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Local Gene Therapy with Indoleamine 2,3-Dioxygenase Protects Against Development of Transplant Vasculopathy in Chronic Kidney Transplant Dysfunction

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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 (2016) 23, 797–806 © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0969-7128/16 www.nature.com/gt ORIGINAL ARTICLE Local gene therapy with indoleamine 2,3-dioxygenase protects against development of transplant vasculopathy in chronic kidney transplant dysfunction D Vavrincova-Yaghi1,2,3, LE Deelman1, H van Goor4, MA Seelen5, P Vavrinec1,2, IP Kema6, P Gomolcak7, A Benigni8, RH Henning1 and M Sandovici1,9 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. Gene Therapy (2016) 23, 797–806; doi:10.1038/gt.2016.59 INTRODUCTION renal transplantation and the search for new targets of interven- Although the rate of acute graft loss has substantially been tion in CTD is still ongoing. reduced during the last decades due to novel (and combination Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme of) immunosuppressive medication together with better organ in the metabolism of tryptophan, whereby the essential amino preservation techniques, long-term graft survival has not acid L-tryptophan is converted into its catabolites, the 11 improved considerably.1,2 Consequently, the main cause of long- kynurenines. It is currently well known that IDO has a 12 term graft loss is the chronic transplant dysfunction (CTD).2 profound immunoregulatory activity, being involved not only 13 CTD is characterized by a progressive loss of renal function, in fetomaternal tolerance, but also in pathological processes proteinuria and de novo or worsening of pre-existing hyperten- such as tumor resistance, chronic infections and autoimmune – sion, coinciding with chronic histopathological lesions of trans- diseases.14 16 In organ transplantation, several studies have plant vasculopathy (TV) with neointima formation, interstitial confirmed the potential of IDO gene therapy in preventing acute fibrosis, tubular atrophy and glomerulosclerosis.3–5 The develop- rejection of skin,17 lungs,18 heart19 and pancreatic islets.20 More ment of CTD is a multifactorial process including both immune recently, it was found that inducible expression of IDO attenuates and nonimmune factors.6,7 Several approaches have been acute rejection of tissue-engineered lung allografts in rats.21 In employed to reduce the occurrence of CTD, including the use of addition, inhibitory effect of locally delivered CTLA4Ig was shown living donors, shortening of cold-ischemia time, the use of to be dependent on IDO activity within the allograft.22 We have machine-perfused instead of cold-stored renal grafts, reduction previously demonstrated protective effects of adenoviral gene of the incidence of acute rejection episodes and optimization of therapy with IDO against acute rejection following kidney chronic immunosuppressive medication.8–10 Despite these efforts, transplantation in rats.23 The evidence about the role of IDO there is still no prevention strategy as well as no effective and/or its therapeutic effect in CTD is however limited. In lungs, treatment available for CTD. Therefore, the improvement of long- sleeping beauty-based gene therapy with IDO inhibited allograft term graft survival remains the major challenge in the field of fibrosis.24 We have recently shown that early posttransplant 1Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 2Faculty of Pharmacy, Department of Pharmacology and Toxicology, Comenius University in Bratislava, Bratislava, Slovakia; 3Graduate School for Drug Exploration - GUIDE, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 4Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 5Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 6Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 7Histopathology Laboratory, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia; 8Department of Molecular Medicine, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Ranica, Bergamo, Italy and 9Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Correspondence: Dr D Vavrincova-Yaghi, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32 Bratislava, Slovakia. E-mail: [email protected] Received 16 March 2016; revised 5 July 2016; accepted 18 July 2016; accepted article preview online 25 July 2016; advance online publication, 4 August 2016 IDO gene therapy of chronic transplant dysfunction D Vavrincova-Yaghi et al 798 tryptophan metabolism predicts long-term outcome of human clinical parameters such as body weight and blood pressure kidney transplantation.25 during the follow-up. Here we employ adenovirus-delivered IDO gene therapy of the renal transplant to study the therapeutic potency of IDO in a rat Urinary protein excretion, plasma creatinine and creatinine model of renal CTD. clearance Proteinuria, a hallmark of progressive renal injury, increased in the RESULTS saline and RGD-AdTL treated groups from, respectively, week 6 and 8 onwards. RGD-AdTIDO treatment significantly attenuated Successful gene delivery and plasma and urinary kyn/trp levels the increase of urinary protein excretion observed in the saline To demonstrate gene delivery in the kidney, four isotransplanta- group (Figure 2c). Plasma levels of creatinine and creatinine tions were performed in Dark Agouti (DA) rats transduced with clearance at the end of the study (12 weeks) were significant, fl arginine-glycine-aspartate (RGD)-AdTL expressing green uores- although mildly altered as compared with the baseline in all three cent protein (GFP). Ten days after transplantation, clear GFP groups. The values of plasma and urine creatinine, and the fi expression was documented mainly in broblast-like interstitial creatinine clearance at the end of the study are summarized in cells in the transduced kidney (Figure 1a), confirming our previous Table 1. RGD-AdTIDO group showed a trend toward increased 23,26 findings. However, no GFP expression was found anymore at levels of urinary creatinine and increased creatinine clearance at 12 weeks in the DA graft in both RGD-AdTL and RGD-AdTIDO the end of the follow-up, compared with the RGD-AdTL and saline group (Figure 1b). Moreover, no human IDO messenger RNA treatment, however, without reaching statistical significance. Thus, (mRNA) could be detected by real-time PCR in the DA grafts of the treatment with RGD-AdTIDO significantly decreased proteinuria in IDO group at 12 weeks. This is in line with our previous findings of time, without significantly affecting kidney function. transgene expression being limited to several weeks with this adenoviral vector. Development of TV, FGS, interstitial pre-fibrosis, interstitial Neither the serum levels of kynurenines and tryptophan, nor macrophage influx and C4d expression those of kyn/trp ratio were significantly different between groups at the end of the study (Table 1). Urinary kyn/trp ratio was slightly CTD in the rat is characterized morphologically by TV, mild glomerular basement membrane thickening and sclerosis, inter- higher in the IDO group at week 4, however, without reaching 2 fi stitial fibrosis and tubular atrophy. TV contributes to the graft statistical signi cance (data not shown). In conclusion, we found 27 GFP expression 10 days after transplantation, however neither GFP loss. The proportion of TV-affected vessels was dramatically staining nor human IDO mRNA was found at 12 weeks, suggesting lower in the IDO treated allografts compared with both RGD-AdTL transient expression of both GFP and IDO. and saline treated group (Figure 3a). When all TV-positive renal vessels were pooled per group, the intraluminal narrowing in the IDO treated allografts was significantly lower compared with both Clinical parameters RGD-AdTL and saline treated group (Figure 3b). IDO treatment had The treatment with RGD-AdTIDO significantly improved body thus a striking beneficial effect on the overall
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