title: Impact of hyperlipidemia on alloimmunity.
abstract: OBJECTIVE
  Hyperlipidemia is a comorbidity affecting a significant number of transplant patients despite treatment with cholesterol lowering drugs. Recently, it has been shown that hyperlipidemia can significantly alter T-cell responses to cardiac allografts in mice, and graft rejection is accelerated in dyslipidemic mice. Here, we review recent advances in our understanding of hyperlipidemia in graft rejection.
  
  
  RESULTS
  Hyperlipidemic mice have significant increases in serum levels of proinflammatory cytokines, and neutralization of interleukin 17 (IL-17) slows graft rejection, suggesting that IL-17 production by Th17 cells was necessary but not sufficient for rejection. Hyperlipidemia also causes an increase in alloreactive T-cell responses prior to antigen exposure. Analysis of peripheral tolerance mechanisms indicated that this was at least in part due to alterations in FoxP3 T cells that led to reduced Treg function and the expansion of FoxP3 CD4 T cells expressing low levels of CD25. Functionally, alterations in Treg function prevented the ability to induce operational tolerance to fully allogeneic heart transplants through costimulatory-molecule blockade, a strategy that requires Tregs.
  
  
  CONCLUSIONS
  These findings highlight the importance of considering the contribution of inflammatory comorbidities to cardiac allograft rejection, and point to the potential importance of managing hyperlipidemia in the transplant population.
authors.affiliation: aDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Boston, Massachusetts bDepartment of Medicine, MetroWest Medical Center, Framingham, Massachusetts, USA.
authors.forename: Jessamyn
authors.initials: J
authors.lastname: Bagley
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.forename: John
authors.initials: J
authors.lastname: Iacomini
mesh_terms: D000818:Animals; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000379:methods*; D006801:Humans; D006949:Hyperlipidemias / Q000628:therapy*; D051379:Mice