Interleukin (<scp>IL</scp>) 31 induces in cynomolgus monkeys a rapid and intense itch response that can be inhibited by an <scp>IL</scp>‐31 neutralizing antibody

Lewis, Katherine E.; Holdren, Matthew S.; Maurer, Mark; Underwood, Steve; Meengs, Brent; Julien, Susan; Byrnes-Blake, Kelly; Freeman, Jeremy A.; Bukowski, Tom; Wolf, Anitra C.; Hamacher, Nels; Rixon, Mark W.; Dillon, Stacey R.

doi:10.1111/jdv.13794

Cited by 36 publications

(40 citation statements)

References 32 publications

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“…19,24 While the eIL-5-CuMV TT vaccine targets the allergy-associated hyper-eosinophilia and thereby reduces the number of toxic cells potentially causing tissue damage of the skin, the eIL-31-CuMV TT vaccine rather targets the allergic itching caused by the underlying allergic immune response in the skin. Comparably to the mAb against IL-31, we suggest that the vaccine-induced anti-IL-31 antibodies mitigate the IL-31-mediated pruritus 40,41 and thus lowering the self-inflicted trauma caused by the horse scratching its skin. When comparing the clinical benefit of blocking IL-31 in horses with other species, we noticed a reduction of skin lesion severity in IBH-affected horses, which is in contrast to atopic dermatitis trials in dogs and humans that only showed reduction of pruritus whereas no improvement of eczema.…”

Section: Discussionmentioning

confidence: 88%

Interleukin 31 in insect bite hypersensitivity—Alleviating clinical symptoms by active vaccination against itch

Olomski

Fettelschoss

Jónsdóttir

et al. 2020

Allergy

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Background Insect bite hypersensitivity (IBH) is the most common seasonal pruritic allergic dermatitis of horses occurring upon insect bites. In recent years, a major role for IL‐31 in allergic pruritus of humans, monkeys, dogs, and mice was acknowledged. Here, we investigate the role of IL‐31 in IBH of horses and developed a therapeutic vaccine against equine IL‐31 (eIL‐31). Methods IL‐31 levels were quantified in allergen‐stimulated peripheral blood mononuclear cells (PBMCs) and skin punch biopsies of IBH lesions and healthy skin from IBH‐affected and healthy horses. The vaccine consisted of eIL‐31 covalently coupled to a virus‐like particle (VLP) derived from cucumber mosaic virus containing a tetanus toxoid universal T‐cell epitope (CuMVTT). Eighteen IBH‐affected horses were recruited and immunized with 300 μg of eIL‐31‐CuMVTT vaccine or placebo and IBH severity score was recorded. Results IL‐31 was increased in PBMCs and exclusively detectable in skin lesions of IBH‐affected horses. Vaccination against eIL‐31 reduced delta clinical scores when compared to previous untreated IBH season of the same horses and to placebo‐treated horses in the same year. The vaccine was well tolerated without safety concerns throughout the study. Conclusion TH2‐derived IL‐31 is involved in IBH pathology and accordingly the immunotherapeutic vaccination approach targeting IL‐31 alleviated clinical scores in affected horses.

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Section: Discussionmentioning

confidence: 88%

Interleukin 31 in insect bite hypersensitivity—Alleviating clinical symptoms by active vaccination against itch

Olomski

Fettelschoss

Jónsdóttir

et al. 2020

Allergy

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“…Although further studies clarifying the mechanism of IL-31 axis in the itch sensation will be needed, blockade of IL-31 signalling can be considered clinically valuable for AD treatment. The recent study by, Lewis et al[22] on the inhibitory effect of antibody against IL-31 in a cynomolgus monkey scratching model also supports the importance of IL-31 axis.Our newly established monkey model of scratching clarified the systemic actions of IL-31 by distinguishing the pruritus effects from the dermatitis effects and also confirmed that a single subcutaneous injection of nemolizumab provides inhibitory action for up to 2 months. This long-lasting effect depends on nemolizumab's long half-life, which is mainly due to the low systemic expression of IL-31RA, but has also been achieved by optimizing the antibody structure to prolong the antipruritic activity.…”

mentioning

confidence: 70%

“…Species is a clear reason for the difference between the two sets of results, but another major difference between the two studies is the method of administration; that is, the distribution of IL-31 would be limited to IL-31. Interestingly, Lewis et al [22] recently reported that cyIL-31 administration elicited an immediate scratching response not only by intravenous and subcutaneous but also by intradermal injection. The late itch response may also be closely related to a cellular mechanism of IL-31 action, which we discuss below.…”

Section: Discussionmentioning

confidence: 99%

Cynomolgus monkey model of interleukin‐31‐induced scratching depicts blockade of human interleukin‐31 receptor A by a humanized monoclonal antibody

Oyama¹,

Kitamura²,

Kuramochi³

et al. 2017

Experimental Dermatology

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Scratching is an important factor exacerbating skin lesions through the so-called itchscratch cycle in atopic dermatitis (AD). In mice, interleukin (IL)-31 and its receptor IL-31 receptor A (IL-31RA) are known to play a critical role in pruritus and the pathogenesis of AD; however, study of their precise roles in primates is hindered by the low sequence homologies between primates and mice and the lack of direct evidence of itch sensation by IL-31 in primates. We showed that administration of cynomolgus IL-31 induces transient scratching behaviour in cynomolgus monkeys and by that were able to establish a monkey model of scratching. We then showed that a single subcutaneous injection of 1 mg/kg nemolizumab, a humanized anti-human IL-31RA monoclonal antibody that also neutralizes cynomolgus IL-31 signalling and shows a good pharmacokinetic profile in cynomolgus monkeys, suppressed the IL-31-induced scratching for about 2 months. These results suggest that the IL-31 axis and IL-31RA axis play as critical a role in the induction of scratching in primates as in mice and that the blockade of IL-31 signalling by an anti-human IL-31RA antibody is a promising therapeutic approach for treatment of AD. Nemolizumab is currently under investigation in clinical trials. K E Y W O R D Santi-IL-31RA antibody, atopic dermatitis, itch-scratch cycle, nemolizumab, pruritus

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“…Serum levels of IL‐31, a member of the IL‐6 cytokine family, have been shown to be higher in patients with CSU than in healthy controls, but lower than patients with atopic dermatitis . IL‐31 promotes Th2 inflammation but has also been reported to induce itch by its interaction with specific IL‐31 receptors on sensory nerves . Although primarily secreted by Th2 lymphocytes, IL‐31 has also been reported to be released from human mast cells .…”

Section: Effects Of the Mast Cell On The Local Environmentmentioning

confidence: 99%

“…195 IL-31 promotes Th2 inflammation 196 but has also been reported to induce itch by its interaction with specific IL-31 receptors on sensory nerves. 197,198 Although primarily secreted by Th2 lymphocytes, 196 IL-31 has also been reported to be released from human mast cells. 199 For this reason we have recently investigated the potential role of this cytokine in causing itch in CSU.…”

Section: Cytokinesmentioning

confidence: 99%

The role and relevance of mast cells in urticaria

Church

Kolkhir

Metz

et al. 2018

Immunological Reviews

215

198

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This review presents evidence that the skin mast cell, in particular the MC subtype, is the primary effector cell in urticaria. Mast cells are located in the upper dermis, the ideal situation for wheal formation and sensory nerve stimulation. Increased numbers of mast cells are found in both lesional and non-lesional skin in CSU and inducible urticaria. Mast cell degranulation in the area of wheals has been demonstrated repeatedly by light and electron microscopy. Histamine, PGD and tryptase are found in the venous blood draining wheal formation. The last 2 are specific for mast cells rather than basophils. Mast cell reactivity is increased in active urticaria by local inflammatory cytokines and neuropeptides. Mast cell cytokines and neuropeptides, particularly nerve growth factor, induce a Th2 type inflammation that is particularly obvious at the sites of whealing. In conclusion, autoimmunity, either of Type 1 viz. IgE antibodies to local autoallergens, or Type 2b, viz. IgG autoantibodies to IgE or its receptor, are considered to be the most frequent causes of CSU. In both cases, the mast cell is likely to be the axial cell in producing the wheals.

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Interleukin (IL) 31 induces in cynomolgus monkeys a rapid and intense itch response that can be inhibited by an IL‐31 neutralizing antibody

Abstract: These results demonstrate that an IL-31 mAb can inhibit IL-31-mediated pruritus in vivo, and could be an effective therapy for pruritic skin conditions like AD where IL-31 upregulation may play a role.

Cited by 36 publications

References 32 publications

Interleukin 31 in insect bite hypersensitivity—Alleviating clinical symptoms by active vaccination against itch

Interleukin 31 in insect bite hypersensitivity—Alleviating clinical symptoms by active vaccination against itch

Cynomolgus monkey model of interleukin‐31‐induced scratching depicts blockade of human interleukin‐31 receptor A by a humanized monoclonal antibody

The role and relevance of mast cells in urticaria

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