Distinct Patterns of Cytokine Gene Suppression by the Equivalent Effective Doses of Cyclosporine and Tacrolimus in Rat Heart Allografts

Abstract

In vitro studies of the mode of action of cyclosporine (CsA) and tacrolimus have indicated that both drugs produce immunosuppression by a quite similar cellular and molecular mechanism to block T cell receptor emanated transcriptional activation of interleukin(IL)-2 and other cytokine genesHerein, we show that there are distinct patterns of cytokine gene expression in rat heart allografts under equivalent effective doses (“optimal dose”) of CsA and tacrolimusThe optimal doses of CsA (10 mg/kg/day) and tacrolimus (3.2 mg/kg/day), which induce similar mean graft survival time (MST), were administered in LEW recipients with ACI heart grafts from day 0 after grafting until sacrificeHeart grafts were harvested at days 3, 5, and 7The expression of various cell surface markers, cytokines, and cytotoxic factors was determined by immunohistology and reverse transcriptase-polymerase chain reaction (RT-PCR)Cell populations that stained positively in the heart tissues of allograft control increased through day 7 for CD4 + and CD8 + T lymphocytes, NKR-Pla + natural killer (NK) cells, and ED2 + macrophagesCsA and tacrolimus have comparable activity to block these cell local infiltrationsThe mRNA levels of the majority of the factors were dramatically up-regulated in the allografts over time, peaking at day 5The optimal doses of CsA and tacrolimus had similar inhibitory effects on Thl type eytokine IL-2 and interferon [INF]-γ), inflammatory cytokine (IL-1β and tumor necrosis factor [TNF]α), and cytotoxic factor (granzyme B and perforin) mRNA expressionHowever, the drugs had different effect on Th2 type cytokines (IL-4 and IL-IO)Whereas IL-4 expression was not affected by tacrolimus and was enhanced by CsA, IL-IO expression was more significantly suppressed by tacrolimus than CsADifferences in the suppression of Th2 type cytokine gene expression indicate that the in vivo molecular networks by which CsA and tacrolimus exert their full immunosuppressive activity are not necessarily the same.