FK778 and FK506 combination therapy to control acute rejection after rat liver allotransplantation.
BACKGROUND
In organ transplantation, several immunosuppressants are currently used to control graft rejection. Clinically, no single immunosuppressive agent can completely prevent posttransplantation immunoreaction; thus, combination therapy is usually performed. Novel agents with more powerful immunosuppressive activity and less toxicity need to be developed.


METHODS
Lewis rat livers were orthotopically transplanted into Brown-Norway recipients. FK778 was administered orally from day 0 to day 6 to prevent acute rejection and from day 7 to day 13 to rescue ongoing rejection. To assess the combined effects, recipients were treated with intramuscular injection of FK506 and oral administration of FK778 from day 0 to day 6. Blood chemistry and histopathologic findings were measured to determine the patient's general condition and the graft condition. Allospecific antibodies were measured using enzyme-linked immunosorbent assays. The FK778 trough concentration was examined by using high-performance liquid chromatography.


RESULTS
The acute immune response was suppressed by FK778 alone in a dose-dependent manner. The optimal FK778 dosage was determined to be 20 mg/kg per day, because adverse effects (weight loss and intestinal bleeding) occurred at 30 mg/kg per day. FK778 treatment from day 7 to day 13 rescued liver grafts from ongoing rejection. The intramuscular FK506 (0.125 mg/kg per day) injection and the oral FK778 (20 mg/kg per day) gavages suppressed acute liver graft rejection effectively and maintained better graft condition compared with monotherapy. CONCLUSIONS.: FK778 treatment effectively prevented acute rejection and rescued ongoing rejection after liver transplantation. The optimal dosage was determined to be 20 mg/kg per day. Combination therapy with FK506 was more beneficial than FK778 monotherapy.
Yamamoto
Satoshi
S
Department of Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. m7577175@msic.med.osaka-cu.ac.jp
Okuda
Toyokazu
T
Yamasaki
Keiichi
K
Tanaka
Hiromu
H
Kubo
Shoji
S
Takemura
Shigekazu
S
Ikeda
Kazuo
K
Minamiyama
Yukiko
Y
Hirohashi
Kazuhiro
K
Suehiro
Shigefumi
S
D000208:Acute Disease; D000480:Alkynes; D000818:Animals; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000517:prevention & control*; D007075:Immunoglobulin M / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007555:Isoxazoles / Q000008:administration & dosage*; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D009570:Nitriles; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage*; D014184:Transplantation, Homologous
D000480:Alkynes; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D016559:Tacrolimus