FK778 and tacrolimus prevent the development of obliterative airway disease after heterotopic rat tracheal transplantation.
BACKGROUND
The effectiveness of the novel immunosuppressive agent FK778 and of tacrolimus to prevent the development of obliterative airway disease (OAD) was investigated in an animal model.


METHODS
Tracheae from Brown-Norway donors were heterotopically transplanted in the greater omentum of Lewis rats. Recipients were treated for 28 days with FK778 (5 or 20 mg/kg), tacrolimus (1 or 4 mg/kg) or combination regimens at varying doses (5 + 1 mg/kg, 10 + 2 mg/kg or 20 + 4 mg/kg). Grafts were harvested and processed for histologic and immunohistochemical evaluation. Lymphocyte surface antigen expression was quantified and in vitro smooth muscle cell (SMC) proliferation assays were performed.


RESULTS
In untreated recipients, very large amounts of infiltrating CD4+, CD8+ and ED1+ mononuclear cells were observed in the peritracheal region with epithelial loss and complete luminal obliteration. Granulation tissue consisted of alpha-actin-positive cells and collagen-rich fibrosis. FK778 and tacrolimus as well as combination regimens of both agents dose-dependently inhibited peritracheal infiltration and luminal obliteration. Only tacrolimus-treated recipients showed preserved luminal epithelial coverage with airway goblet cells, whereas, in animals that received FK778, no epithelium was found. Both agents equally suppressed in vivo lymphocyte CD25 expression. Only FK778-treated animals were completely free of adverse drug side effects. FK778 but not tacrolimus showed potent anti-proliferative effects on SMC in vitro.


CONCLUSIONS
Although both agents proved effective to prevent OAD development, histology revealed major differences. The anti-proliferative potency of FK778 on SMC may be an important mechanism of action. Combination regimens showed favorable drug interaction and allowed dose reduction of both agents to achieve maximal immunosuppressive efficacy.
Deuse
Tobias
T
Department of Cardiovascular Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Schrepfer
Sonja
S
Koch-Nolte
Friedrich
F
Haddad
Munif
M
Schwedhelm
Edzard
E
Böger
Rainer
R
Schäfer
Hansjörg
H
Detter
Christian
C
Reichenspurner
Hermann
H
D000199:Actins / Q000378:metabolism; D000480:Alkynes; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000517:prevention & control*; D004195:Disease Models, Animal; D006097:Granulation Tissue / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use*; D007555:Isoxazoles / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D009570:Nitriles; D011183:Postoperative Complications / Q000517:prevention & control*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000097:blood / Q000627:therapeutic use*; D014132:Trachea / Q000637:transplantation*
D000199:Actins; D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D016559:Tacrolimus