymal cells in the allograft to produce chemokines and other inflammatory mediators as well as modifying expression of MHC and adhesion molecules. We have begun investigating differences in chemokine profiles generated between TNF R-KO mice and controls.