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Interferon-γ-mediated allograft rejection exacerbates cardiovascular disease of hyperlipidemic murine transplant recipients.
Zhou, Jing; Qin, Lingfeng; Yi, Tai; Ali, Rahmat; Li, Qingle; Jiao, Yang; Li, Guangxin; Tobiasova, Zuzana; Huang, Yan; Zhang, Jiasheng; Yun, James J; Sadeghi, Mehran M; Giordano, Frank J; Pober, Jordan S; Tellides, George.
Afiliação
  • Zhou J; 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
  • Qin L; 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
  • Yi T; 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
  • Ali R; 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
  • Li Q; 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
  • Jiao Y; 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
  • Li G; 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
  • Tobiasova Z; 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
  • Huang Y; 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
  • Zhang J; 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
  • Yun JJ; 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
  • Sadeghi MM; 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
  • Giordano FJ; 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
  • Pober JS; 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
  • Tellides G; 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
Circ Res ; 117(11): 943-55, 2015 Nov 06.
Article em En | MEDLINE | ID: mdl-26399469
ABSTRACT
RATIONALE 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. METHODS AND

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.
Assuntos
Doenças Cardiovasculares/etiologia; Rejeição de Enxerto/complicações; Transplante de Coração/efeitos adversos; Hiperlipidemias/complicações; Mediadores da Inflamação/sangue; Interferon gama/sangue; Aloenxertos; Animais; Doenças da Aorta/sangue; Doenças da Aorta/etiologia; Doenças da Aorta/imunologia; Doenças da Aorta/prevenção & controle; Apolipoproteínas E; Aterosclerose/sangue; Aterosclerose/etiologia; Aterosclerose/imunologia; Aterosclerose/prevenção & controle; Cardiomiopatias/sangue; Cardiomiopatias/etiologia; Cardiomiopatias/imunologia; Cardiomiopatias/prevenção & controle; Doenças Cardiovasculares/sangue; Doenças Cardiovasculares/diagnóstico; Doenças Cardiovasculares/genética; Doenças Cardiovasculares/imunologia; Doenças Cardiovasculares/fisiopatologia; Doenças Cardiovasculares/prevenção & controle; Modelos Animais de Doenças; Feminino; Rejeição de Enxerto/sangue; Rejeição de Enxerto/imunologia; Hemodinâmica; Antígenos de Histocompatibilidade Classe II/imunologia; Hiperlipidemias/sangue; Hiperlipidemias/genética; Mediadores da Inflamação/imunologia; Interferon gama/imunologia; Ativação Linfocitária; Masculino; Camundongos Endogâmicos BALB C; Camundongos Endogâmicos C57BL; Camundongos Knockout; Transdução de Sinais; Células Th1/imunologia; Células Th1/metabolismo; Disfunção Ventricular Esquerda/sangue; Disfunção Ventricular Esquerda/etiologia; Disfunção Ventricular Esquerda/imunologia; Disfunção Ventricular Esquerda/prevenção & controle; Função Ventricular Esquerda
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Cardiovasculares / Transplante de Coração / Interferon gama / Mediadores da Inflamação / Rejeição de Enxerto / Hiperlipidemias Tipo de estudo: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Circ Res Ano de publicação: 2015 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Cardiovasculares / Transplante de Coração / Interferon gama / Mediadores da Inflamação / Rejeição de Enxerto / Hiperlipidemias Tipo de estudo: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Idioma: En Revista: Circ Res Ano de publicação: 2015 Tipo de documento: Article