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

Egli, Adrian and Köhli, Sabrina and Dickenmann, Michael and Hirsch, Hans H.. (2009) Inhibition of polyomavirus BK-specific T-Cell responses by immunosuppressive drugs. Transplantation : official journal of the Transplantation Society, Vol. 88. pp. 1161-1168.

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Official URL: http://edoc.unibas.ch/dok/A6003723

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Abstract

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.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Nephrologie > Transplantationsimmunologie und Nephrologie (Steiger)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Nephrologie > Transplantationsimmunologie und Nephrologie (Steiger)
03 Faculty of Medicine > Departement Biomedizin > Division of Medical Microbiology > Transplantation Virology (Hirsch)
UniBasel Contributors:Hirsch, Hans H. and Dickenmann, Michael Jan
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Lippincott Williams & Wilkins
ISSN:0041-1337
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Mar 2013 11:13
Deposited On:01 Mar 2013 11:09

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