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Trichuris Suis Secrete Products That Reduce Disease Severity in a Multiple Sclerosis Model

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Trichuris Suis Secrete Products That Reduce Disease Severity in a Multiple Sclerosis Model DOI: 10.1515/ap-2017-0002 © W. Stefański Institute of Parasitology, PAS Acta Parasitologica, 2017, 62(1), 22–28; ISSN 1230-2821 Trichuris suis secrete products that reduce disease severity in a multiple sclerosis model Christine Søholm Hansen1†, Henrik Hasseldam1*†, Idahella Hyldgaard Bacher2, Stig Milan Thamsborg2, Flemming Fryd Johansen1 and Helene Kringel2 1University of Copenhagen, Biotech Research and Innovation Center, Ole Maaloes vej 5, 2200-N Copenhagen, Denmark; 2University of Copenhagen, Faculty of Health, Parasitology and Aquatic Diseases, Dyrlægevej 100, Frederiksberg 1870-C, Denmark Abstract Multiple sclerosis is a chronic inflammatory central nervous system (CNS) disease, which affects about 1 in 1000 individuals in the western world. It has been suggested that this relatively high prevalence is linked to a high level of hygiene, i.e. a reduced exposure to various microorganisms, including parasites. Parasites are known to employ different immunomodulatory and anti- inflammatory strategies, which enable them to evade destruction by the immune system. We have investigated the im- munomodulation by the swine whipworm, Trichuris suis, by measuring the impact of oral administration of T. suis ova as well as of intraperitoneal administration of T. suis excretory/secretory products on the development and progression of experimen- tal autoimmune encephalomyelitis – an animal model that shares clinical and pathological characteristics with multiple scle- rosis. Intraperitoneal administration of excretory/secretory products before disease onset, resulted in a significant decrease in disease severity as well as markedly reduced TH1 and TH17 T-cell responses, centrally in the spinal cord as well as in the pe- riphery, i.e. the spleen. Thus, parenteral administration of T. suis-derived products results in a skewing of the immune response with a significant impact on disease severity in a CNS inflammatory disease model. Keywords Trichuris suis, multiple sclerosis, immunomodulation, t-cells Introduction were found to have fewer disease exacerbations and reduced disease symptoms before parasite elimination (La Flamme Co-evolution of parasites and their hosts has been driven by et al. 2003; Correale and Farez 2011). the parasites’ aim to survive and reproduce, and the host’s aim Parasitic worms, or products thereof, have been tested as to eliminate the invaders. Thus, parasites have developed treatments in experimentally induced models of autoimmune mechanisms that suppress the host’s immune reaction. The ab- diseases. In an animal model of MS - experimental autoim- sence of parasite exposure and thus disease pressure in some mune encephalomyelitis (EAE) – disease severity was reduced areas of the world has been correlated to a rise in atopic and if treatment was initiated before or around the time of disease autoimmune diseases, and has led to the formulation of the induction (La Flamme et al. 2003; Gruden-Movsesijan et al. "hygiene hypothesis". This hypothesis suggests that a lack of 2008; Walsh et al. 2009; Gruden-Movsesijan et al. 2010; Wu certain early pathogenic stimuli is causative of the develop- et al. 2010), whereas treatment in the effector phase of the dis- ment of atopic or autoimmune diseases, later in life (Strachan ease, where T-cells are primed and migrate to the CNS, had no 1989; Milo and Kahana 2010; Rook 2012). Fleming and Cook impact on disease severity (Sewell et al. 2003; Zheng et al. (2006) have reported a reverse relationship between the global 2008). presence of the human whipworm, Trichuris trichiura, and the Both MS and EAE have demyelinating and neurodegener- prevalence of Multiple Sclerosis (MS) (Fleming and Cook ative pathologies, which are intimately associated with inflam- 2006). Similarly, patients suffering from MS that had become matory cells (T-cells, macrophages, B-cells etc.) in the central naturally infected with parasitic worms, such as T. trichiura, nervous system (CNS) (Compston and Coles 2002). Disease *Corresponding author: [email protected] †The authors contributed equally as the first author Brought to you by | University of Sussex Library Authenticated Download Date | 1/20/17 5:48 AM T. suis inhibits experimental multiple sclerosis 23 exacerbation of MS has been linked to TH17 cells infiltrating Materials and Methods the CNS (Kebir et al. 2009), and although no specific cytokine of the TH17 lineage has been found to be key for development EAE induction and scoring of MS, both IL-17 and IL-22 can make the Blood-Brain Barrier (BBB) leaky and facilitate lymphocyte extravasation into the Female Dark Agouti (DA) (Harlan, The Netherlands or the CNS (Kebir et al. 2007). Parasitic stimulation has been shown U.S., for the ova and E/S study, respectively) rats, age to suppress the autoimmune pro-inflammatory T-cell expansion, 5 weeks, were acclimatized for 5 wk in individually ventilated which is believed to be central in the pathology of EAE (Cua cages (IVC), with free access to food and water. et al. 2003). As such, treatment studies in EAE have shown this EAE was induced by subcutaneous injection of 100 µl to be associated with clinical disease amelioration, where both emulsification consisting of spinal cord homogenate (SCH) in the pro-inflammatory TH1 and TH17 cells were down-regulated, PBS (1:2; v/w) and Complete Freund’s Adjuvant (CFA) (1:1; while the tolerogenic TReg and the humoral TH2 cells were found v/v), at the tail root. All studies were conducted with random- to be up-regulated (Hasseldam et al. 2013). ized treatment and control groups, and in accordance with the Most parasites have immunomodulatory properties and guidelines of the Danish Animal Experiments Committee many parasitic infections are chronic and potentially harmful, (#2012-DY-2934-00001). Animals were scored on a daily basis in their natural host. Trichuris suis, the porcine whipworm, is for clinical disease symptoms (paresis), by an observer who did- an intestinal helminth of pigs with a direct life cycle (Beer n’t knew whether the rats were given PBS or T. suis, according 1973). By using this parasite in non-natural and non-permis- to the EAE clinical scoring system (0: no clinical symptoms; sive hosts, one can avoid chronic infections, while potentially 1: tail paralysis; 2: mild paralysis in 1 or 2 hind limbs; 3: mod- maintaining the beneficial immunomodulatory effects. Crude erate hind limb paralysis in 1 or 2 limbs; 4: severe paralysis in adult worm homogenate of T. suis, has been shown to sup- 1 or 2 hind limbs; 5: paralysis in 1 or 3 hind limbs and paraly- press EAE development and clinical disease in a murine host, sis starting in 4 limbs, 6: moribund or dead) devised by the Dan- if administered before disease induction (Kuijk et al. 2012). In ish Animal Experiments Inspectorate. When the scores reached patients suffering from inflammatory bowel disease (IBD) - 2, animals were provided with food and water-gel at the bottom another T-cell associated autoimmune disease - multiple ad- of the cage. If the score reached 4 or more, or if weight loss was ministrations of infective T. suis ova showed therapeutic ef- above 20% of initial live weight, the animal was euthanized. fects (Summers et al. 2005; Summers et al. 2005). Recently, The animal that did not develop disease was excluded from the this treatment regimen was copied in a study with 5 MS pa- experiment. All clinical scores of all the remaining rats are in- tients in whom 3 months of treatment with T. suis ova, de- cluded in the data analysis (Fig. 1; Table I). creased the number of new demyelinating lesions in the CNS The experimental timeframe lasted from the day of disease (Fleming et al. 2011). A similar small-scale trial primarily de- debut (clinical score >0), and until the approximate day of the signed to document safety, including 10 MS patients without first relapse peak (a unidirectional rise in scores over a few days), appropriate controls, found this treatment regimen to be safe, which was reached approximately 10-12 days after disease but ineffective (Voldsgaard et al. 2015). debut. If no relapse occurred, rats were euthanized at the esti- We have conducted a series of experiments with the aim of mated day of the relapse peak. The EAE model is highly sensi- investigating whether T. suis ova and adult T. suis E/S prod- tive to many environmental and genetic factors, and we did find ucts, administrated repeatedly and starting immediately after some variation in disease onset and severity between the studies. EAE disease induction, have the potential to dampen EAE dis- ease severity. E/S products are molecules that are shed or ex- Embryonated T. suis ova creted/secreted (E/S) from the ova, larvae or adult worms, and partially constitute the immune interacting potential of the par- Fresh T. suis ova were isolated from feces of pigs and embry- asite (Lightowlers and Rickard 1988). onated in vermiculite (90 days at 22 C) and stored in H2SO4 Table I. Clinical disease manifestations in PBS, T. suis ova and T. suis E/S groups Days before disease onset Cumulative score index Score at relapse peak Group Incidence (mean ± SD) (mean ± SD) (mean ± SD) Control 8/8 8.23 ± 0.89 1.48 ± 0.95 3.25 ± 0.76 T. suis ova 8/8 7.63 ± 0.74 1.63 ± 1.88 3.45 ± 0.50 Control 10/10 10.10 ± 1.85 1.31 ± 0.78 3.45 ± 1.12 T. suis E/S 9/10 10.78 ± 1.72 0.94** ± 0.81 2.89 ± 1.36 Clinical disease manifestations in (define) PBS, T. suis ova and T. suis define E/S groups. Treatment was initiated at day of immunization (0-dpi), and all animals, but one, developed disease. The cumulative score index is the mean score of the experimental timeframe, while the relapse peak is the mean score at the day of the relapse peak day (or estimated day if no relapse occurred).
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