Everolimus-Treated Renal Transplant Recipients Have a More Robust CMV-Specific CD8+ T-Cell Response Compared With Cyclosporine- or Mycophenolate-Treated Patients

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. (C) 2012 Lippincott Williams & Wilkins, Inc.

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Página original: http://pdfs.journals.lww.com/transplantjournal/9000/00000/Everolimus_Treated_Renal_Transplant_Recipients.98779.pdf