Prevention and inhibition but not reversion of chronic allograft vasculopathy by FK778.
BACKGROUND
This study aimed at investigating the efficacy of the novel immunosuppressant FK778 to prevent the development and progression of chronic allograft vasculopathy (CAV).


METHODS
Orthotopic aortic transplantations were performed in the PVG-to-ACI rat model and followed over the course of 120 days. Immunosuppression with FK778 (20 mg/kg) or sirolimus (2 mg/kg) was either started early or delayed when CAV was already present. Trough levels were monitored. Aortic luminal obliteration was quantified using computer morphometry and intragraft cytokine profiles were analyzed with Western Blotting. Donor-reactive antibodies were quantified by flow cytometry.


RESULTS
Untreated animals developed CAV with luminal obliteration of 25.2+/-13.6% and 41.4+/-23.3% after 80 and 120 days, respectively. Continuous immunosuppression with FK778 or sirolimus effectively prevented the development of vasculopathy. When the start of the immunosuppressive regimen was delayed until postoperative day 80, FK778 and sirolimus inhibited a progression of established CAV but did not reverse the luminal obliteration. Intragraft tumor growth factor-beta activity increased over the course of time in untreated recipients but was significantly suppressed after continuous immunosuppression with either agent. Expression of platelet-derived growth factor, intercellular adhesion molecule-1, and vascular adhesion molecule-1 also was moderately suppressed. A stable elevation of donor-reactive IgG-antibody levels was found over 120 days in the absence of treatment. With FK778 or sirolimus, antibody levels were effectively decreased. FK778 was very well tolerated and only sirolimus showed side effects with elevation of BUN, cholesterol, triglycerides, and ALT after 120 days.


CONCLUSIONS
FK778 prevents the development of CAV and inhibits a progression of established disease. It shows a similar efficacy but a safer drug profile when compared to sirolimus.
Deuse
Tobias
T
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Hoyt
Grant
G
Koyanagi
Tomoyoshi
T
Robbins
Robert C
RC
Schrepfer
Sonja
S
D000480:Alkynes / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000637:transplantation*; D001018:Aortic Diseases / Q000517:prevention & control*; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D009570:Nitriles / Q000627:therapeutic use*; D051381:Rats; D011912:Rats, Inbred ACI; D014184:Transplantation, Homologous / Q000473:pathology*
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D016572:Cyclosporine