Tacrolimus-based immunosuppression only marginally affects monocyte activation after kidney transplantation

N.M. Kannegieter, D.A. Hesselink, M. Dieterich, G.N. de Graav, R. Kraaijeveld, A.T. Rowshani, P.J.M. Leenen, C.C. Baan

Chair(s): Dr. E.M. van Maarseveen

Thursday 9 march 2017

12:45 - 13:00h

Categories: Poster - Basaal

Parallel session: Postersessie - Basaal 2

Monocytes significantly contribute to ischemia reperfusion injury and allograft rejection after kidney transplantation. However, the knowledge about the effects of immunosuppressive drugs on monocyte activation is limited. Here, the phosphorylation profile of 3 signaling proteins was measured to determine the effects of immunosuppression on monocyte activation in kidney transplant patients.

Peripheral blood samples (n=20 patients) were studied before and 4, 30, 90, 180 and 360 days after kidney transplantation. Patients received maintenance therapy consisting of tacrolimus, mycophenolate mofetil and prednisolone in combination with basiliximab induction therapy. Phosphorylation (median fluorescence intensity) of p38MAPK, ERK and Akt was measured by phospho-specific flowcytometry on whole blood samples. Isotype controls were used as negative controls.

After transplantation, in ex vivo whole blood samples, p38MAPK phosphorylation was inhibited after transplantation compared to pre-transplantation (mean inhibition ±30%; p < 0.05). The other MAPK family member, ERK, showed a predominant decrease in phosphorylation in the first month after transplantation (mean inhibition 35% and 45% at day 4 and 30; p < 0.05 and p < 0.001, respectively). Finally, p-Akt was also inhibited at all time points after transplantation (mean inhibition ±20%; p < 0.05). Interestingly, maximal inhibition was 45% for the tested signalling proteins. At day 4 after transplantation, when the highest whole blood trough levels were measured, p38MAPK and p-Akt inversely correlated with tacrolimus concentrations (rs = -0.65; p = 0.012 and rs = -0.58; p = 0.030, respectively). This correlation was not found for p-ERK.

In conclusion, phospho-specific flowcytometry is a novel technique to pharmacodynamically monitor immunosuppressive drug effects on monocytes. The currently prescribed immunosuppressive drugs only partially inhibit monocyte activation pathways in kidney transplant recipients, explaining the active contribution of these cells to rejection processes.

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