The schistosome glutathione S-transferase P28GST, a unique helminth protein, prevents intestinal inflammation in experimental colitis through a Th2-type response with mucosal eosinophils

Abstract

Intestinal helminth parasites are potent inducers of T helper type 2 (Th2) response and have a regulatory role, notably on intestinal inflammation. As infection with schistosomes is unlikely to provide a reliable treatment of inflammatory bowel diseases, we have investigated the beneficial effect of a schistosome enzymatic protein, the 28-kDa glutathione S-transferase (P28GST), on the modulation of disease activity and immune responses in experimental colitis. Our results showed that immunization with recombinant P28GST is at least as efficient as established schistosome infection to reduce colitis lesions and expression of pro-inflammatory cytokines. Considering underlying mechanisms, the decrease of inflammatory parameters was associated with the polarization of the immune system toward a Th2 profile, with local and systemic increases of interleukin (IL)-13 and IL-5. Dense eosinophil infiltration was observed in the colons of P28GST-immunized rats and mice. Depletion of eosinophils by treatment with an anti-Siglec-F monoclonal antibody and use of IL-5-deficient mice led to the loss of therapeutic effect, suggesting the crucial role for eosinophils in colitis prevention by P28GST. These findings reveal that immunization with P28GST, a unique recombinant schistosome enzyme, ameliorates intestinal inflammation through eosinophil-dependent modulation of harmful type 1 responses, representing a new immuno-regulatory strategy against inflammatory bowel diseases.

Safety of P28GST, a Protein Derived from a Schistosome Helminth Parasite, in Patients with Crohn’s Disease: A Pilot Study (ACROHNEM)

“…Calprotectin synthesis occurs in activated inflammatory cells, including neutrophils and macrophages. These cells were targeted by the anti-inflammatory properties of P28GST [5,8]. In contrast, the total serum CRP levels did not change in parallel with the CDAI values or SC levels, at either 3 or 12 months after treatment.…”

“…P28GST, an enzymatic protein derived from Schistosoma haematobium (Sh28GST), induced an IL-10 response mediated by Th2/T-regulatory cells (Tregs), in several animal species, including human [5,6]. P28GST was first developed as a vaccine against schistosomiasis.…”

“…The P28GST-driven reduction in colonic inflammation was associated with a reduction in the Th1/Th17 inflammatory response, and an increase in the immunoregulatory response involving Th2/Treg cells and M2 macrophages [5,8,9]. Specifically, P28GST combines the antigenic properties and regulatory enzymatic activities of the antioxidant GST with the anti-inflammatory properties of prostaglandin-D-synthase.…”

Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution

“…Alternative therapeutic strategies that exploit counter‐regulatory pathways, such as parasites used to skew mucosal immune responses and favour barrier protection, involve alternatively activated macrophages, eosinophils, Th2 cells and Tregs (Smith et al ., ; Hunter et al ., ; Gause et al ., ; Driss et al ., ). These cells play a key role in the resolution of intestinal inflammation, for example, by producing anti‐inflammatory lipid mediators that activate this process (Sherman and Kalman, ; Wang and Colgan, ).…”

“…Additionally, CCL2 enhances IL-4 secretion by T cells and elicits Th2 polarising effects, and miR-142 has an important role in DC priming of Th2 responses (Gu et al, 2000;Belz, 2013), both up-regulated in MNC-treated mice. Alternative therapeutic strategies that exploit counterregulatory pathways, such as parasites used to skew mucosal immune responses and favour barrier protection, involve alternatively activated macrophages, eosinophils, Th2 cells and Tregs (Smith et al, 2007;Hunter et al, 2010;Gause et al, 2013;Driss et al, 2016). These cells play a key role in the resolution of intestinal inflammation, for example, by producing anti-inflammatory lipid mediators that activate this process (Sherman and Kalman, 2004;Wang and Colgan, 2017).…”