Both tacrolimus and cyclosporine were shown to cause dose-depende

Both tacrolimus and cyclosporine were shown to cause dose-dependent inhibition of IFN-�� expression. Specifically, tacrolimus concentrations >6ng/mL were shown to cause >50% inhibition of BKV-specific T cells, while concentrations of <3ng/mL led to <30% inhibition. Inhibition by cyclosporine was >50% at concentrations of 1920ng/mL and <30% at concentrations of <960ng/mL. In contrast, addition of clinically relevant concentrations of MPA (up to 8/mL) and sirolimus (up to 64ng/mL) had no effect on BKV-specific T cell IFN-�� production. Of note, addition of increasing concentrations of sirolimus during T-cell expansion led to reductions in total cell count, consistent with the well-established anti-proliferative effect of this drug.

This suggests that while sirolimus had no effect on T-cell activation, it was able to inhibit BKV-specific T-cell expansion. The above in vitro data suggest that cyclosporine, MPA, and sirolimus may be protective Inhibitors,Modulators,Libraries against BK replication, as compared to tacrolimus and corticosteroids. Inhibitors,Modulators,Libraries However, whether the postulated antiviral effects of these agents are sufficient to outweigh their immunosuppressive properties in vivo cannot be elucidated from these studies. 2.2. Clinical Studies 2.2.1. Calcineurin Inhibitors, Antimetabolites, and Risk of BKV Replication BKVAN was essentially an unknown entity in the era of cyclosporine-based immunosuppression, with increasing identification of BKVAN coinciding with inclusion of tacrolimus and MPA in immunosuppressive regimens [6]. This has led to the suggestion that these agents may be specifically responsible.

In support of this, multiple retrospective and observational studies Inhibitors,Modulators,Libraries have demonstrated substantial increases in the risk of BKV replication in the context of tacrolimus and MPA use [14, 59, 60]. Table 2 details these studies. Of importance, however, Inhibitors,Modulators,Libraries in the first Inhibitors,Modulators,Libraries four of the studies tabulated [14, 20, 59, 60], conversion to tacrolimus occurred in response to episodes of rejection. This makes it likely that the development of BKVAN was preceded by overall intensification of immunosuppression. Additionally, it is possible that the renal injury arising from rejection episodes may have had a predisposing effect [61]. In the subsequent three studies tabulated [35, 61, 62], no information was provided as to why recipients were administered a particular calcineurin inhibitor or antimetabolite over the other.

Given the general belief that tacrolimus and MPA have increased immunosuppressive potency compared to cyclosporine and azathioprine, use of these drugs may have been reserved for patients at higher immunological Batimastat risk and were possibly dosed to achieve higher levels of immunosuppression. Consequently, the potential for indication bias limits any conclusions that may be drawn regarding drug-specific effects on BKV replication.

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