Evaluation of the in vivo dose-response relationship of immunosuppressive drugs using a mouse heart transplant model: application to cyclosporine.
We have developed a 2-week bioassay that quantitates the effect of immunosuppressive drugs on organ allograft rejection. This assay is not only rapid and reliable, but also simple and relatively inexpensive and sparing of test substances. We refined the method by which neonatal mouse hearts are transplanted into pouches in the pinnae of ears of adult recipient mice and used cyclosporine treatment as an example of how this method might be generally applied to study the dose-response relationship of immunosuppressive drugs. Five- to 10-week-old C3H/km mice were used as cardiac recipients, and unsexed newborn BALB/c (allograft) or C3H/km (isograft) mice (24-48 hr old) were used as cardiac graft donors. The heart grafts were examined by two independent observers every other day at 10- to 20-fold magnification for up to 14 days. The immunosuppressive effect of cyclosporine was studied at doses of 3, 7.5, 15, 22.5 and 30 mg/kg per day administered i.p. The accrued data were analyzed by two methods: dose-response curves at days 12 and 14 and mean survival scores from day 8 to day 14. The dose-response curves on days 12 and 14 were similar, and the calculated ED50 values were 9.83 and 15 mg/kg/day, respectively. The results of this study demonstrate the potential usefulness and the sensitivity of the ear-heart transplantation bioassay for relative potency evaluations of immunosuppressive drugs.
Babany
G
G
Cardiology Division, Stanford University School of Medicine, California.
Morris
R E
RE
Babany
I
I
Kates
R E
RE
D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D003524:Cyclosporins; D007166:Immunosuppressive Agents