CD8 + T cells mediate aortic allograft vasculopathy by direct killing and an interferon-γ-dependent indirect pathway

Anton I. Skaro, Robert S. Liwski, Juan Zhou, Ellen L. Vessie, Timothy D.G. Lee, Gregory M. Hirsch

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

17 Citas (Scopus)

Resumen

Allograft vasculopathy (AV) has emerged as the major obstacle to long-term survival in clinical heart transplantation. Immune events are implicated in the development of AV, but the cellular and molecular mechanisms involved remain unclear. We sought to determine whether and by what mechanism CD8 + T lymphocytes are able to generate AV in a murine aortic allograft model. Allo-primed CD8 + T lymphocytes were transferred into immunodeficient (RAG-1 -/-) mouse recipients of aortic allografts. We also transferred primed CD8 + T cells with targeted deletions of effector molecules (perforin, Fas-ligand) to determine the role of direct cytolysis (CTL) in CD8 + T-cell-mediated AV. We determined the role of non-CTL effector mechanisms through the transfer of either wildtype or interferon-γ (IFN-γ)-deficient CD8 + T cells into RAG-1 -/- recipients of MHC class I-deficient allografts. Adoptive transfer of primed wildtype CD8 + T lymphocytes into immunodeficient recipients of aortic allografts resulted in the development of robust AV lesions. Transfer of CD8 + T lymphocytes with targeted deletions in CTL effector molecules resulted in reduction of AV lesion size but not abrogation. Transfer of wildtype CD8 + T cells into recipients of MHC class I-deficient grafts resulted in a reduction in AV lesion size, while transfer of interferon-γ-deficient CD8 + T cells into MHC class I-deficient grafts abrogated AV. These data indicate that CD8 + T cells mediate AV through direct cytolysis and a distinct interferon-γ-dependent non-CTL effector pathway. Given the resistance of this cell type to conventional immunosuppression, these results may have important therapeutic implications.

Idioma originalEnglish
Páginas (desde-hasta)283-291
Número de páginas9
PublicaciónCardiovascular Research
Volumen65
N.º1
DOI
EstadoPublished - ene. 1 2005

Nota bibliográfica

Funding Information:
These studies were supported by grants from the Heart and Stroke Foundation of Canada and the Canadian Institutes for Health Research (to G.M.H. and T.D.G.L.), and a Post-doctoral Fellowship provided by the Heart and Stroke Foundation of Canada and Canadian Institutes for Health Research (to A.I.S.), and Izaak Walton Killam Memorial Scholarship (to A.I.S.).

ASJC Scopus Subject Areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Huella

Profundice en los temas de investigación de 'CD8 + T cells mediate aortic allograft vasculopathy by direct killing and an interferon-γ-dependent indirect pathway'. En conjunto forman una huella única.

Citar esto