A Novel Therapeutic Approach Targeting Articular Inflammation Using the Filarial Nematode-Derived Phosphorylcholine-Containing Glycoprotein ES-62

Abstract

Understanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence of pathology and this appears to reflect parasite-induced suppression of host proinflammatory immune responses. Consistent with this, we have previously described a filarial nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, with immunomodulatory activities that are broadly anti-inflammatory in nature. We sought to evaluate the therapeutic potential of ES-62 in vitro and in vivo in an autoimmune disease model, namely, collagen-induced arthritis in DBA/1 mice. ES-62 given during collagen priming significantly reduced initiation of inflammatory arthritis. Crucially, ES-62 was also found to suppress collagen-induced arthritis severity and progression when administration was delayed until after clinically evident disease onset. Ex vivo analyses revealed that in both cases, the effects were associated with inhibition of collagen-specific pro-inflammatory/Th1 cytokine (TNF-α, IL-6, and IFN-γ) release. In parallel in vitro human tissue studies, ES-62 was found to significantly suppress macrophage activation via cognate interaction with activated T cells. Finally, ES-62 suppressed LPS-induced rheumatoid arthritis synovial TNF-α and IL-6 production. Evolutionary pressure has promoted the generation by pathogens of diverse mechanisms enabling host immune system evasion and induction of “tolerance.” ES-62 represents one such mechanism. We now provide proof of concept that parasite-derived immunomodulatory strategies offer a novel therapeutic opportunity in inflammatory arthritis.

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells

“…The immunological studies conducted show for the first time that helminth-mediated protection against autoimmunity is associated with increases in numbers of natural T-regulatory cells and that helminth infections can induce a Th2 shift in autoantigen-specific antibody production. As has been shown with other helminths, [21][22][23] live infection is not required for protection against autoimmune disease as treatment with a crude homogenate of L. sigmodontis antigens also protected against diabetes.…”

“…Indeed, animal models of arthritis, 22 type I diabetes, [12][13][14]21,24 Graves hyperthyroidism, 25 experimental autoimmune encephalitis 15,26 and colitis [16][17][18] have all been inhibited or ameliorated by infections with helminth parasites or parasite-derived products. In this study, we found that infection with filarial helminths also protects against autoimmunity.…”

The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

“…However, in areas of the world where helminth infections are endemic, rates of autoimmune diseases such as RA remain low, leading to the hypothesis that certain helminth infections may protect against the development of autoimmunity (1). In support of this theory, we have previously shown that ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, has broad immunomodulatory activities and can exert powerful antiinflammatory action in the mouse collagen-induced arthritis (CIA) model of RA (2,3).…”

“…Originally, it was proposed that the ability of ES-62 to inhibit disease severity in the CIA model reflected the suppression of tumor necrosis factor ␣ (TNF␣) production and associated Th1-mediated inflammation (2,3). However, it has become increasingly clear that Th17, rather than Th1, cells appear to be the pathogenic drivers of inflammation in many autoimmune conditions, including CIA and RA (4).…”

Immuno-Modulatory Effect and Therapeutic Potential of Brugia malayi Cystatin in Experimentally Induced Arthritis

“…5 lm cross sections were cut and stained with haematoxylin and eosin. Sections were scored in the range of 0-3 for the parameters: synovial hyperplasia, cartilage and bone erosion and fibrosis [15].…”