Proton pump inhibitors reduce mycophenolate exposure in heart transplant recipients-a prospective case-controlled study.

This prospective study investigates the impact of proton pump inhibitors (PPI) on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) and tacrolimus. MPA plasma concentrations at baseline (C(0 h)), 30 min (C(0.5 h)), 1(C(1 h)) and 2 h (C(2 h)) were obtained by high-performance liquid chromatography (HPLC) in 22 patients treated with pantoprazole 40 mg and MMF 2000 mg. Measurements were repeated 1 month after pantoprazole withdrawal. A four-point limited-sampling strategy was applied to calculate the MPA area under the curve (MPA-AUC). Predose MPA concentrations with PPI were 2.6 +/- 1.6 mg/L versus 3.4 +/- 2.7 mg/L without PPI (p = ns). Postdose MPA concentrations were lower with PPI at C(0.5 h) (8.3 +/- 5.7 mg/L vs. 18.3 +/- 11.3 mg/L, p = 0.001) and C(1 h) (10.0 +/- 5.6 mg/L vs. 15.8 +/- 8.4 mg/L, p = 0.004), without significant differences at C(2 h) (8.3 +/- 6.5 mg/L vs. 7.6 +/- 3.9 mg/L). The MPA-AUC was significantly lower with PPI medication (51.2 +/- 26.6 mg x h/L vs. 68.7 +/- 30.3 mg x h/L; p = 0.003). The maximum concentration of MPA (MPA-C(max)) was lower (12.2 +/- 7.5 mg/L vs. 20.6 +/- 9.3 mg/L; p = 0.001) and the time to reach MPA-C(max) (t(max)) was longer with PPI (60.0 +/- 27.8 min vs. 46.4 +/- 22.2 min; p = 0.05). This is the first study to document an important drug interaction between a widely used immunosuppressive agent and a class of drugs frequently used in transplant patients. This interaction results in a decreased MMF drug exposure which may lead to patients having a higher risk for acute rejection and transplant vasculopathy.

Involvement of dendritic cells in allograft rejection new implications of dendritic cell-endothelial cell interactions.

For almost half a century immunologists have tried to tear down the MHC barrier, which separates two unrelated individuals during transplantation. Latest experimental data suggest that a breakthrough in vitro is imminent. Dendritic cells (DCs), which activate naïve allo-reactive T-cells (TCs), play a central role in the establishment of allo-antigen-specific immunity. Allograft solid organ rejection is initiated at the foreign endothelial cell (EC) layer, which forms an immunogenic barrier for migrating DCs. Thus, DC/EC interactions might play a crucial role in antigen-specific allograft rejection. Organ rejection is mediated by host allo-reactive TCs, which are activated by donor DCs (direct activation) or host DCs (indirect activation). Direct allo-antigen presentation by regulatory dendritic cells (DCreg) can play an instructive role towards tolerance induction. Several groups established that, DCregs, if transplanted beforehand, enter host thymus, spleen, or bone marrow where they might eventually establish allo-antigen-specific tolerance. A fundamental aspect of DC function is migration throughout the entire organism. After solid organ transplantation, host DCs bind to ECs, invade allograft tissues, and finally transmigrate into lymphoid vessels and secondary lymphoid organs, where they present allo-antigens to naïve host TCs. Recent data suggest that in vitro manipulated DCregs may mediate allo-transplantation tolerance induction. However, the fundamental mechanisms on how such DCregs cause host TCs in the periphery towards tolerance remain unclear. One very promising experimental concept is the simultaneous manipulation of DC direct and indirect TC activation/suppression, towards donor antigen-specific allo-transplantation tolerance. The allo-antigen-specific long-term tolerance induction mediated by DCreg pre-transplantation (with simultaneous short-term immunosuppression) has become reproducible in the laboratory animal setting. Despite the shortcomings of laboratory animal studies, strong promises are deriving from these studies for clinical kidney, heart, and liver transplantation.