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Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

Gene Therapy volume 11, pages 701–710 (2004)Cite this article

Abstract

Elevated expression of heme oxygenase-1 (HO-1), an intracellular enzyme that degrades heme into carbon monoxide (CO), biliverdine and free iron, has anti-inflammatory and antiapoptotic effects in diverse models. Here, we analyzed the effects of specific overexpression of HO-1 following adenovirus-mediated (AdHO-1) gene transfer in an acute cardiac allograft rejection model. The intragraft (i.g.) injection of AdHO-1 into cardiac allografts, as well as intramuscular (i.m.) or intravenous (i.v.) administration, prolonged allograft survival with, respectively, 13.3, 62.5 and 80% of the grafts surviving long term (>100 days), whereas control grafts were rejected with acute kinetics. HO-1 overexpression was associated with inhibited allogeneic responses in MLRs using graft-infiltrating leukocytes and splenocytes, but not with lymph node cells. The inhibition of splenocyte proliferation was mediated by soluble factors and was dependent on the presence of APCs, since purified T cells proliferated normally. i.v. but not i.g. AdHO-1 administration decreased the number of graft-infiltrating leukocytes, cytokine mRNA accumulation and apoptosis in transplanted hearts, whereas i.v. and i.g. AdHO-1 did not modify normal immune responses against cognate antigens, indicating that there was no general immunosuppression. These results indicate that HO-1 overexpression prolongs the survival of vascularized allografts by promoting tolerogenic mechanisms acting on allogeneic cellular immune responses.

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Acknowledgements

This work was financed in part by the Fondation Transvie, the Fondation Treille and EC Grant HO-1 QLK3-CT-2001-00422. We are grateful to all the researchers who kindly contributed reagents, to the Vector Core of the University Hospital of Nantes, supported by the Association Française contre les Myopathies (AFM), for producing the adenoviral vectors used in this study, to Dr B LeMauf for helpful discussions and to Claire Usal and Emmanuel Merieau for heart transplantation.

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  1. C Braudeau and D Bouchet: Both authors contributed equally to this work

  2. I Anegon and C Chauveau: Both authors shared senior authorship

Authors and Affiliations

  1. Institut National de la Santé Et de la Recherche Médicale (INSERM) U437, Institut de Transplantation et de Recherche en Transplantation (ITERT), CHU de Nantes, Nantes, Cedex, France

    C Braudeau, D Bouchet, L Tesson, S Rémy, I Anegon & C Chauveau

  2. SangStat Medical Corporation, Fremont, California, USA

    S Iyer & R Buelow

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  1. C Braudeau
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  2. D Bouchet
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Braudeau, C., Bouchet, D., Tesson, L. et al. Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer. Gene Ther 11, 701–710 (2004). https://doi.org/10.1038/sj.gt.3302208

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