Inhibition of polyomavirus BK-specific T-Cell responses by immunosuppressive drugs

Transplantation
Adrian EgliHans H Hirsch

Abstract

Reducing immunosuppression is the treatment of choice for polyomavirus-associated nephropathy in kidney transplant (KT) patients, but strategies and targets are uncertain. Using interferon-gamma ELISpot assays, we investigated immunosuppressive drug levels and polyomavirus BK (BKV) large T-antigen-specific T-cell responses in KT patients in vivo and in healthy donors after titrating immunosuppression in vitro. In KT patients, BKV-specific T-cell responses were inversely correlated with tacrolimus trough levels (R=0.28, P<0.002), but not with mycophenolate levels, prednisone, or overall immunosuppressive dosing. In vitro tacrolimus concentrations above 6 ng/mL inhibited BKV- and cytomegalovirus-specific T-cells more than 50%, whereas less than 30% inhibition was observed below 3 ng/mL. Inhibition by cyclosporine A was more than 50% at concentrations of 1920 ng/mL and less than 30% below 960 ng/mL, corresponding to clinical C0 trough levels of 200 and 100 ng/mL, respectively. However, mycophenolate up to 8 microg/mL, leflunomide 50 microg/mL, or sirolimus concentrations 64 ng/mL did not inhibit BKV-specific interferon-gamma production, but antigen-dependent T-cell expansion. Calcineurin-inhibitor concentrations are critical for B...Continue Reading

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