Mechanism of the combination immunosuppressive effects of rapamycin with either cyclosporine or tacrolimus

Background. The combination of rapamycin with Cyclosporine has demonstrated beneficial effects in organ transplantation; however, the mechanism of this combination immunosuppression is not fully understood. The mechanism of action of cyclosporine and tacrolimus has been explained on the basis of their inhibition of interleukin-2 (IL-2), and induction of transforming growth factor-beta (TGF-beta). In this study, we explored the effects of rapamycin in combination with either tacrolimus or cyclosporine on lymphocyte proliferation, and expression of interleulin-2 (IL-2) and TGF-beta Methods. Peripheral blood mononuclear cells/lymphocytes were isolated from huffy coats obtained from blood center, and activated with phytohemagglutinin (PHA) in the presence or absence of rapamycin, cyclosporine, and tacrolimus alone or in various combinations. The activation was quantified by H-3-thymidine uptake assay and using reverse transcriptase assisted polymerase chain reaction and ELISA, we studied the TGF-beta and IL-2 mRNA and protein expression, respectively, Results. In this study, we report that rapamycin in combination with either tacrolimus or cyclosporine significantly inhibited the lymphocyte proliferation, IL-2 expression, and induced TGF-beta, compared with these drugs alone. The levels of TGF-beta and IL-2 correlated positively and negatively, respectively, with inhibition of lymphocyte proliferation. Conclusions. These novel findings provide the mechanism as well as the rationale to use these drugs in combination at subclinical dosages in organ transplantation.