SRL plus CsA prevented allograft arteriopathy, correlating with suppression of intragraft interferon-gamma, suggesting that SRL effects may result from anti-inflammatory consequences from inhibiting interferon-gamma.
Background
Graft arteriosclerosis (GA) is an important factor limiting long-term outcomes after organ transplantation. We have used a chimeric humanized mouse system to model this arteriopathy in human vessels and found the morphologic and functional changes of experimental GA to be interferon (IFN)-γ-dependent. This study evaluated if HMG-CoA reductase inhibitors, described as inhibitors of IFN-γ production, affect GA in our model.
Methods
C.B-17 SCID/beige mice were transplanted with human artery segments as aortic interposition grafts and inoculated with allogeneic human PBMCs or replication-deficient adenovirus encoding human IFN-γ. Transplant arteries were analyzed from recipients treated with vehicle vs. atorvastatin or simvastatin at different doses. The effects of statins on T cell alloresponses to vascular endothelial cells (ECs) were also investigated in vitro.
Results
PBMC-induced GA-like arteriopathy was reduced by atorvastatin at 30 mg/kg/day or simvastatin at 100 mg/kg/day that correlated with decreased graft-infiltrating CD3+ T cells. Circulating IFN-γ was also reduced, as were graft IFN-γ and IFN-γ-inducible chemokine transcripts and graft HLA-DR expression. GA directly induced by human IFN-γ in the absence of human PBMCs was also reduced by atorvastatin, but only at the highest dose of 100 mg/kg/day. Finally, atorvastatin decreased the clonal expansion and production of IL-2, but not IFN-γ, by human CD4+ T cells in response to allogeneic ECs in co-culture.
Conclusions
Our results suggest a benefit of statin administration in transplantation may include amelioration of GA primarily by inhibiting alloreactive T cell accumulation and consequent IFN-γ production and secondarily through suppression of the arterial response to IFN-γ.
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