Amelioration of human allograft arterial injury by atorvastatin or simvastatin correlates with reduction of interferon-γ production by infiltrating T cells

Tai Yi, Deepak A. Rao, Paul C.Y. Tang, Yinong Wang, Lisa A. Cuchara, Alfred L.M. Bothwell, Christopher M. Colangelo, George Tellides, Jordan S. Pober, Marc I. Lorber

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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)-γ dependent. This study evaluated whether 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, described as inhibitors of IFN-γ 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-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 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-γ was also reduced, as were graft IFN-γ and IFN-γ-inducible chemokine transcripts and graft human leukocyte antigen-DR expression. Graft arteriosclerosis 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 interleukin-2, but not IFN-γ, 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-γ production and secondarily through suppression of the arterial response to IFN-γ.

Original languageEnglish (US)
Pages (from-to)719-727
Number of pages9
JournalTransplantation
Volume86
Issue number5
DOIs
StatePublished - Sep 15 2008
Externally publishedYes

Keywords

  • Allograft arteriopathy
  • HMG-CoA reductase inhibitors
  • Interferon-γ.
  • Statin
  • Transplant arteriosclerosis

ASJC Scopus subject areas

  • Transplantation

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