Substantial proliferation of human renal tubular epithelial cell-reactive CD4+CD28null memory T cells, which is resistant to tacrolimus and everolimus

Background: In spite of maintenance treatment with immunosuppressive drugs, tubulitis still occurs and can lead to structural kidney graft damage. We hypothesize that human renal tubular epithelial cells (TECs) trigger selective proliferation of recipient T-cell subsets with variable sensitivity to immunosuppressive drugs. Methods: Recipient peripheral blood mononuclear cells were cocultured with donor-derived TECs for 7 days. The proliferation of the total CD4+ T-cell pool was assessed. Next, we analyzed which CD4 + T-cell subset proliferated and how this response was affected by tacrolimus, everolimus, prednisolone, and mycophenolic acid (MPA) in clinically relevant concentrations. Results: CD4+ T-cell proliferation upon TEC encounter was mainly executed by memory T cells. Interestingly, 38%±7% of the proliferating CD4+ T-cell pool showed a CD28null phenotype. These proliferating CD4+CD28null memory T cells produced high levels of interferon-γ, tumor necrosis factor-α, and the cytolitic protease granzyme B. TEC-reactive CD4+ T-cell proliferation was significantly suppressed by tacrolimus, everolimus, prednisolone, and MPA (P<0.05). Surprisingly and in contrast to prednisolone and MPA, neither tacrolimus nor everolimus could inhibit the CD4 +CD28null T-cell proliferative response. Conclusion: Our data show substantial proliferation of TEC-reactive CD4+CD28 null memory T cells, which are resistant to tacrolimus and everolimus. This phenomenon might play an important mechanistic role during cellular rejection under full immunosuppression. Copyright

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