Mycophenolate mofetil significantly reduces chronic rejection after heart transplantation in rats: A comparative study with cyclosporin A and FK-506

Chronic rejection still remains a serious problem after heart transplantation and limits long-term survival. The introduction of cyclosporin A has dramatically improved patient survival in the first year after transplantation but has not led to a decrease in the incidence of chronic rejection. New immunosuppressive agents may also influence chronic rejection. Therefore the objective of this study was to test the ability of cyclosporin A, FK-506 and mycophenolate mofetil to reduce chronic rejection in a rat cardiac transplant model. Heterotopic rat heart transplantation (Lewis to Fisher) was carried out. The animals were randomly divided into four groups and then given immunosuppressive treatment with 0.3 mg/kg/d i.m. FK-506 or 3 mg/kg/d s.c. cyclosporin A or 40 mg/kg/d p.o. mycophenolate mofetil for the whole study Untreated animals served as control. The animals were sacrificed 60 days after transplantation and allografts were prepared for histological evaluation. The extent of neointimal proliferation of the vessels was assessed by digitizing morphometry. Data are expressed as mean ± standard error. Cyclosporin A, FK-506 and mycophenolate mofetil could not reduce the incidence of chronic rejection compared with untreated control animals. Acute rejection in the control group was given a score of IV (ISHLT); animals treated with cyclosporin A, FK-506 and mycophenolate mofetil an acute rejection score of llia. Neointimal proliferation in the control group reached 58.8 ± 10.31%. By treatment with cyclosporin A at a mean level of 413 ng/ml ± 124, neointimal proliferation was reduced to 34.1 ± 16% (p <0.005), by treatment with FK-506 at a mean level of 6.6 ng/ml ± 2.4 it was reduced to 36 ± 12.3% (p <0.05). At a mean mycophenolic acid level of 5.8 μg/ml ± 2.3, mycophenolate mofetil reduced the extent of neointimal proliferation to 15.1 ± 8.3%, which was statistically significant to the controls (p <0.0005) as well as to the cyclosporin A and FK-506 groups (p <0.02). Our results suggest that because of its different mode of action, mycophenolate mofetil may be able to further decrease the severity of chronic rejection not only after rat heart transplantation but also in human cardiac transplantation.