Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection.
Mizoribine (MZ) inhibits the proliferation of lymphocytes selectively via inhibition of inosine monophosphate dehydrogenase, like mycophenolate mofetil (MMF). The clinical dosage of MZ (2-5 mg/kg) is much lower than that of MMF (20-60 mg/kg). The purpose of this study was to examine whether high-dose MZ would be effective for treatment of acute humoral rejection. Renal transplantation was performed in a different pig strain combination. Group 1 (n = 2) received no treatment. Group 2 (n = 4) received cyclosporine microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg) as baseline immunosuppression. Groups 3 (n = 4), 4 (n = 4) and 5 (n = 4) were additionally treated with MZ for rescue therapy, 30, 10 and 3 mg/kg, respectively, immediately after rejection was observed. All pigs developed acute vascular rejection between days 4 and 8. Complete reversal of acute rejection including reduction of elevated serum creatinine, suppression of anti-donor antibody production and pathological finding, was obtained in 3/4 (group 3), 1/4 (group 4) and 0/4 (group 5). Rescue with high-dose MZ (30 mg/kg) reversed ongoing acute humoral rejection. Such a high dose of MZ was tolerable for pigs. However, leukocytopenia was observed when MZ trough level was maintained over 10 mug/ml. Treatment with high-dose MZ would be applicable to a clinical trial, if blood level is carefully monitored.
Liu
DaGe
D
Department of Surgery II, Nagoya University School of Medicine, Japan.
Kobayashi
Takaaki
T
Nagasaka
Takaharu
T
Yokoyama
Itsuo
I
Ma
Yu
Y
Miwa
Yuko
Y
Kuzuya
Takafumi
T
Morozumi
Kunio
K
Oikawa
Tadashi
T
Shimano
Yasunobu
Y
Takeuchi
Oki
O
Uchida
Kazuharu
K
Nakao
Akimasa
A
D000208:Acute Disease; D000818:Animals; D001706:Biopsy; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000188:drug therapy*; D006470:Hemorrhage / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007518:Isoantibodies / Q000187:drug effects; D016030:Kidney Transplantation / Q000276:immunology; D009336:Necrosis; D051437:Renal Insufficiency / Q000401:mortality / Q000473:pathology; D012263:Ribonucleosides / Q000008:administration & dosage* / Q000627:therapeutic use; D016879:Salvage Therapy; D016019:Survival Analysis; D013552:Swine; D013997:Time Factors
D007166:Immunosuppressive Agents; D007518:Isoantibodies; D012263:Ribonucleosides; C010052:mizoribine; D003404:Creatinine