Clinical Use of Schistosoma mansoni Antigens as Novel Immunotherapies for Autoimmune Disorders

Abstract

The hygiene hypothesis states that improved hygiene and the resulting disappearance of once endemic diseases is at the origin of the enormous increase in immune related disorders such as autoimmune diseases seen in the industrialized world. Helminths, such as Schistosoma mansoni, are thought to provide protection against the development of autoimmune diseases by regulating the host's immune response. This modulation primarily involves induction of regulatory immune responses, such as generation of tolerogenic dendritic cells and alternatively activated macrophages. This points toward the potential of employing helminths or their products/metabolites as therapeutics for autoimmune diseases that are characterized by an excessive inflammatory state, such as multiple sclerosis (MS), type I diabetes (T1D) and inflammatory bowel disease (IBD). In this review, we examine the known mechanisms of immune modulation by S. mansoni, explore preclinical and clinical studies that investigated the use of an array helminthic products in these diseases, and propose that helminthic therapy opens opportunities in the treatment of chronic inflammatory disorders.

Keywords: M2 macrophages; Schistosoma mansoni; autoimmune diseases; helminths; hygiene hypothesis; immune modulation; tolerogenic dendritic cells.

Figure 1

Immune responses induced by Schistosoma mansoni. Antigens present on the surface of or secreted by the parasitic worm or its eggs, regulate the host's immune response by modulating both the adaptive and the innate immune response. S. mansoni products downregulate Th1 and Th17 responses and reduce levels of the associated pro-inflammatory cytokines, while promoting Th2 and regulatory B- (Bregs) and T-cell (Tregs) responses. Furthermore, S. mansoni products also promote the differentiation of tolerogenic dendritic cells (DCs) and alternatively activated (M2) macrophages, which in turn induce Breg and Th2-mediated responses, while simultaneously inhibiting the proinflammatory response of Th1 and Th17 cells.

Figure 2

Life cycle of S. mansoni. (1) Eggs are excreted with the feces of an infected human host. (2) Under the right conditions in a freshwater environment, the eggs hatch and release the larvae (termed miracidia). (3) The miracidia infect the intermediate snail host, where they develop into sporocysts, asexually replicate, and mature into cercariae. (4) The cercariae are released back into the water. (5) Once the cercariae encounter a human host, they penetrate the skin. (6) After penetration, the cercariae transform into schistosomules and migrate to the hepatic portal vein. (7) The schistosomules mature into adult male and female worms and copulate. (8) The female worm migrates to the mesenteric venules of the bowels and begins egg deposition, that are secreted with the feces and reiterate the cycle.

Figure 3

Overview of the findings of S. mansoni/helminth therapy in pre-clinical and in clinical studies. All the in vivo studies were performed using S. mansoni antigens. For all studies, either cercariae, adult worms, eggs or secretions were used as a therapeutic agent. Preclinical studies in colitis models have found S. mansoni therapy to reduce the severity of the disease course, its mortality and modulate the immunological profile by shifting the immune response from a Th1 to a Th2/regulatory profile. Clinical trials using S. haematobium, T. suis, and Necator americanus found that helminth therapy effectively improves disease activity. Regarding T1D, preclinical studies in NOD mice showed that helminth therapy inhibits the development of diabetes through the induction of a Th2/regulatory profile and tolerogenic DCs. Clinical studies investigating helminth therapy in T1D have not been conducted and epidemiological data on this subject is conflicting. S. mansoni therapy has been shown to prevent onset and delay the severity of EAE in vivo, through a shift from a Th1 to a Th27regulatory profile. Similarly, clinical studies have observed that helminth therapy might be able to reduce relapse frequency and improve lesions via induction of a Th2/regulatory profile.