Lessons from helminth infections: ES-62 highlights new interventional approaches in rheumatoid arthritis

Abstract

Parasitic worms are able to survive in their mammalian host for many years due to their ability to manipulate the immune response by secreting immunomodulatory products. It is increasingly clear that, reflecting the anti-inflammatory actions of such worm-derived immunomodulators, there is an inverse correlation between helminth infection and autoimmune diseases in the developing world. As the decrease in helminth infections due to increased sanitation has correlated with an alarming increase in prevalence of such disorders in industrialized countries, this ‘hygiene hypothesis’ has led to the proposal that worms and their secreted products offer a novel platform for the development of safe and effective strategies for the treatment of autoimmune disorders. In this study we review the anti-inflammatory effects of one such immunomodulator, ES-62 on innate and adaptive immune responses and the mechanisms it exploits to afford protection in the murine collagen-induced arthritis (CIA) model of rheumatoid arthritis (RA). As its core mechanism involves targeting of interleukin (IL)-17 responses, which despite being pathogenic in RA are important for combating infection, we discuss how its selective targeting of IL-17 production by T helper type 17 (Th17) and γδ T cells, while leaving that of CD49b+ natural killer (NK and NK T) cells intact, reflects the ability of helminths to modulate the immune system without immunocompromising the host. Exploiting helminth immunomodulatory mechanisms therefore offers the potential for safer therapies than current biologicals, such as ‘IL-17 blockers’, that are not able to discriminate sources of IL-17 and hence present adverse effects that limit their therapeutic potential.

Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis)

“…Also, EmTIP evoked a strong release of IFN-␥ by CD4+ T-cells, hence suggesting that the secretion of this factor could "secondarily" induce a potentially protective Th1 response. Prospectively, secretory products of worms as those described above offer a novel platform for the development of safe and effective strategies for the treatment of autoimmune and/or inflammatory disorders (Pineda et al, 2014).…”

Larval Echinococcus multilocularis infection reduces dextran sulphate sodium‐induced colitis in mice by attenuating T helper type 1/type 17‐mediated immune reactions

“…The ‘hygiene hypothesis’ proposes that the stimulation of the immune system by microbes or microbial products protects from the development of inflammatory diseases. Reflecting the anti‐inflammatory actions of parasite‐derived immunomodulators, an inverse correlation exists between helminthic infections and the occurrence of autoimmune diseases, best documented in the industrially developed world . Furthermore, it has become evident that many helminthic infections are associated with reduced allergic reactivities, and most respective studies demonstrated an increased Treg cell activity in infected murine or human hosts …”

“…Reflecting the anti-inflammatory actions of parasitederived immunomodulators, an inverse correlation exists between helminthic infections and the occurrence of autoimmune diseases, best documented in the industrially developed world. 12 Furthermore, it has become evident that many helminthic infections are associated with reduced allergic reactivities, and most respective studies demonstrated an increased Treg cell activity in infected murine or human hosts. 13 Crohn's disease and ulcerative colitis are the main and distinct clinical and pathophysiological entities of inflammatory bowel diseases (IBD).…”

Parasitic Infection and Immunomodulation: A Possible Explanation for the Hygiene Hypothesis in Autoimmune and Allergic Disease

“…28 Aside from administering the parasitic agents themselves as therapy for allergic or inflammatory diseases, a proposed alternative modality is the administration of therapeutic agents which are based upon secreted parasitic glycoproteins such as ES-62. 29,30 However, the therapeutic applicability of such products is limited by large molecular size of these a p o l l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 9 7 e2 0 0 proteins and their potential immunogenicity, which may be overcome through the development of small molecule analogues which are currently under evaluation and show promise in mouse models. 30 …”