The new malononitrilamide immunosuppressant FK778 prolongs corneal allograft survival in the rat keratoplasty model.
OBJECTIVE
Aim of this study was to prove the efficacy and safety of the new malononitrilamide immunosuppressive FK778 in prolonging clear graft survival following allogeneic orthotopic keratoplasty in rats.


METHODS
Sixty-seven penetrating keratoplasties were performed using Fisher and Lewis rats as donors and recipients, respectively: group 1 (n=11), allogeneic control without therapy; group 2 (n=12), syngeneic control; group 3 (n=11), mycophenolate mofetil (MMF) 40 mg/kg bodyweight; group 4 (n=12), FK778 5 mg/kg bodyweight; group 5 (n=12), FK778 10 mg/kg bodyweight; and group 6 (n=9), FK778 20 mg/kg bodyweight. Four animals in each group were killed for immunohistological evaluation on day 14. Therapy was administered orally for 18 days. The grafts were evaluated every three days by means of a scoring system including opacity, oedema, and vascularization. Time to rejection was analysed with the Kaplan-Meier survival analysis and compared with the log-rank test. The densities of infiltrating immune cells were compared statistically using the non-parametric Mann-Whitney test.


RESULTS
Mean rejection-free graft survival was 11.4 days in group 1 (allogeneic control), 100 days (total follow-up time) in group 2 (syngeneic control), 24.0 days in group 3 (MMF 40 mg/kg), 15.7 days in group 4 (FK778 5 mg/kg), 19.1 days in group 5 (FK778 10 mg/kg), and 25.4 days in group 6 (FK778 20 mg/kg) (P<0.005).


CONCLUSIONS
Systemic immunosuppression with FK778 prolongs graft survival in the rat keratoplasty model. FK778's efficacy is comparable with that of MMF in preventing immunologic graft rejection.
Birnbaum
F
F
Eye Hospital, Albert-Ludwigs University, Killianstr. 5, Freiburg, Germany. florian.birnbaum@uniklinik-freiburg.de
Schwartzkopff
J
J
Scholz
C
C
Reis
A
A
Reinhard
T
T
D000480:Alkynes / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D003315:Cornea / Q000276:immunology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use* / Q000633:toxicity; D007555:Isoxazoles / Q000627:therapeutic use* / Q000633:toxicity; D015948:Keratoplasty, Penetrating / Q000276:immunology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D009570:Nitriles / Q000627:therapeutic use* / Q000633:toxicity; D011182:Postoperative Care / Q000379:methods; D011184:Postoperative Period; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D016019:Survival Analysis; D016896:Treatment Outcome
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D009173:Mycophenolic Acid