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A short course of mycophenolate immunosuppression inhibits rejection, but not tolerance, of rat liver allografts in association with inhibition of interleukin-4 and alloantibody responses

Background. Some immunosuppressive drug therapies inhibit transplant tolerance in animal models, and we have shown that treatment of recipients with methylprednisolone, but not cyclosporine, inhibits spontaneous acceptance of liver transplants. This study investigates the effects of mycophenolate mofetil (MMF) on liver acceptance and rejection. Methods. Piebald Virol Glaxo rat livers were transplanted into Dark Agouti recipients, which spontaneously tolerate (TOL) the liver, or into Lewis recipients, which reject (REJ) the liver. MMF (40 mg/kg/day subcutaneously) was given for 5 days from days 0 to 4 (early) or from days 3 to 7 (late). In separate experiments, liver grafts were collected for assessment of infiltrate and of interleukin (IL)-2, IL-4, IL-10, and interferon-&ggr; mRNA expression. Results. TOL liver transplants had a median survival time (MST) of more than 100 days (n=6), and neither early nor late MMF treatment of TOL transplants reduced survival (MST 85 days, P =0.19 and 78 days, P =0.08, respectively). Liver failure in most of these animals was the result of biliary problems, not rejection. There were few consistent differences between treated and untreated TOL animals in infiltrate or liver cytokine expression, although there was a moderate reduction in T-cell infiltrate in MMF-treated TOL animals (P =0.003 on day 5 TOL). In contrast, REJ transplants had an MST of 13 days (n=10), and early MMF treatment led to five of six animals surviving more than 100 days (P =0.0002), whereas late treatment was much less effective, with one of six animals surviving more than 100 days. REJ livers had significantly more IL-4 mRNA expression and immunoglobulin G1 deposition in the graft than TOL livers, and this was inhibited by early, but not late, MMF treatment. Conclusions. MMF treatment inhibited rejection but not acceptance of liver allografts. Early administration was more effective in preventing rejection and demonstrated a more marked effect on IL-4 expression and alloantibody deposition than on graft T-cell infiltrate and expression of other cytokines.