Background: Immunosuppression of kidney allograft recipients is currently the indispensable method to avoid graft rejection. Nevertheless, suppression of the cellular immunity is an important risk factor for the reactivation of latent viruses such as Polyomavirus BK (BKV) and the development of a BKV-associated nephropathy (BKVAN). Reduction or modulation of the immunosuppressive drug regimen are recommended by the current guidelines as the therapeutic strategies. However, the level of evidences for such recommendation is low due to the lack of appropriate in vivo or in vitro studies. To address this issue, we analyzed the impact of diverse immunosuppressive (IS) drugs on the phenotypic and functional characteristics of BKV-specific T-cells in the present study.

Methods: BKV-specific T-cell lines were generated from BKV-seropositive healthy donors and cultured under treatment of Prednisone, Mycophenolate Mofetil (MMF), Rapamycin, Cyclosporin A (CsA) and Tacrolimus, respectively (all drugs in physiologic concentrations). Subsequently, the phenotype, proliferation, cytokine production and killing capacity of the obtained BKV-specific T-cells were assed applying multiparameter flow cytometry and a flow cytometry-based cytotoxic T-cell assay, respectively.

Results: Our in vitro generated BKV-specific T-cell lines demonstrated the predicted negative effect on the proliferative capacity of all five IS drugs, headed by MMF and Rapamycin. The downregulation of IFNg production by calcineurin inhibitors and by prednisone was observed, whereas Tacrolimus revealed the highest suppressive potential. Furthermore, calcineurin inhibitors and Prednisone, but not Rapamycin and MMF, deteriorated the multifunctionality of BKV-specific T-cells. Importantly, CsA, Tacrolimus and Prednisone treated T-cells retained their virus specific cytolytic abilities, although at lower levels.

Conclusion: We demonstrated that phenotype and functionality of BKV-specific T cells is differently affected by certain immunosuppressive drugs. Our data provide therefore hints for therapeutic modifications of immunosuppressive regimen, and should be be considered in the context of an adoptive T-cell-therapy as well as for vaccine development to ensure therapeutic feasibility.

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