Establishment of an Intradermal Canine IL-31-Induced Pruritus Model to Evaluate Therapeutic Candidates in Atopic Dermatitis

Abstract

Pruritic models in healthy dogs utilizing intravenous administration of interleukin 31 (IL-31) bypass the “natural” itch sensation in AD, which is initiated by pruriceptive primary afferent neurons in the skin. This study aimed to evaluate the immediate/delayed pruritus responses and the pruritic behaviors observed in an intradermal IL-31-induced pruritic model of healthy dogs and the anti-pruritic effect of oclacitinib on said model. In Phase 1, all the dogs were randomized and video-recorded for 300 min after intradermal canine recombinant IL-31 injections (1.75 µg/kg) and vehicle (phosphate-buffered saline) injections. In Phase 2, all the dogs received oral oclacitinib (0.4–0.6 mg/kg, twice daily for 4 consecutive days and once daily on day 5), with the intradermal IL-31 injection performed on day 5. Two blinded investigators reviewed the pruritic behaviors in all the video recordings. Intradermal IL-31 administration to healthy dogs caused a significant increase in the total (p = 0.0052) and local (p = 0.0003) seconds of pruritic behavior compared to the vehicle control. Oral oclacitinib administration significantly reduced the total (p = 0.0011) and local (p = 0.0156) intradermal IL-31-induced pruritic seconds; there was no significant difference in pruritic seconds between the vehicle and oclacitinib within the IL-31 groups. Significant delayed pruritic responses at 150–300 min after IL-31 injections were observed, and intradermal IL-31 failed to induce acute itch (first 30 min). Intradermal injection of IL-31 induces delayed itch responses in dogs that are diminished by the effect of oclacitinib, an oral JAK inhibitor.

Characterization of the Pro-Inflammatory and Pruritogenic Transcriptome in Skin Lesions of the Experimental Canine Atopic Acute IgE-Mediated Late Phase Reactions Model and Correlation to Acute Skin Lesions of Human Atopic Dermatitis

“…Interleukin 13, along with receptors IL4R and IL13Rα1, was the dominant Th2 cytokine in the anti-canine IgE skin lesions in this study, whereas IL-4 was not affected by the IgE-mediated activation. Interleukin 31 is another Th2 cytokine with a dominant pruritogenic effect across different species, such as humans, primates, mice, and dogs [ 28 , 29 ]. Increased IL-31 serum levels have been observed in some AD dogs; a subset of dogs with AD had no detectable levels of IL31 in circulation [ 30 ].…”

Studies Using Antibodies against Filaggrin and Filaggrin 2 in Canine Normal and Atopic Skin Biopsies

“…When puppies belonging to this colony were adopted out young, they were reported to spontaneously develop AD as private pets, even if they had never been sensitized when they were research dogs. Thus, these dogs were different from other models published in the literature, which typically utilize normal dogs to create a model of acute inflammation [41][42][43][44][45][46] or pruritus [47,48].…”

Establishment of an experimental model of ovalbumin-induced atopic dermatitis in canines

“…Environmental factors, such as exposure to allergens, play a significant role in triggering this condition (2). AD treatment in both humans and dogs involves utilizing medication that can suppress the T-helper 2 (Th2) cell response (3)(4)(5)(6) and maintain longterm disease control (7)(8)(9)(10).…”