Mizoribine as sole immunosuppressive agent in islet xenotransplantation models: a candidate immunosuppressant causing no adverse effects on islets.
Mizoribine (MZ) inhibits the differentiation and proliferation of helper T and B cells after antigen recognition by suppressing the purine biosynthesis pathway and nucleic acid synthesis. MZ has been used in kidney transplantation, but distinct data are unavailable for islet transplantation.  The present study investigated the efficacy of MZ for islet xenotransplantation. Immunosuppressive effects of MZ were determined by mixed lymphocyte reaction (MLR) assay in vitro. Toxicities for Wistar rat islets were determined by adenosine triphosphate (ATP) contents of islets during 3-day  culture and stimulation index in response to glucose after culture. Immunosuppressive effects in vivo were tested in a Wistar-to-B6 islet xenotransplantation model. MZ was administered continuously for 28 days subcutaneously or intramuscularly. MZ inhibited MLR response by approximately 50%  at 0.1 μg/ml. ATP contents decreased with MZ >100 μg/ml, while stimulation index was maintained. Continuous infusion of MZ at 10 mg/kg maintained blood concentrations at 0.13-0.19 μg/ml, while intramuscular injection of MZ at 100 mg/kg/day (peak 520 μg/ml at 1 h postinjection)  resulted in below measurable levels (<0.03 μg/ml) within 24 h. Graft survival was significantly prolonged following continuous infusion of 10 mg/kg/day compared to controls (31.0 ± 9.5 vs. 13.2 ± 5.2 days; p = 0.002). Furthermore, animals with intramuscular injection  at doses of 3.2, 10, or 100 mg/kg/day showed significantly longer graft survival (20.0 ± 7.5, 22.0 ± 7.31, and 24.5 ± 8.1 days, respectively; p < 0.05 each). Histological examination showed significant suppression of lymphocyte infiltration by MZ administration.  MZ showed immunosuppressive effects in an experimental islet xenotransplantation model without adverse effects on endocrine function of islet grafts.
Department of Surgery I, School of Medicine, Fukushima Medical University, Fukushima, Japan.
Michitoshi
M
Yamashita
Takuro
T
Saito
Kazuya
K
Ise
Show
S
Ishii
Yoshihiro
Y
Satoh
Takaharu
T
Saito
Ikuro
I
Oshibe
Hirofumi
H
Shimizu
Akira
A
Kenjo
Takashi
T
Kimura
Mitsukazu
M
Gotoh
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000601:surgery*; D006085:Graft Survival / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000633:toxicity; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D012263:Ribonucleosides / Q000008:administration & dosage* / Q000633:toxicity; D014183:Transplantation, Heterologous
D001786:Blood Glucose; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine; D000255:Adenosine Triphosphate