title: Interferon-γ-mediated allograft rejection exacerbates cardiovascular disease of hyperlipidemic murine transplant recipients.
abstract: BACKGROUND
  Transplantation, the most effective therapy for end-stage organ failure, is markedly limited by early-onset cardiovascular disease (CVD) and premature death of the host. The mechanistic basis of this increased CVD is not fully explained by known risk factors.
  
  
  OBJECTIVE
  To investigate the role of alloimmune responses in promoting CVD of organ transplant recipients.
  
  
  RESULTS
  We established an animal model of graft-exacerbated host CVD by combining murine models of atherosclerosis (apolipoprotein E-deficient recipients on standard diet) and of intra-abdominal graft rejection (heterotopic cardiac transplantation without immunosuppression). CVD was absent in normolipidemic hosts receiving allogeneic grafts and varied in severity among hyperlipidemic grafted hosts according to recipient-donor genetic disparities, most strikingly across an isolated major histocompatibility complex class II antigen barrier. Host disease manifested as increased atherosclerosis of the aorta that also involved the native coronary arteries and new findings of decreased cardiac contractility, ventricular dilatation, and diminished aortic compliance. Exacerbated CVD was accompanied by greater levels of circulating cytokines, especially interferon-γ and other Th1-type cytokines, and showed both systemic and intralesional activation of leukocytes, particularly T-helper cells. Serological neutralization of interferon-γ after allotransplantation prevented graft-related atherosclerosis, cardiomyopathy, and aortic stiffening in the host.
  
  
  CONCLUSIONS
  Our study reveals that sustained activation of the immune system because of chronic allorecognition exacerbates the atherogenic diathesis of hyperlipidemia and results in de novo cardiovascular dysfunction in organ transplant recipients.
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.). george.tellides@yale.edu zhou.jing@yale.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Rahmat
authors.initials: R
authors.lastname: Ali
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Qingle
authors.initials: Q
authors.lastname: Li
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Guangxin
authors.initials: G
authors.lastname: Li
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tobiasova
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: James J
authors.initials: JJ
authors.lastname: Yun
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Mehran M
authors.initials: MM
authors.lastname: Sadeghi
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Giordano
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.).
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.affiliation: From the Departments of Surgery (J.Z., L.Q., R.A., Q.L., Y.J., G.L., J.J.Y., G.T.) and Immunobiology (T.Y., Z.T., J.S.P.) and Medicine (Y.H., J.Z., M.M.S., F.J.G.) and the Interdepartmental Program in Vascular Biology and Therapeutics (J.J.Y., M.M.S., F.J.G., J.S.P., G.T.), Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare System, West Haven (J.J.Y., M.M.S., F.J.G., G.T.); Research Institute, Nationwide Children's Hospital, Columbus, OH (T.Y.); and Department of Vascular Surgery, Peking University People's Hospital, Beijing, P.R. China (Q.L., Y.J.). george.tellides@yale.edu zhou.jing@yale.edu.
authors.forename: George
authors.initials: G
authors.lastname: Tellides
mesh_terms: D064591:Allografts; D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D009202:Cardiomyopathies / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000150:complications* / Q000276:immunology; D016027:Heart Transplantation / Q000009:adverse effects*; D006439:Hemodynamics; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications* / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood* / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood* / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D016277:Ventricular Function, Left
chemical_list: D001057:Apolipoproteins E; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D007371:Interferon-gamma
keywords: atherosclerosis; cardiovascular disease; interferons; lymphocytes; transplantation