ransplantation and Clinical Virology, Institute for Medical Microbiology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Transplantation. 2009 Nov 27;88(10):1161-8. doi: 10.1097/TP.0b013e3181bca422.
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 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.
减少免疫抑制是治疗肾移植（KT）患者多瘤病毒相关性肾病的首选方法，但策略和目标尚不确定。
使用干扰素-γ ELISpot 检测，我们研究了 KT 患者体内和健康供体体外调整免疫抑制后药物水平和多瘤病毒 BK（BKV）大 T 抗原特异性 T 细胞反应。
在 KT 患者中，BKV 特异性 T 细胞反应与他克莫司谷浓度呈负相关（R=0.28，P<0.002），但与霉酚酸水平、泼尼松或总免疫抑制剂量无关。体外他克莫司浓度高于 6ng/ml 时，BKV 和巨细胞病毒特异性 T 细胞抑制率超过 50%，而低于 3ng/ml 时抑制率低于 30%。环孢素 A 的抑制作用在浓度为 1920ng/ml 时超过 50%，而在低于 960ng/ml 时低于 30%，分别对应于临床 C0 谷浓度 200 和 100ng/ml。然而，霉酚酸高达 8μg/ml、来氟米特 50μg/ml 或西罗莫司浓度 64ng/ml 不会抑制 BKV 特异性干扰素-γ产生，但会抑制抗原依赖性 T 细胞扩增。
钙调神经磷酸酶抑制剂浓度对 BKV 特异性 T 细胞激活至关重要。减少钙调神经磷酸酶抑制剂应作为第一步考虑，而转换为 mTOR 抑制剂可能是一种有吸引力的替代方案或第二步，应在临床 BKV 干预试验中验证。
