Amelioration of human allograft arterial injury by atorvastatin or simvastatin correlates with reduction of interferon-gamma production by infiltrating T cells.
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 that the morphologic and functional changes of experimental GA are interferon (IFN)-gamma dependent. This study evaluated whether 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, described as inhibitors of IFN-gamma production, affect GA in our model.


METHODS
C.B.-17 severe combined immunodeficiency-beige mice were transplanted with human artery segments as aortic interposition grafts and inoculated with allogeneic human peripheral blood mononuclear cells (PBMCs) or replication-deficient adenovirus encoding human IFN-gamma. 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 were also investigated in vitro.


RESULTS
Graft arteriosclerosis-like arteriopathy induced by PBMCs 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-gamma was also reduced, as were graft IFN-gamma and IFN-gamma-inducible chemokine transcripts and graft human leukocyte antigen-DR expression. Graft arteriosclerosis directly induced by human IFN-gamma 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 interleukin-2, but not IFN-gamma, by human CD4+ T cells in response to allogeneic endothelial cells in coculture.


CONCLUSIONS
Our results suggest that a benefit of statin administration in transplantation may include amelioration of GA primarily by inhibiting alloreactive T-cell accumulation and consequent IFN-gamma production and secondarily through suppression of the arterial response to IFN-gamma.
Yi
Tai
T
Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT, USA.
Rao
Deepak A
DA
Tang
Paul C Y
PC
Wang
Yinong
Y
Cuchara
Lisa A
LA
Bothwell
Alfred L M
AL
Colangelo
Christopher M
CM
Tellides
George
G
Pober
Jordan S
JS
Lorber
Marc I
MI
D000328:Adult; D000818:Animals; D001158:Arteries / Q000637:transplantation; D000069059:Atorvastatin; D005434:Flow Cytometry; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D017710:Lymphocyte Transfusion; D051379:Mice; D016513:Mice, SCID; D011758:Pyrroles / Q000627:therapeutic use*; D019821:Simvastatin / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology; D014184:Transplantation, Homologous
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D007371:Interferon-gamma; D000069059:Atorvastatin; D019821:Simvastatin
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