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A Transgenic Probiotic Secreting a Parasite Immunomodulator for Site-Directed Treatment of Gut Inflammation

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A Transgenic Probiotic Secreting a Parasite Immunomodulator for Site-Directed Treatment of Gut Inflammation © The American Society of Gene & Cell Therapy original article original article Transgenic Probiotic Inhibits Gut Inflammation © The American Society of Gene & Cell Therapy A Transgenic Probiotic Secreting a Parasite Immunomodulator for Site-Directed Treatment of Gut Inflammation Rose A Whelan1, Sebastian Rausch1, Friederike Ebner1, Dorothee Günzel2, Jan F Richter2,3, Nina A Hering4, Jörg-Dieter Schulzke4, Anja A Kühl5, Ahmed Keles2, Pawel Janczyk6, Karsten Nöckler6, Lothar H Wieler7 and Susanne Hartmann1 1Center for Infection Medicine, Institute of Immunology, Freie Universität Berlin, Berlin, Germany; 2Institute of Clinical Physiology, Charité- University Medicine Berlin, Berlin, Germany; 3Current address: Institute for Anatomy II, Friedrich-Schiller-University, Jena, Germany; 4Department of Gastroenterology, Division of Nutritional Medicine, Charité-University Medicine Berlin, Berlin, Germany; 5Department of Internal Medicine, Rheumatology and Clinical Immunology/Research Center ImmunoSciences (RCIS), Charité-University Medicine Berlin, Berlin, Germany; 6Unit for Molecular Diagnostics, Genetics and Pathogen Characterisation, Department of Biological Safety Federal Institute for Risk Assessment, Berlin, Germany; 7Institute for Microbiology and Animal Health, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany New treatment strategies for inflammatory bowel disease INTRODUCTION are needed and parasitic nematode infections or appli- Parasitic worms modulate host immune responses in order to cation of helminth components improve clinical and induce an anti-inflammatory environment that favors their per- experimental gut inflammation. We genetically modified sistence and reproduction for many years in immunocompetent the probiotic bacterium Escherichia coli Nissle 1917 to hosts. Parasite-driven immunoregulation has been exploited secrete the powerful nematode immunomodulator cys- to ameliorate inflammatory disorders in mice1 and humans.2 In tatin in the gut. This treatment was tested in a murine particular, immunoregulatory excretory/secretory components colitis model and on post-weaning intestinal inflamma- of parasitic nematodes offer potential biologics for future treat- tion in pigs, an outbred model with a gastrointestinal ment of inflammatory disorders.3 Protease inhibitors from the system similar to humans. Application of the transgenic cystatin family are important in host immunomodulation by probiotic significantly decreased intestinal inflammation parasitic worms, in particular shown for nematodes.4 In previous in murine acute colitis, associated with increased fre- studies, we demonstrated that cystatin from the rodent nematode quencies of Foxp3+ Tregs, suppressed local interleukin Acanthocheilonema viteae (AvCys) has strong anti-inflammatory (IL)-6 and IL-17A production, decreased macrophage properties when in contact with immune cells.5,6 Intraperitoneal inflammatory protein-1α/β, monocyte chemoattrac- application of the recombinant protein in murine disease models, tant protein -1/3, and regulated upon activation, nor- namely dextran sodium sulfate-induced colitis and ovalbumin- mal T-cell expressed, and secreted expression and fewer or birch pollen-induced allergic airway hyperreactivity led to a 6,7 inflammatory macrophages in the colon. High dosages significant reduction of inflammatory processes and pathology. of the transgenic probiotic were well tolerated by post- Macrophages are the main target of nematode cystatin and the 16April2014 weaning piglets. Despite being recognized by T cells, ameliorating effect in airway hyperreactivity could be reversed by 6 secreted cystatin did not lead to changes in cytokine macrophage depletion. Immunoregulation by nematode cystatin 25June2014 expression or macrophage activation in the colon. How- was associated with induction of interleukin (IL)-10 via exploi- ever, colon transepithelial resistance and barrier function tation of the host cell mitogen-activated protein kinase (MAPK) 6,8 10.1038/mt.2014.125 were significantly improved in pigs receiving the trans- pathway. Together these results provide evidence for the poten- genic probiotic and post-weaning colon inflammation tial of AvCys as a candidate to ameliorate inflammatory bowel Molecular Therapy was reduced. Thus, the anti-inflammatory efficiency of disease (IBD). a probiotic can be improved by a nematode-derived IBD is an auto-inflammatory disorder characterized by phases of unregulated intestinal inflammation separated by intermittent 22 immunoregulatory transgene. This treatment regimen phases of asymptomatic remission. The induction and propaga- should be further investigated as a potential therapeutic tion of IBD is multifactorial, involving both genetic and environ- 10 option for inflammatory bowel disease. mental risk factors. Over 163 gene loci and numerous lifestyle Received 16 April 2014; accepted 25 June 2014; advance online and environmental factors such as diet, smoking, and gastrointes- 1730 publication 5 August 2014. doi:10.1038/mt.2014.125 tinal microbial composition have been associated with the onset 1740 The first two authors contributed equally to this work. Correspondence: Susanne Hartmann, Center for Infection Medicine, Institute of Immunology, Robert-von-Ostertag-Str. 7–13, 14163, Freie Universität 00oct2014 Berlin, Germany. E-mail: [email protected] 5August2014 1730 www.moleculartherapy.org vol. 22 no. 10, 1730–1740 oct. 2014 © The American Society of Gene & Cell Therapy Transgenic Probiotic Inhibits Gut Inflammation 9 of IBD. To date no therapy is able to efficiently treat all patients a kb b afflicted with the condition. As a result, most IBD patients are kDa unable to maintain lifelong remission and therefore endure recur- rent symptomatic relapse. In the current study, we aimed to develop a treatment strat- 0.5 AvCys egy focusing on a site-directed and prolonged release of the 23 nematode immunomodulator, AvCys, in the gut. We chose 1234 17 Escherichia coli Nissle 1917 (EcN) as a carrier. This probiotic c 10 kDa is successfully used to maintain remission in IBD patients. In clinical trials involving patients with both active and inac- 12 3 tive colitis, EcN was comparable to the standard non-steroidal anti-inflammatory treatment in reducing disease activity indi- 25 ces and maintaining remission phases.11 In experimental murine 17 colitis models, EcN led to a marked decrease in gut inflamma- 12 tion and reduced expression of pro-inflammatory cytokines. 1234 EcN has been shown to suppress the adhesion and invasion of pathogenic bacteria,13,14 support intestinal barrier function,15 Figure 1 Generation of transgenic EcN expressing AvCys. (a) Polymerase chain reaction with AvCys specific primers amplified the and prevent epithelial damage induced by dextran sodium sul- AvCys gene in EcN-AvCys (2) and positive control (4), but not in EcN 16 fate. EcN has also been reported to reduce T cell expression (1) or the negative water control (3). (b) Western blot analyses using an of pro-inflammatory cytokines and up-regulate the expression AvCys-specific antibody on supernatants of EcN (1) and EcN-AvCys (2) of anti-inflammatory IL-10.17 Additionally, EcN colonizes the grown in Luria broth medium and recombinant AvCys as positive control (3). (c) Western blot of 1 ml of an Iscove’s modified Dulbecco medium human intestine, while lacking virulence factors, making it a (IMDM) control (1), supernatant from EcN-AvCys grown in IMDM (2), 18 safe and effective probiotic for use in colitis patients. Hence, supernatant from EcN grown in IMDM (3), and 7 lanes loaded with we chose EcN as an ideal carrier organism for the site-directed recombinant AvCys as a standard ranging from 200–5 ng (4). delivery of AvCys to the gut and tested whether we can enhance the probiotics’ anti-inflammatory activity by a nematode immu- (18 ± 6 ng/ml) were determined by ELISA in multiple batches of nomodulatory component. EcN-AvCysSN (data not shown). In this study, we describe for the first time a transgenic pro- In a preceding study we found that recombinantly expressed biotic generated to express a parasite-derived immunoregulatory AvCys applied intraperitoneally reduced colon inflammation in protein (PCT 12183268.7). Applying the transgenic EcN secreting acute dextran sodium sulfate (DSS) colitis.6 Thus, we aimed to test A. viteae cystatin (EcN-AvCys) in vivo we show the following: (i) for anti-colitic effects of site directed prolonged delivery of AcCys the secretion of AvCys by the transgenic probiotic enhanced EcN- in the gut via application of the generated transgenic EcN-AvCys. mediated amelioration of gut inflammation in a murine model of EcN-AvCys and EcN were fed to mice receiving 3% DSS in drink- colitis, (ii) the transgene was safe when applied in high doses to ing water to induce acute inflammation of the colon. Preliminary pigs as an outbred model organism providing an intestinal tract results suggested that EcN did not naturally colonize the gastro- highly similar to the human gut, and (iii) the transgene signifi- intestinal tract of mice (data not shown); therefore, 2 × 109 trans- cantly ameliorated post-weaning gut inflammation in pigs and genic or control bacteria were applied by oral gavage in 100 µl of increased intestinal epithelial barrier function. saline every 2nd day, while control mice received 100 µl of saline alone (Figure 2a). While body weight development in response RESULTS to treatment was relatively heterogenous (not shown), treatment Transgenic EcN secretes
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