Impairment of recipient cytolytic activity attenuates allograft vasculopathy

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

We investigated the role of CD4+ and CD8+ T subsets as well as T cell cytolytic effector mechanisms in the aortic allograft model of allograft vasculopathy using CD4 and CD8 gene knockout mice (CD4-/-, CD8-/-) and mice deficient in cytolytic effector pathways. Medial apoptosis at 2 weeks was reduced in CD8-/- mice and in mice where cytotoxic T cell activity was compromised. At 8 weeks, substantial medial damage was observed in wild-type (WT) and CD4-/- recipients but medial preservation was evident in CD8-/- mice and in mice with impaired cytotoxic T cell activity. The intima/media ratio, a comprehensive measure of allograft vasculopathy, was similar in WT and CD4-/- recipients but was significantly reduced in CD8-/- mice and mice with impaired cytotoxic T cell activity. These data indicate that CD8+ T cells contribute to the vascular remodeling that is characteristic of allograft vasculopathy. They also show that CD8+ T cells participate in allograft vasculopathy in the absence of CD4+ T cell help. We further demonstrated that WT mice exhibited robust allograft vasculopathy in the presence of cyclosporin A immunosuppression but that allograft vasculopathy was ablated in cyclosporin-treated CD8-/- mice. This supports the hypothesis that non-CD8+ T cell effector mechanisms are sensitive to calcineurin inhibitor therapy but that CD8+ T cell-mediated allograft vasculopathy is refractory to such treatment. Taken together, our data suggest that CD8+ T cells contribute to the induction of vascular remodeling in allograft vasculopathy and provide evidence that novel therapies which target CD8+ T cell effector function might be effective in mitigating AV in the clinical setting.

Original languageEnglish (US)
Pages (from-to)27-35
Number of pages9
JournalTransplant Immunology
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2005

Keywords

  • Allograft arteriosclerosis
  • Allograft vasculopathy
  • CD8 T cells
  • Chronic rejection
  • Cytotoxic T cells
  • Transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Transplantation

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