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

Pineda, Miguel A.; McGrath, Mairi; Smith, Pauline C.; Al-Riyami, Lamyaa; Rzepecka, Justyna; Gracie, J. Alastair; Harnett, William; Harnett, Margaret M.

doi:10.1002/art.34581

Cited by 94 publications

(166 citation statements)

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“…2B, right panel). The Th17 levels detected in the joints in our model are comparable with those reported by other investigators (27,31). These results indicate that a2 integrin is associated with CD4 T cells from CIA mice and that the CD4/a2 integrin cell population is enriched in the joint tissue.…”

Section: A2b1 Integrin Blockade Inhibits the Development Of Ciasupporting

confidence: 91%

α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

Azreq

Boisvert

Césaro

et al. 2013

The Journal of Immunology

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Th17 cells play a critical role in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms by which these cells regulate the development of RA are not fully understood. We have recently shown that α2β1 integrin, the receptor of type I collagen, is the major collagen-binding integrin expressed by human Th17 cells. In this study, we examined the role of α2β1 integrin in Th17-mediated destructive arthritis in the murine model of collagen-induced arthritis (CIA). We found that α2β1 integrin is expressed on synovial Th17 cells from CIA mice and its neutralization with a specific mAb significantly reduced inflammation and cartilage degradation, and protected the mice from bone erosion. Blockade of α2β1 integrin led to a decrease in the number of Th17 cells in the joints and to a reduction of IL-17 levels in CIA mice. This was associated with an inhibition of receptor activator of NF-κB ligand levels and osteoclast numbers, and reduction of bone loss. We further show that α2β1 integrin is expressed on synovial Th17 cells from RA patients, and that its ligation with collagen costimulated the production of IL-17 by polarized human Th17 cells by enhancing the expression of retinoic acid receptor–related orphan receptor C through ERK and PI3K/AKT. Our findings provide the first evidence, to our knowledge, that α2β1 integrin is an important pathway in Th17 cell activation in the pathogenesis of CIA, suggesting that its blockade can be beneficial for the treatment of RA and other Th17-associated autoimmune diseases.

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Section: A2b1 Integrin Blockade Inhibits the Development Of Ciasupporting

confidence: 91%

α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

Azreq

Boisvert

Césaro

et al. 2013

The Journal of Immunology

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“…[36][37][38][39] Excitingly, ES-62-treated mice undergoing CIA showed reduced levels of IL-17 compared to control animals. 24 In line with the observed correlation of elevated serum IL-17 levels with disease activity in RA patients, 39 ES-62 not only reduced the levels of IL-17 in serum derived from mice with CIA but also those in the draining lymph nodes and joints. Indeed, ES-62 was found to reduce IL-17 production by CD4 þ T cells and gd T cells, targeting both adaptive and innate arms of a complex cellular network controlled by dendritic cells (DCs).…”

Section: Es-62 Targets Il-17 Responses In the Mouse Model Of Ciasupporting

confidence: 72%

“…# LPS-mediated MAPK activation, including p38, Erk and JNK # CD80/CD86 in response to LPS # ability to prime Th17 differentiation and gd-T cell-dependent IL-17 production 14,15,24,28,29 Mast cells Inhibited degranulation and cytokine production.…”

Section: Es-62 Targets Il-17 Responses In the Mouse Model Of Ciamentioning

confidence: 99%

“…ES-62 indeed protects mice against experimental autoimmune arthritis in the CIA model of RA, 30 in which immune tolerance is broken by immunization with bovine collagen and complete Freund's adjuvant. The CIA model exhibits many of the immunological parameters of human RA, such as persistent inflammation of the synovial membrane, synovial fibroblast proliferation and pannus development, the latter of which invades joint tissue and releases pro-inflammatory factors (cytokines, chemokines), matrix TCR, TLR4 # anti-CD3-mediated proliferation in Jurkat T cells # PKC, PI-3K and RasErk signalling # MyD88 in Th17 differentiation [24][25][26][27] Antigen-presenting cells Downregulated cytokine production and co-stimulatory ability.…”

Section: Es-62 Targets Il-17 Responses In the Mouse Model Of Ciamentioning

confidence: 99%

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From the worm to the pill, the parasitic worm product ES-62 raises new horizons in the treatment of rheumatoid arthritis

Pineda

Eason

Harnett

et al. 2015

Lupus

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Evidence from human studies suggests that parasitic worm infection can protect humans against rheumatoid arthritis (RA) and this idea is strengthened by data generated in model systems. Although therapeutic use of parasitic worms is currently being explored, there are obvious benefits in pursuing drug development through identification and isolation of the 'active ingredients'. ES-62 is a secreted glycoprotein of the filarial nematode Acanthocheilonema viteae, which we have found to protect against the development of collagen-induced arthritis (CIA) in mice. ES-62 activity is dependent on the inflammatory phenotype of the local environment and protection arises via inhibition of Th17- and γδT cell-dependent IL-17 production. At the same time, NK and NK T cell IL-17 production is left intact, and such selectivity suggests that ES-62 might make a particularly attractive therapeutic for RA. However, as a potentially immunogenic protein, ES-62 is unsuitable for development as a drug. Nevertheless, ES-62 activity is dependent on covalently attached phosphorylcholine (PC) residues and we have therefore produced a library of PC-based drug-like ES-62 small-molecule analogues (SMAs) as an alternative therapeutic strategy. Screening this library, we have found an ES-62 SMA that mirrors ES-62 in protecting against CIA and by the same IL-17-dependent mechanism of action.

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“…Indeed, the presence of helminth infections has been associated (to a small degree) with modulation of the severity of inflammatory bowel disease, 5 diabetes, 6 and arthritis [7][8][9] to cite just a few examples. There is little consensus among the many studies that have examined the interaction between helminth infection and atopy (Table 1).…”

mentioning

confidence: 99%

Human Helminths and Allergic Disease: The Hygiene Hypothesis and Beyond

Santiago

Nutman

2016

The American Journal of Tropical Medicine and Hygiene

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Abstract. There is much debate about the interaction between helminths and allergic disease. The "Hygiene Hypothesis," a very popular concept among scientists and the lay public, states that infections, especially during childhood, can protect against allergic diseases. Indeed, helminth infections are known to induce regulatory responses in the host that can help the control of inflammation (including allergic inflammation). However, these infections also induce type-2-associated immune responses including helminth-specific IgE that can cross-react against environmental allergens and mediate IgE-driven effector responses. Thus, it is the delicate balance between the parasites' anti-and pro-allergenic effects that define the helminth/allergy interface.The immune system has evolved, in large part, through its interaction with microbes and parasites, an interaction that drives specific or specialized immune responses to deal with the widely varying groups of microorganisms. For example, parasite-derived induction of interleukin (IL)-4, IL-5, and IL-13 coordinate the prototypical responses to metazoan helminth pathogens, 1 whereas viral-and bacterial-specific induction of Type 1 and Type 2 interferons are required for control of these types of infections.

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

Cited by 94 publications

References 50 publications

α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

From the worm to the pill, the parasitic worm product ES-62 raises new horizons in the treatment of rheumatoid arthritis

Human Helminths and Allergic Disease: The Hygiene Hypothesis and Beyond

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