M. Richter et al., Mycophenolate mofetil significantly reduces chronic rejection after heart transplantation in rats: A comparative study with cyclosporin A and FK-506, INT J IMM T, 16(3-4), 2000, pp. 37-44
Chronic rejection still remains a serious problem after heart transplantati
on and limits long-term survival The introduction of cyclosporin A has dram
atically improved patient survival in the first year after transplantation
but has not led to a decrease in the incidence of chronic rejection. New im
munosuppressive agents may also influence chronic rejection. Therefore the
objective of this study was to test the ability of cyclosporin A, FK-506 an
d mycophenolate mofetil to reduce chronic rejection in a rat cardiac transp
lant model. Heterotopic rat heart transplantation (Lewis to Fisher) was car
ried out. The animals were randomly divided into four groups and then given
immunosuppressive treatment with 0.3 mg/kg/d im. 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 af
ter transplantation and allografts were prepared for histological evaluatio
n. The extent of neointimal proliferation of the vessels was assessed by di
gitizing morphometry! Data are expressed as mean +/- standard error Cyclosp
orin 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-SOB and mycophenolate mofetil an acute rejection score of
iiia. 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, n
eointimal proliferation was reduced to 34.1 +/- 16 % (p < 0.005), by treatm
ent with FK-506 a? a mean level of 6.6 ng/ml <plus/minus> 2.4 it was reduce
d to 36 +/- 12.346 (p < 0.05). At a mean mycophenolic acid level of 5.8 <mu
>g/ml +/- 2.3, mycophenolate mofetil reduced the extent of neointimal proli
feration to 15.1 +/- 8.3 %, which was statistically significant to the cont
rols (p < 0.0005) as weil as to the cyclosporin A and FK-506 groups (p < 0.
02). Our results suggest that because of its different mode of action, myco
phenolate mofetil may be able to further decrease the severity of chronic r
ejection not only after rat heart transplantation but also in human cardiac
transplantation.