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

Abstract

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.

Posttransplant Interleukin-4 Treatment Converts Rat Liver Allograft Tolerance to Rejection

“…3) (Pϭ0.01). The extent of macrophage infiltration in PVG3 Lewis livers (median score, 5; range, [5][6] was intermediate between the two. The pattern of MHC class II expression appeared to reflect its expression by the macrophage infiltrate, and IL-4 -treated recipients had a median score of 6 (range, 6 -7) that was significantly greater than untreated recipients that had a median score of 5 (range, 5-5) (Pϭ0.01).…”

“…There was a difference in the pattern of expression of interleukin (IL)-4, however, with an early increase of IL-4 mRNA in PVG3 DA grafts at day 3 that subsequently decreased. In contrast, in rejecting PVG3 Lewis liver transplants, IL-4 levels continued to increase until they were significantly higher than in PVG3 DA livers (5). Further support for an association between intragraft expression of IL-4 and rejection came from the finding that treatment of PVG3 Lewis liver graft recipients with mycophenolate mofetil abrogated both rejection and IL-4 expression (5).…”

“…Previous studies from this laboratory have characterized the immune response that occurs early after transplantation in livers that are accepted in the fully major histocompatibility complex (MHC)-mismatched strain combination of Piebald Virol Glaxo (PVG) donor-toDark Agouti (DA) recipient compared with those in the PVG3 Lewis combination that reject. They show that liver tolerance is associated with immune activation, resulting in early infiltration and an increase of intragraft cytokine mRNA expression that is difficult to distinguish from rejection (3)(4)(5). There was a difference in the pattern of expression of interleukin (IL)-4, however, with an early increase of IL-4 mRNA in PVG3 DA grafts at day 3 that subsequently decreased.…”

“…IL-4 was injected from days 3 to 7 after transplant, based on the finding that there is increased intragraft expression of IL-4 in the rejecting strain over this period (5). The dose of IL-4 used was 30,000 U/day, based on previous studies in rats (13).…”

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“…Both mycophenolate mofetil and mammalian target of rapamycin inhibitor (mTORi) inhibit proliferation of T and B lymphocytes, which is a key mechanism thought to cause their immunosuppressive effects. 16,17 Rapamycin (RAPA) (also known as sirolimus) is a macrolide antibiotic produced by Streptomyces hygroscopicus. The RAPA binds to FK506-binding protein-12, a highly conserved cytoplasmic receptor.…”