Inhibition of polyomavirus BK-specific T-Cell responses by immunosuppressive drugs.
BACKGROUND
Reducing immunosuppression is the treatment of choice for polyomavirus-associated nephropathy in kidney transplant (KT) patients, but strategies and targets are uncertain.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Calcineurin-inhibitor concentrations are critical for BKV-specific T-cell activation. Reducing calcineurin inhibitors should be considered as first step, whereas conversion to mTOR inhibitors may be an attractive alternative or second step that should be validated in clinical BKV intervention trials.
Egli
Adrian
A
ransplantation and Clinical Virology, Institute for Medical Microbiology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Köhli
Sabrina
S
Dickenmann
Michael
M
Hirsch
Hans H
HH
D000328:Adult; D000368:Aged; D001739:BK Virus / Q000187:drug effects / Q000276:immunology*; D016572:Cyclosporine / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D007555:Isoxazoles / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D000077339:Leflunomide; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D027601:Polyomavirus Infections / Q000276:immunology; D012016:Reference Values; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D007555:Isoxazoles; D007371:Interferon-gamma; D016572:Cyclosporine; D000077339:Leflunomide; D009173:Mycophenolic Acid; D016559:Tacrolimus