Cynomolgus monkey model of interleukin‐31‐induced scratching depicts blockade of human interleukin‐31 receptor A by a humanized monoclonal antibody
Sohei OyamaHidetomo KitamuraTaichi KuramochiYoshinobu HiguchiHiroaki MatsushitaTsukasa SuzukiMasaaki GotoHideki AdachiKeiko KasutaniAkihisa SakamotoYuki IwayanagiAkihisa KanekoMasahiko NanamiEtsuko FujiiKeiko EsakiYoshiaki TakashimaShin ShimaokaKunihiro HattoriYoshiki Kawabe
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Abstract:
Abstract Scratching is an important factor exacerbating skin lesions through the so‐called itch‐scratch cycle in atopic dermatitis ( AD ). In mice, interleukin ( IL )‐31 and its receptor IL ‐31 receptor A ( IL ‐31 RA ) 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 ‐31 RA 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 ‐31 RA 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 ‐31 RA antibody is a promising therapeutic approach for treatment of AD . Nemolizumab is currently under investigation in clinical trials.Keywords:
Scratching
Subcutaneous injection
Pathogenesis
Summary Forms of head‐scratching are described and classified. Indirect‐scratching differs from the direct chiefly in that it involves the positive movements of lowering one wing and bringing the foot up over it. Both methods of scratching exist on two main levels: basic‐scratching is a reflex‐like response to irritation, etc., on the bill or head, while extended‐scratching functions as part of the feather‐maintenance system. Indirect‐scratching has been recorded as an apparent displacement‐activity in some species. Possible evolutionary trends in head‐scratching are discussed. The two methods may have evolved independently from a more primitive method or successively one from the other. If the two methods evolved successively, then it is argued, contrary to the classical view of Heinroth, that indirect‐scratching evolved later than direct‐scratching, probably after, or concurrently with, the development of the extended function of scratching. Support is provided for this view by the distribution of indirect‐scratching in the bird‐kingdom and by the occasional use, by species in which indirect‐scratching is the rule, of a scratching method with some characters of the direct. The latter may be explained as either a reversion to the primitive method and/or the use of incomplete or wrongly co‐ordinated indirect movements. Variation in scratching within the avian family may be similarly explained and/or is due to incorrect taxonomy (e.g. in Parulidae and Timaliidae). As the method of scratching, generally speaking, is uniform in related birds up to at least the family level (in truly monophyletic groups), head‐scratching method is a potentially useful taxonomic character. The scratching movements of a number of species are described and discussed, including the peculiar scratching of penguins, and a number of new records are given in the Appendix.
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Interleukin-31 (IL-31), a novel cytokine, is upregulated in atopic dermatitis skin lesions in humans and skin lesions in the NC/Nga mice, a murine model for atopic dermatitis.Here, we investigated the effect of a monoclonal IL-31 antibody on scratching behaviour, weight gain and dermatitis in NC/Nga mice.Mice were divided into three groups, n = 10 in each group. Mice were given monoclonal IL-31 rat-anti-mouse antibody 10 mg/kg or albumin intraperitoneally every fifth day for seven weeks. In addition, the mice in one group were not exposed to any form of intervention. The dermatitis score was clinically assessed twice a week. The scratching behaviour was automatically detected and objectively evaluated.Intervention with IL-31 antibody 10 mg/kg intraperitoneally every fifth day in NC/Nga mice from age 7 weeks reduced the scratching behaviour, but did not have any impact on weight gain or dermatitis.IL-31 antibody reduces scratching behaviour in an atopic dermatitis-like murine model during the onset of clinical skin manifestations. Our findings suggest IL-31 antibody as a new potential therapeutic approach for pruritus in atopic dermatitis and other pruritic diseases.
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Intradermal injection
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5-HT2 receptor
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Itch can be suppressed by scratching. At the same time, scratching evokes a pleasurable sensation. In the present study, we investigated the peripheral mechanism of scratching-induced pleasurability and its association with itch relief using compression nerve block. We found that myelinated nerve fibers (Aβ-fibers and possibly Aδ-fibers), are involved in transmission of scratching-induced pleasurability. We observed that itch relief effect was the same regardless of whether the pleasurable sensation was evoked by scratching an itch, indicating that pleasure is not a necessary component to induce itch relief. This is the first study to investigate the peripheral mechanism of scratching-induced pleasurability and itch relief.
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To elucidate the actual state of scratching behavior of NC mice noted when PiCl-induced dermatitis occurs, the circadian rhythm in scratching behavior of this mouse model was examined, and the time when scratching behavior, which is useful to evaluate the severity of itch, occurs was assessed. A steroid drug (Prednisolone ointment), which has been confirmed to inhibit dermatitis from worsening, was used to examine whether or not, or how it inhibits scratching behavior in this mouse model. It became clear that scratching behavior increased during a period from the evening to the night in the animals which had not been sensitized (normal animals); compared with the day time, scratching behavior occurred more often in the nighttime. It also became clear that scratching behavior increased in the animals with PiCl-induced dermatitis increase in the frequency of induction of dermatitis, and Prednisolone ointment significantly inhibited scratching behavior in the animals in which dermatitis had been induced with PiCl six times. From these results, it can be said that scratching behavior increases in PiCl-induced mouse atopic dermatitis models correlatively with the increase in the frequency of induction of dermatitis, and steroid drugs decrease the frequency of the scratching behavior. In conclusion, it is strongly suggested that this mouse model is useful for development of therapeutic methods and novel medicinal drugs for atopic dermatitis.
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We investigated the role of serotonin (5-hydroxytryptamine; 5-HT)2 and 5-HT3 receptor subtypes in acute itch-associated scratching behavior as well as in an allergic pruritus model in rats. Intradermal 5-HT evoked hind limb scratching directed toward the injection site in naïve rats. Scratching behavior was significantly reduced by pretreatment with the 5-HT2 receptor antagonist ketanserin. Intradermal injection of α-methylserotonin, a 5-HT2 receptor agonist, also elicited scratching behavior in a dose-dependent manner, indicating that acute 5-HT-induced scratching is mediated via peripheral 5-HT2 receptors. To produce a model of allergic pruritus, skin was sensitized by topical application of 5% dinitrofluorobenzene (DNFB). One month later, repeated challenge of the skin with 0.2% DNFB at weekly intervals elicited scratching as part of the immediate allergic response. Scratching was not affected by ketanserin or by the 5-HT3 receptor antagonist ondansetron, indicating that neither 5-HT2 nor 5-HT3 receptors is involved in itch-associated scratching behavior caused by allergic skin dermatitis in rats.
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We evaluated and characterized the mouse scratching behavior using a new apparatus, MicroAct. Scratching behavior was evoked in ICR and BALB/c mice by compound 48/80, passive cutaneous anaphylaxis or repeated hapten application. Under the present experimental condition, MicroAct detected consecutive scratching behavior (events) consisting of 3 or more beats. Although the detecting standard of MicroAct was not identical to that of an observer, the number of events detected by MicroAct and by an observer were almost comparable with each other. Frequency of events, total scratching time and total number of beats detected by MicroAct increased depending on the intensity of the causing stimuli for scratching. In contrast, the duration of each event and the number of beats in each event increased only slightly, but the scratching speed was almost constant. The present results demonstrate that MicroAct is a useful tool for evaluating mouse scratching behavior. Mouse scratching behavior seems to have a relatively fixed pattern and the causing stimulus increases mainly in the frequency of event without affecting the scratching speed.
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Measurements of oxygen consumption (VO2) were made during sleep in 10 patients with atopic dermatitis. Two groups of healthy children acted as controls. All subjects were studied in bed in an environmental temperature of 24-26 degrees C, and sleep was confirmed during continuous electroencephalographic monitoring. Mean (SD) values of VO2 in sleeping patients who were not scratching ranged from 4.0 (0.4) to 7.4 (0.7), which was not statistically significantly different from control values which ranged from 3.24 (0.3) to 5.56 (0.4). During scratching (while asleep), which occurred in nine out of 10 patients with atopic dermatitis, the mean values of VO2 ranged from 4.5 (0.04) to 10.4 (2.7), and this was significantly higher than the non-scratching patients and the control values. Scratching during sleep in children with atopic dermatitis is associated with increased VO2.
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Antipruritic
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