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Local gene therapy with indoleamine 2,3-dioxygenase protects against development of transplant vasculopathy in chronic kidney transplant dysfunction

Gene Therapy volume 23, pages 797–806 (2016)Cite this article

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An Erratum to this article was published on 03 November 2016

Abstract

Chronic transplant dysfunction (CTD) is the primary cause of late allograft loss in kidney transplantation. Indoleamine 2,3-dioxygenase (IDO) is involved in fetomaternal tolerance and IDO gene therapy inhibits acute rejection following kidney transplantation. The aim of this study is to investigate whether gene therapy with IDO is able to attenuate CTD. Transplantation was performed in a rat Dark-Agouti to Wistar-Furth CTD model. Donor kidneys were incubated either with an adenovirus carrying IDO gene, a control adenovirus or saline. During the first 10 days recipients received low-dose cyclosporine. Body weight, blood pressure, serum creatinine and proteinuria were measured every 2 weeks. Rats were killed after 12 weeks. IDO had a striking beneficial effect on transplant vasculopathy at week 12. It also significantly improved body weight gain; it reduced blood pressure and decreased proteinuria during the follow-up. However, it did not affect the kidney function. In addition, IDO therapy significantly decreased the number of graft-infiltrating macrophages at week 12. The messenger RNA levels of forkhead box p3 and transforming grow factor-β were elevated in the IDO treated group at week 12. Here we show for first time a clear beneficial effect of local IDO gene therapy especially on transplant vasculopathy in a rat model of renal CTD.

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Acknowledgements

This work was supported by a Dutch Kidney Foundation grant, the Netherlands and by a Science Grant Agency (VEGA 1/0667/14 and VEGA 1/0223/15), Slovak Republic.

Author contributions

Vavrincova-Yaghi wrote the paper, participated in research design, performance of the research and data analyses. Deelman participated in revising the paper, research design and data analyses. van Goor participated in revising the paper, research design and immunohistology/histology analyses. Seelen participated in revising the paper, research design and data analyses. Vavrinec participated in performance of the research and data analyses. Kema participated in sample analyses and revising the paper. Gomolcak participated in immunohistology analysis. Benigni participated in revising the paper. Henning participated in revising the paper, research design and data analyses. Sandovici participated in revising the paper, research design and data analyses.

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Authors and Affiliations

  1. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    D Vavrincova-Yaghi, L E Deelman, P Vavrinec, R H Henning & M Sandovici

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia

    D Vavrincova-Yaghi & P Vavrinec

  3. Graduate School for Drug Exploration - GUIDE, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    D Vavrincova-Yaghi

  4. Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    H van Goor

  5. Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    M A Seelen

  6. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    I P Kema

  7. Histopathology Laboratory, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia

    P Gomolcak

  8. Department of Molecular Medicine, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Ranica, Bergamo, Italy

    A Benigni

  9. Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    M Sandovici

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  1. D Vavrincova-Yaghi
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Correspondence to D Vavrincova-Yaghi.

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Vavrincova-Yaghi, D., Deelman, L., van Goor, H. et al. Local gene therapy with indoleamine 2,3-dioxygenase protects against development of transplant vasculopathy in chronic kidney transplant dysfunction. Gene Ther 23, 797–806 (2016). https://doi.org/10.1038/gt.2016.59

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