Abstracts (complete list) - Wissenschaft Online

Manije Sabet, Maja Frankuski, Anja Reutzel-Selke, Andreas Pascher, Peter Neuhaus,
Johann Pratschke, Katja Kotsch
Donor pretreatment with Simvastatin reduces graft
immunogenicity following prolonged cold ischemia in an
experimental model of kidney transplantation
The protective effects of 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(HMG-CoARIs, statins) have been demonstrated in numerous cerebral, cardiac and
renal ischemia models. The inhibition of free radicals substantially contribute to the
beneficial effects of statins, however the exact modulatory mechanisms remain unclear.
Based on their anti-inflammatory and anti-oxidative properties, we investigated the
potential beneficial effect of donor pretreatment with statins on ischemia/reperfusion
injury in a rat model of kidney transplantation (Tx). F-344 donor rats were pretreated
with Simvastatin for 3 days prior to transplantation (10 mg/kg/day). Kidneys were
grafted into Lewis recipients following a prolonged cold ischemia of 24h. Grafts and
spleens of recipients were harvested 24h and 14 days post transplantation (n=6/group).
Frequencies of cell populations were analyzed by flow cytometry and the mRNA
expression of relevant candidate genes (CD3, IL-12, MHC class II, CD80, CCR7, CCL19
and CCL21) was evaluated by real-time RT-PCR. After 24h and 14 days post Tx number
of CD4+ cells were slightly reduced in spleens of recipients following donor
pretreatment with Simvastatin (Simvastatin vs. control, 24h: 43.9±2.3% vs. 49.2
±3.7%, p=0.027; d14: 44.3±2.4% vs. 49.8±1.8%, p=0.07). Interestingly, the
frequency of CD3-CD4+ monocytes was significantly reduced in the Simvastatin group
(Simvastatin vs. control, 24h: 6.8±2.1% vs. 12.1±2.6%, p=0.007; d14: 20.3±2.9 vs.
25.0±1.0%, p=0.018), whereas the number of CD3+CD4+ T cells was comparable in
both groups. In the spleen reduced mRNA expression level of CD3 as a marker of T cell
infiltration as well reduced mRNA expression of IL-12 and CD80 were detected.
Furthermore the chemokine receptor CCR7 was markedly reduced in the spleen as well
as its ligands CCL19 and CCL21 displayed enhanced mRNA expression in the graft.
Additionally we revealed a notable decrease of MHC class II in both kidney and spleen.
Our data suggest that donor pretreatment with Simvastatin following prolonged cold
ischemia reduces graft immunogenicity by modulating potential antigen presenting cells
and their homing to lymphoid organs. Donor pretreatment with Simvastatin may
therefore represent an attractive tool to preserve renal function after ischemia/
reperfusion injury.