Tacrolimus treatment effectively inhibits progression of obliterative airway disease even at later stages of disease development.
BACKGROUND
Obliterative bronchiolitis (OB) is the most prominent cause of morbidity and mortality among lung transplant patients. No effective treatment for OB exists, but preliminary clinical studies have suggested that a calcineurin inhibitor, tacrolimus, may delay the development of OB when compared with standard cyclosporine-based immunosuppression.


METHODS
Using a murine tracheal transplantation model, we examined the effects of tacrolimus prophylaxis and treatment on the development of obliterative airway disease (OAD). Tracheal allografts were transplanted heterotopically from BALB/c to C57 black mice into a subcutaneous pouch. The mice received different doses of tacrolimus monotherapy, ranging from 0 to 3 mg/kg/day, subcutaneously initiated at 0 (prophylaxis), 7 (early treatment) or 14 (late treatment) days. We harvested the grafts 30 days after transplantation for histologic and immunohistochemical analyses.


RESULTS
We found that tacrolimus prophylaxis dose-dependently inhibited OAD, and that early treatment halts OAD progression and that late treatment delays progression. Syngeneic grafts showed no obliterative changes. Tacrolimus prophylaxis was associated with inhibition of recruitment of CD4+, CD8+ and interleukin-2R+ inflammatory cells into the allografts, suggesting a central role for interleukin-2 in the development of OAD. In addition, a dose-dependent correlation between epithelial necrosis and tracheal occlusion was observed, suggesting that epithelial injury is required for the development of OAD. When tacrolimus treatment was initiated at the time the obliterative lesion had already started to develop, it inhibited the progression of OAD significantly.


CONCLUSIONS
The findings from this study suggest that tacrolimus therapy is effective during the early stages of clinical OB.
Hollmén
Maria
M
Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
Tikkanen
Jussi M
JM
Nykänen
Antti I
AI
Koskinen
Petri K
PK
Lemström
Karl B
KB
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D065095:Calcineurin Inhibitors; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012044:Regression Analysis; D016559:Tacrolimus / Q000627:therapeutic use*; D014132:Trachea / Q000473:pathology / Q000637:transplantation; D016896:Treatment Outcome
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016559:Tacrolimus