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Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes

Nature Medicine volume 4, pages 1392–1396 (1998)Cite this article

Abstract

We investigated the pathogenesis of chronic allograft rejection in mouse cardiac allografts. Long-term survival occurred after administration of monoclonal antibody to CD4 or CD40-ligand (CD40L) plus donor cells. Both treatments induced permanent graft survival, but, in contrast to transplants in mice treated with CD4 monoclonal antibody, grafts in mice treated with CD40L monoclonal antibody lacked evidence of chronic rejection, including transplant arteriosclerosis. Freedom from chronic rejection in the group treated with CD40L monoclonal antibody correlated with vascular expression of the 'protective' genes heme oxygenase-1 (HO-1), Bcl-xL and A20. Moreover, arteriosclerosis was induced in allografts in immunoglobulin-deficient mice by antibody transfer only when the transfer was done before expression of protective genes. A direct role for protective gene expression in endothelial cells was demonstrated by in vitro experiments in which induction of HO-1 or Bcl-xL suppressed alloantibody-stimulated endothelial activation. Finally, induction of HO-1 in vivo protected allografts against chronic injury. These data show a role for protective genes in the prevention of chronic rejection, and indicate new approaches to protect grafts against development of transplant arteriosclerosis.

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Figure 1: Cardiac allografts collected on day 100 from mice receiving CD4 monoclonal antibody (CD4 mAb) or CD40L monoclonal antibody/donor-specific transfusion (CD40L/DST).
Figure 2: Immunoglobulin-deficient mice as cardiac allograft recipients (day 100).
Figure 3: In vitro studies of protective gene induction in mouse endothelial cells.
Figure 4: In vivo studies of the effects of CoPP treatment on the long-term development of transplant arteriosclerosis in allograft recipients treated with CD4 monoclonal antibody.

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Acknowledgements

Supported by NIH grants AI40152 (W.W.H.) and AI37691 (L.A.T.).

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Authors and Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02215, Massachusetts, USA

    Wayne W. Hancock

  2. LeukoSite, Cambridge, 02142, Massachusetts, USA

    Wayne W. Hancock

  3. SangStat Medical Corporation, Menlo Park, 94205, California, USA

    Roland Buelow

  4. Department of Immunogenetics and transplantation, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Mohamed H. Sayegh

  5. Department of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Laurence A. Turka

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  1. Wayne W. Hancock
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  4. Laurence A. Turka
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Correspondence to Wayne W. Hancock.

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Hancock, W., Buelow, R., Sayegh, M. et al. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes. Nat Med 4, 1392–1396 (1998). https://doi.org/10.1038/3982

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