Inhibition of Polyomavirus BK-Specific T-Cell Responses by Immunosuppressive Drugs

被引:117
作者
Egli, Adrian [1 ]
Koehli, Sabrina [1 ]
Dickenmann, Michael
Hirsch, Hans H. [1 ,2 ]
机构
[1] Univ Basel, Dept Biomed, Inst Med Microbiol, CH-4003 Basel, Switzerland
[2] Univ Basel Hosp, Infect Dis & Hosp Epidemiol, CH-4031 Basel, Switzerland
关键词
Polyomavirus; BKV; Cytomegalovirus; Viral replication; Immunosuppression; Tacrolimus; Cyclosporine A; Sirolimus; Leflunomide; KIDNEY-TRANSPLANT RECIPIENTS; VIRUS-ASSOCIATED NEPHROPATHY; RENAL-TRANSPLANTATION; IMMUNE-RESPONSE; RISK-FACTORS; REPLICATION; ANTIGEN; CYCLOSPORINE; NEPHRITIS; TACROLIMUS;
D O I
10.1097/TP.0b013e3181bca422
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-2=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 C-0 trough levels of 200 and 100 ng/mL, respectively. However, mycophenolate up to 8 mu g/mL, leflunomide 50 mu g/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.
引用
收藏
页码:1161 / 1168
页数:8
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