Everolimus-Treated Renal Transplant Recipients Have a More Robust CMV-Specific CD8+ T-Cell Response Compared With Cyclosporine- or Mycophenolate-Treated Patients
Everolimus-Treated Renal Transplant Recipients Have a More Robust CMV-Specific CD8+ T-Cell Response Compared With Cyclosporine- or Mycophenolate-Treated Patients
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DOI：
10.1097/tp.0b013e318276a1ef
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发表时间：
2013-01-15
期刊：
影响因子：
6.2
通讯作者：
Bemelman, Frederike J.
中科院分区：
文献类型：
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作者：
Havenith, Simone H. C.;La Yong, Si;Bemelman, Frederike J.
背景在肾移植受者中，已报道哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂可预防巨细胞病毒（CMV）疾病。在这里，我们质疑mTOR抑制剂是否特异性地影响人CMV诱导的T细胞应答。我们研究了肾移植受者在移植后前6个月接受泼尼松龙、环孢素A（CsA）和霉酚酸钠（MPS）治疗，随后接受泼尼松龙/依维莫司（mTOR抑制剂）（P/EVL; n=10）、泼尼松龙/CsA（P/CsA; n=7）或泼尼松龙/MPS（P/MPS; n=9）双重治疗。所有患者移植前均为CMV-IgG阳性。在移植后的前6个月可检测到CMV再激活，此后则不可检测。本研究纳入的患者均未患CMV疾病。在移植前和移植后6个月和24个月测量了已知与CMV感染相关的CD 27（-）CD 8（+）和CD 27（-）CD 28（-）CD 4（+）效应型T细胞计数。此外，我们在这些时间点测定CMV特异性CD 8（+）T细胞的数量和功能。转换为P/EVL治疗后，总CD 8（+）T细胞、CD 27（-）CD 8（+）T细胞和CD 28（-）CD 4（+）T细胞数量显著增加，但转换为P/CsA或P/MPS治疗后未增加。具体而言，CMV特异性CD 8（+）T细胞计数在转换为P/EVL治疗后显著增加。此外，mTOR抑制剂西罗莫司在体外强烈抑制同种异体反应，而不影响CMV特异性反应。我们观察到依维莫司治疗患者的（CMV特异性）效应型CD 8（+）和CD 4（+）T细胞计数显著增加。这些发现至少可以部分解释在依维莫司治疗的患者中CMV相关病理学的低发生率。
Background. In renal transplant recipients, mammalian target of rapamycin (mTOR) inhibitors have been reported to protect against cytomegalovirus (CMV) disease. Here, we questioned whether mTOR inhibitors specifically influence human CMV-induced T-cell responses.Methods. We studied renal transplant recipients treated with prednisolone, cyclosporine A (CsA), and mycophenolate sodium (MPS) for the first 6 months after transplantation followed by double therapy consisting of prednisolone/everolimus, which is an mTOR inhibitor (P/EVL; n=10), prednisolone/CsA (P/CsA; n=7), or prednisolone/MPS (P/MPS; n=9). All patients were CMV-IgG positive before transplantation. CMV reactivation was detectable in the first 6 months after transplantation and not thereafter. None of the patients included in this study suffered from CMV disease. Both CD27(-)CD8(+) and CD27(-)CD28(-)CD4(+) effector-type T-cell counts, known to be associated with CMV infection, were measured before transplantation and at 6 and 24 months after transplantation. Additionally, we determined both number and function of CMV-specific CD8(+) T cells at these time points.Results. The number of total CD8(+) T cells, CD27(-)CD8(+) T cells, and CD28(-)CD4(+) T cells increased significantly after switch to therapy with P/EVL but not after switch to P/CsA or P/MPS. Specifically, CMV-specific CD8(+) T-cell counts significantly increased after switch to therapy with P/EVL. Furthermore, the mTOR inhibitor sirolimus strongly inhibited alloresponses in vitro, whereas it did not affect CMV-specific responses.Conclusion. We observed a significant increase in (CMV-specific) effector-type CD8(+) and CD4(+) T-cell counts in everolimus-treated patients. These findings may at least in part explain the reported low incidence of CMV-related pathology in everolimus-treated patients.