title: Hyperlipidemia Promotes Anti-Donor Th17 Responses That Accelerate Allograft Rejection.
abstract: Hyperlipidemia occurs in 95% of organ transplant recipients, however its effect on organ allograft rejection has not been investigated. We found that induction of hyperlipidemia in mice caused a significant acceleration of rejection of cardiac allografts. Accelerated rejection was associated with an aggressive T cell infiltrate that mediated significant tissue damage as well as increased serum levels of the proinflammatory cytokines IL-2, IL-6, and IL-17. Hyperlipidemic mice had an increased number of Th17 cells in their periphery and rejecting allografts from hyperlipidemic mice contained significant numbers of IL-17 producing T cells that were not detectable in transplants harvested from controls. Neutralization or genetic ablation of IL-17 prolonged survival of cardiac allografts transplanted into hyperlipidemic recipients, suggesting that IL-17 production promotes accelerated rejection. Analysis of alloreactive T cell frequencies directly ex vivo in naïve mice revealed that the frequency of donor reactive IL-17 producing cells in hyperlipidemic was increased prior to antigen exposure, suggesting that hyperlipidemia was sufficient to alter T cell alloreactivity and promote anti-donor Th17 responses on first exposure to antigen. Together, our data suggest that hyperlipidemia alters rejection by altering the types of T cell subsets that respond to donor antigen by promoting Th17 biased anti-donor reactivity.
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Boston, MA.
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Boston, MA.
authors.forename: J
authors.initials: J
authors.lastname: Bagley
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Sackler School of Biomedical Sciences Programs in Immunology and Genetics, Boston, MA.
authors.forename: J
authors.initials: J
authors.lastname: Iacomini
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002454:Cell Differentiation; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation; D006949:Hyperlipidemias / Q000503:physiopathology*; D007108:Immune Tolerance / Q000276:immunology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D020381:Interleukin-17
keywords: T cell biology; hyperlipidemia; rejection; rejection: T cell mediated (TCMR)