title: Local gene therapy with indoleamine 2,3-dioxygenase protects against development of transplant vasculopathy in chronic kidney transplant dysfunction.
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.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Faculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University in Bratislava, Bratislava, Slovakia.|Graduate School for Drug Exploration - GUIDE, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Vavrincova-Yaghi
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: L E
authors.initials: LE
authors.lastname: Deelman
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Goor
authors.affiliation: Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Seelen
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Faculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University in Bratislava, Bratislava, Slovakia.
authors.forename: P
authors.initials: P
authors.lastname: Vavrinec
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: I P
authors.initials: IP
authors.lastname: Kema
authors.affiliation: Histopathology Laboratory, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia.
authors.forename: P
authors.initials: P
authors.lastname: Gomolcak
authors.affiliation: Department of Molecular Medicine, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Ranica, Bergamo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Benigni
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: Henning
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Sandovici
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D051799:Delayed Graft Function / Q000628:therapy*; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine