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

Arthritis Rheum. 2012 Oct;64(10):3168-78. doi: 10.1002/art.34581.

Abstract

Objective: Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62.

Methods: DBA/1 mice progressively display arthritis following immunization with type II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cell populations, and in situ analysis of joint inflammation in mice with CIA.

Results: ES-62 was found to down-regulate IL-17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL-17 responses by targeting a complex IL-17-producing network, involving signaling between dendritic cells and γ/δ or CD4+ T cells. In addition, ES-62 directly targeted Th17 cells by down-regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL-1 and Toll-like receptor ligands. Moreover, ES-62 modulated the migration of γ/δ T cells and this was reflected by direct suppression of CD44 up-regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17-producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas.

Conclusion: Our findings indicate that ES-62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL-17 inflammatory network. ES-62 could be exploited in the development of novel therapeutics for RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / metabolism*
  • Arthritis, Experimental / pathology
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • Dendritic Cells / drug effects*
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Helminth Proteins / pharmacology*
  • Interleukin-17 / metabolism*
  • Joints / drug effects
  • Joints / metabolism
  • Joints / pathology
  • Male
  • Mice
  • Up-Regulation

Substances

  • ES-62 protein, Acanthocheilonema viteae
  • Helminth Proteins
  • Interleukin-17