NIV Congres

Sotrastaurin (AEB071) is a small-molecular weight immunosuppressant that selectively targets PKC including the PKCα,β and theta isoforms. In experimental heart and kidney allo-transplantation animal models Sotrastaurin markedly prolonged graft survival times. Although a phase II clinical trial using Sotrastaurin plus MPA in renal transplant recipients was associated with increased rejection from week 4 onwards, this calcineurin inhibitor (CNI)-free regimen showed an acceptable safety profile and improved renal function. These results support further study of Sotrastaurin as a component of multidrug immunosuppressive regimens. Here, we show that the pan-PKC inhibitor Sotrastaurin differentially affected human Treg and Tconv (conventional T-cells). Sotrastaurin dose-dependently prevented TCR/CD28-induced Tconv activation characterized by pro-inflammatory cytokine production and expression of activation markers. Also, Sotrastaurin neither favored the generation of induced Treg nor the induction of T-cell anergy.

In contrast, in CD4^pos CD25^highCD127^lowFoxp3^pos Treg Sotrastaurin preserved a stable Treg phenotype as evidenced by maintenance of suppressive capacity, high Foxp3 and CD25 expression, and lack of IL-17A and IFNγ production, even when stimulated with the Th17-enhancing cytokine IL-1β. Thus, next to inhibiting Tconv, pharmacological inhibition of PKC by Sotrastaurin preserves Treg stability and may serve as a powerful tool to improve Treg-based immunotherapy.