ILC2s: Unraveling the innate immune orchestrators in allergic inflammation.

The prevalence rate of allergic diseases including asthma, atopic rhinitis (AR) and atopic dermatitis (AD) has been significantly increasing in recent decades due to environmental changes and social developments. With the study of innate lymphoid cells, the crucial role played by type 2 innate lymphoid cells (ILC2s) have been progressively unveiled in allergic diseases. ILC2s, which are a subset of innate lymphocytes initiate allergic responses. They respond swiftly during the onset of allergic reactions and produce type 2 cytokines, working in conjunction with T helper type 2 (Th2) cells to induce and sustain type 2 immune responses. The role of ILC2s represents an intriguing frontier in immunology; however, the intricate immune mechanisms of ILC2s in allergic responses remain relatively poorly understood. To gain a comphrehensive understanding of the research progress of ILC2, we summarize recent advances in ILC2s biology in pathologic allergic inflammation to inspire novel approaches for managing allergic diseases.

A placebo-controlled, double-blind study evaluating the effect of orally administered polyunsaturated fatty acids on the oclacitinib dose for atopic dogs.

BACKGROUND: Supplementation of polyunsaturated fatty acids (PUFA) enables dose reduction of prednisolone and ciclosporin in canine atopic dermatitis (cAD). OBJECTIVE: To determine if oral administration of PUFA reduces the dose of oclacitinib in cAD. ANIMALS: Twenty-two client-owned dogs with cAD receiving oclacitinib. MATERIALS AND METHODS: Dogs received a fish oil product (PUFA) or paraffin oil (placebo) for 16 weeks. Owners adjusted the oclacitinib dose according to daily pruritus assessments. On Day (D)0, D56 and D112, Canine Atopic Dermatitis Extent and Severity Index, fourth iteration (CADESI-04), pruritus Visual Analog Scale (PVAS), quality-of-life score (QoL), Global Assessment (GA), quality-of-coat (QoC) and adverse events were recorded. RESULTS: Mean daily oclacitinib dose was significantly reduced in the PUFA group from 0.51 ± 0.20 mg/kg/24 h (D0) to 0.19 ± 0.14 mg/kg/24 h (D85-112; p < 0.00001) and not in the placebo group (D0: 0.70 ± 0.33 mg/kg/24 h; D85-112: 0.53 ± 0.35 mg/kg/24 h, p = 0.5422). CADESI-04 did not change over time or differ between groups. PVAS was significantly lower in the PUFA group (2.8 ± 1.5) compared to placebo (4.2 ± 1.6) at D112 (p = 0.0375). QoL and QoC improved only in the PUFA group (QoL: D0: 20 ± 7, D112: 12 ± 5, p = 0.0057; QoC: D0: 0 ± 0.5, D112: 1 ± 0.5, p = 0.0410). GA on D112 was higher in the PUFA group (p = 0.008). No adverse events were observed. CONCLUSION: Oral supplementation of PUFA allowed dose reduction of oclacitinib and improved PVAS, QoL, QoC and GA. The use of PUFA is recommended and was safe in the atopic study dogs receiving oclacitinib.

A randomised, double-blinded trial to assess the effect of oclacitinib and prednisolone on intradermal allergen and prick tests in dogs with atopic dermatitis.

BACKGROUND: Intradermal (IDT) and prick (PT) tests are used to select allergens for allergen-specific immunotherapy in dogs with atopic dermatitis (cAD). However, the use of antipruritic drugs before performing these tests may influence the results. OBJECTIVE: To evaluate the influence of the drugs oclacitinib and prednisolone on the immediate-phase reactions of IDT and PT. ANIMALS: Thirty client-owned dogs with cAD with positive reactions to at least one allergen extract on IDT or PT. MATERIALS AND METHODS: Dogs were randomly assigned to receive oclacitinib 0.4-0.58 mg/kg per os, every 12 h (n = 14), or prednisolone 0.37-0.65 mg/kg p.o., every 12 h (n = 16) for 14 days. IDT and PT were performed on Day (D)0 before treatment and on D14. RESULTS: At D14 there was no significant reduction in the means of the orthogonal diameters of the positive immediate-phase reactions of the IDT (p = 0.064) in the oclacitinib group; however, in the PT, the diameter of the positive reactions reduced significantly (p = 0.048). In both tests, there was no significant reduction in the total number of positive reactions (IDT, p > 0.999; PT, p = 0.735). In the prednisolone group, the means of the orthogonal diameters of positive immediate-phase reactions were significantly reduced in both tests (IDT, p = 0.001; PT, p ≤ 0.001) and there also was a reduction in the total number of positive reactions (IDT, p = 0.022; PT, p = 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: The use of oclacitinib 0.4-0.58 mg/kg twice daily for 14 days does not interfere with IDT results in dogs with cAD. However, oclacitinib may reduce PT reactivity. The use of prednisolone 0.37-0.65 mg/kg twice daily results in a reduction in both IDT and PT results.

Assessment of owner perceptions of caregiver burden, veterinarian-client relationship and satisfaction with the provider in canine pruritus: An experimental vignette study.

BACKGROUND: Complicated treatments for skin disease are linked to owner-caregiver burden and poorer perception of the veterinarian-client relationship, regardless of disease severity. HYPOTHESES/OBJECTIVES: Using experimental vignettes, we explored the impact on owner perception of the interaction of treatment complexity and skin disease outcomes. We hypothesised that: (i) vignette conditions involving injection therapy would result in lower burden, better veterinary-client relationship and greater satisfaction relative to multimodal therapy conditions; (ii) the vignette condition of injection therapy with a completely effective outcome would be superior to all other conditions; (iii) ineffective vignette conditions would be inferior to all other conditions; and (iv) the vignette condition injection with a mostly effective outcome would be similar or superior to the multimodal therapy with a completely effective outcome condition. PARTICIPANTS: Three hundred and nine owners of pruritic dogs recruited from a general veterinary practice, pet-related podcast, or social media dog allergy group. MATERIALS AND METHODS: Participants were presented with six counterbalanced online vignettes representing three levels of treatment effectiveness (Completely Effective, Mostly Effective, Ineffective) and two treatment regimens (Multimodal, Injection). Measurements of participant perceptions of caregiver burden, veterinarian-client relationship and satisfaction were recorded. RESULTS: Injection with perfect outcome was superior to other conditions (p < 0.001). Conditions with poor effectiveness were inferior (p < 0.001). Comparison of Injection with a mostly effective outcome to Multimodal treatment with perfect outcome yielded small-to-medium effects of preference for the latter in veterinarian-client relationship and satisfaction (p < 0.01); no difference was observed for caregiver burden. When good effectiveness was assured, injection was preferred (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Owners preferred a Completely Effective outcome and were prepared to select the Injection regimen or Multimodal therapy to achieve this; Injection was preferred when effectiveness was assured.

Analysis of Intestinal Microbiota and Metabolic Pathways before and after a 2-Month-Long Hydrolyzed Fish and Rice Starch Hypoallergenic Diet Trial in Pruritic Dogs.

Intestinal microbiota alterations were described in allergic individuals and may improve with diets. Farmina Ultra Hypo (FUH), a hydrolyzed fish/rice starch hypoallergenic diet, is able to improve clinical signs in allergic dogs. Study objectives were to determine microbiota differences in allergic dogs before and after feeding with FUH for eight weeks. Forty skin allergic dogs were evaluated clinically before and after the diet. Unresponsive dogs were classified as canine atopic dermatitis (CAD); responsive dogs relapsing after challenge with previous foods were classified as being food reactive (AFR), and those not relapsing as doubtful (D). Sequencing of feces collected pre- and post-diet was performed, with comparisons between and within groups, pre- and post-diet, and correlations to possible altered metabolic pathways were sought. Microbiota in all dogs was dominated by Bacteroidota, Fusobacteriota, Firmicutes and Proteobacteria, albeit with large interindividual variations and with some prevalence changes after the diet. In general, bacteria producing short-chain fatty acids were increased in all samples. CAD dogs showed pre-and post-diet microbiota patterns different from the other two groups. Bacteria taxa were enriched post-diet only in the AFR group. Changes in metabolic pathways were observed mainly in the CAD group. FUH may be able to improve intestinal microbiota and thus clinical signs of skin allergy.

Translational Selenium Nanoparticles to Attenuate Allergic Dermatitis through Nrf2-Keap1-Driven Activation of Selenoproteins.

Easy recurrence and strong treatment side effects significantly limit the clinical treatment of allergic dermatitis. The human trace element selenium (Se) plays essential roles in redox regulation through incorporation into selenoproteins in the form of 21st necessary amino acid selenocysteine, to participates in the pathogenesis and intervention of chronic inflammatory diseases. Therefore, based on the safe and elemental properties of Se, we construct a facile-synthesis strategy for antiallergic selenium nanoparticles (LET-SeNPs), and scale up the production by employing a spray drying method with lactose (Lac-LET-SeNPs) or maltodextrin (Mal-LET-SeNPs) as encapsulation agents realizing larger scale production and a longer storage time. As expected, these as-prepared LET-SeNPs could effectively activate the Nrf2-Keap1 signaling pathway to enhance the expression of antioxidative selenoprotein at mRNA and protein levels, then inhibit mast cell activation to achieve efficient antiallergic activity. Interestingly, LET-SeNPs undergo metabolism to seleno-amino acids to promote biosynthesis of selenoproteins, which could suppress ROS-induced cyclooxygenase-2 (COX-2) and MAPKs activation to suppress the release of histamine and inflammatory cytokines. Allergic mouse and Macaca fascicularis models further confirm that LET-SeNPs could increase the Se content and selenoprotein expression in the skin, decrease mast cells activation and inflammatory cells infiltration, and finally exhibit the high therapeutic effects on allergic dermatitis. Taken together, this study not only constructs facile large-scale synthesis of translational Se nanomedicine to break through the bottleneck problem of nanomaterials but also sheds light on its application in the intervention and treatment of allergies.

Skin Reactions Following Primary Total Knee Arthroplasty With an Adhesive Superficial Closure System: A Case Series.

BACKGROUND: We investigated a skin adhesive closure device consisting of a self-adhesive polyester mesh placed over the surgical incision, followed by a liquid adhesive that is spread over the mesh and surrounding the skin. It is intended to reduce wound closure times, scarring, and skin complications associated with traditional closure with sutures or staples. The aim of this study was to report on skin reactions in patients who underwent primary total knee arthroplasty (TKA) using the skin adhesive closure system. METHODS: A retrospective review of patients who underwent TKA using adhesive closure between 2016 to 2021 at a single institute was performed. A total of 1,719 cases were analyzed. Patient demographics were collected. The primary outcome was any postoperative skin reaction. Skin reactions were classified as allergic dermatitis, cellulitis, or other. Treatment(s), duration of symptoms, and surgical infections were also collected. RESULTS: A total of 5.0% (86) of patients were found to have any type of skin reaction following their TKA. Of these 86, 39 (2.3%) had symptoms of allergic dermatitis (AD), 23 (1.3%) had symptoms of cellulitis, and 24 (1.4%) had other symptoms. A total of 27 (69%) allergic dermatitis patients were treated with a topical corticosteroid cream only; their symptoms resolved within an average of 25 days. There was only 1 case of superficial infection (<0.001%). No prosthetic joint infections were observed. CONCLUSION: Despite skin reactions appearing in 5.0% of cases, the rate of infection was low. A patient-specific preoperative workup and effective treatment strategies can minimize complications associated with adhesive closure system and increase patient satisfaction following TKA.

rMBP-NAP Suppresses OXA-induced Allergic Dermatitis by Regulating the Th1/Th2 Balance.

Background: Allergic dermatitis (AD) is an inflammatory skin disease that arises from abnormal T lymphocyte activation. A recombinant fusion protein comprising Helicobacter pylori neutrophil-activating protein and maltose binding protein, rMBP-NAP, has been documented as a novel immunomodulatory TLR agonist. Objective: To explore the effect of the rMBP-NAP on the OXA-induced AD in a mouse model and clarify the possible action mechanism. Methods: The AD animal model was induced by repeated administration of oxazolone (OXA) in BALB/c mice. H&E staining was used to analyze the ear epidermis thickness and the number of infiltrating inflammatory cells. TB staining was used to detect mast cell infiltration in the ear tissue. ELISA was used to analyze the secretion of cytokines IL-4 and IFN-γ in peripheral blood. qRT-PCR was used to determine the expression levels of IL-4, IFN-γ, and IL-13 in ear tissue. Results: OXA induced the establishment of an AD model. After the rMBP-NAP treatment, the thickness of the ear tissue and the number of mast cells infiltrated in AD mice reduced, and the serum and ear tissue levels of IL-4 and IFN-γ increased, but the ratio of IFN-γ (rMBP-NAP group)/IL-4 (rMBP-NAP group) was greater than the ratio of IFN-γ (sensitized group)/IL-4 (sensitized group). Conclusion: The rMBP-NAP improved the disease symptoms including skin lesions in AD, alleviated the inflammation in ear tissue, and restored the Th1/2 balance by inducing a shift from the Th2 to the Th1 response. The results of our work support the use of rMBP-NAP as an immunomodulator for AD treatment in future investigations.

Adverse Skin Reactions to Personal Protective Equipment Among Healthcare Workers in Oman During the Coronavirus Disease 2019 Pandemic.

Background During the coronavirus disease 2019 (COVID-19) pandemic, healthcare workers (HCWs) were required to use personal protective equipment (PPE) for unusually prolonged periods of time in order to protect themselves. This study was conducted to assess the prevalence of adverse skin reactions to PPE among HCWs from occupational and domestic exposure in Oman. Methods This was a cross-sectional study that used a self-administered questionnaire, modified based on the Nordic Occupational Skin Questionnaire, and was conducted in different categories of healthcare facilities in Oman from September to December 2020. This study involved 431 different categories of HCWs. Stata statistical software, version 12 (StataCorp, College Station, TX), was used to analyze the data, with a P value <0.05 indicating statistical significance. Results Findings indicated that 58.24% of HCWs reported new skin symptoms since the pandemic started, compared to 33.41% of HCWs who had skin symptoms before the pandemic (P<0.001). From the multivariate analysis, being female (odds ratio, or OR, 3.512; 95% confidence interval, or CI: 2.193-5.625), allergic rhinitis diagnosis (OR 2.420; 95% CI: 1.097-5.347), history of skin symptoms (OR 3.166; 95% CI: 1.856-5.400), and total glove use time (OR 1.160; 95% CI: 1.078-1.247) were associated with an increased risk of acquiring new skin symptoms. Conclusion This study demonstrates that there is some association between the prolonged use of PPE during an event such as a pandemic and a previous history of allergic rhinitis and skin symptoms. This study also emphasizes the importance of appropriate protective skin care before and after the use of PPE.

Laboratory safety evaluation of lokivetmab, a canine anti-interleukin-31 monoclonal antibody, in dogs.

Lokivetmab (Cytopoint®, Zoetis) is a canine monoclonal antibody that specifically binds and neutralizes interleukin (IL)-31. Lokivetmab is approved for use in dogs for the treatment of atopic dermatitis (AD) and allergic dermatitis. The laboratory safety of lokivetmab was evaluated in 2 studies by adapting the science-based, case-by-case approach used for preclinical and early clinical safety evaluation of human biopharmaceuticals. The main objectives were to demonstrate the safety of lokivetmab in healthy laboratory Beagle dogs by using integrated clinical, morphologic, and functional evaluations. In Study 1, dogs were treated s.c. with saline or lokivetmab at 3.3 mg/kg (1X, label dose) or 10 mg/kg (3X intended dose) for 7 consecutive monthly doses, with terminal pathology and histology assessments. In Study 2, the functional immune response was demonstrated in naïve dogs using the T-cell dependent antibody response (TDAR) test with 2 different dose levels of unadjuvanted keyhole limpet hemocyanin (KLH) as the model immunogen. The primary endpoint was anti-KLH IgG antibody titer, and secondary endpoints were ex vivo IL-2 enzyme-linked immunospot (ELISpot) and peripheral blood mononuclear cell lymphoproliferation assays. Both studies included monitoring general health, periodic veterinary clinical evaluations, serial clinical pathology and toxicokinetics, and monitoring for anti-drug antibodies. In both studies, the health of dogs receiving lokivetmab was similar to controls, with no treatment-related changes uncovered. Extensive pathology evaluations of immune tissues (Study 1) revealed no lokivetmab-related morphologic changes, and in dogs treated at 10 mg/kg lokivetmab, immunization with the model antigen KLH did not impair the functional antibody or T-cell recall responses. There were no immunogenicity-related or hypersensitivity-related responses observed in either study. These studies in healthy laboratory dogs showed that lokivetmab was well-tolerated, did not produce any treatment-related effects, and had no effect on immune system morphology or its functional response. These studies also demonstrated the utility of a science-based case-by-case approach to the safety evaluation of a veterinary biopharmaceutical product.

Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment - Disease-Specific Findings (Part 1).

PURPOSE OF REVIEW: Recent high-level publications have shown an intricate connection between immune effector function and the metabolic state of the respective cells. In the last years, studies have begun analyzing the metabolic changes associated with allergies. As the first part of a two-article series, this review will briefly summarize the basics of immune metabolism and then focus on the recently published studies on metabolic changes observed in allergic patients. RECENT FINDINGS: In the last 3 years, immune-metabolic research in allergology had a clear focus on asthma with some studies also reporting findings in food allergy and atopic dermatitis. Current results suggest asthma to be associated with a shift in cellular metabolism towards increased aerobic glycolysis (Warburg metabolism), while also displaying substantial changes in fatty acid- and amino acid metabolism (depending on investigated patient collective, asthma phenotype, and disease severity). Understanding immune-metabolic changes in allergies will allow us to (I) better understand allergic disease pathology and (II) modulate immune-metabolic pathways to improve allergy treatment.

Use of Cytopoint in the Allergic Dog.

Allergic dermatitis is the most common type of skin disease in dogs. Of all dogs, 20 to 30% present with some type of allergic dermatitis. Pruritus is one of the most important signs of allergic dermatitis and is often the most challenging to control. Interleukin-31 (IL-31) has been found to be one of the main initiators of pruritus in dogs with allergic dermatitis. Cytopoint®, a caninized monoclonal anti-IL-31 antibody, has been shown to be effective for the treatment of dogs against allergic dermatitis and atopic dermatitis. US label indication. A recent retrospective study reported that Cytopoint achieved treatment success in 87.8% of the cases with allergic dermatitis. No prospective cohort studies have been performed investigating the effects of Cytopoint in dogs with allergic dermatitis using the dosing protocol prescribed on the product label in the United States. In this study, our objectives were to assess the efficacy of Cytopoint for treatment of canine allergic dermatitis of variable etiologies and management of the associated pruritus, and add to the body of evidence available to the veterinarian as they make treatment recommendations. Dogs included in this study had moderate to severe pruritus according to the Pruritus Visual Analog Scale (PVAS; ≥ 50 mm) and a history of likely continuation of pruritus at the time of presentation. On day 0, investigators recorded the initial body weight and every patient received one dose of Cytopoint (minimum 2 mg/kg SQ) and an isoxazoline product for parasite control. Treatment success for this study was defined as a ≥20 mm reduction in PVAS from Day 0. On Day 7, 94% of the dogs had achieved treatment success. On Day 28, 98% had achieved treatment success and cumulatively by day 56, 100% of the dogs achieved treatment success. This prospective study provides evidence that Cytopoint effectively treats dogs with allergic dermatitis of different types and the associated pruritus.

Acceptance of oclacitinib maleate (Apoquel®) chewable tablets in client-owned dogs with allergic and atopic dermatitis.

BACKGROUND: The oral acceptance of oclacitinib maleate (Apoquel®) chewable tablets administered twice daily for 7 days at the labeled dose range of 0.4-0.6 mg/kg was evaluated in 121 dogs treated at ten general practice veterinary clinics in the United States. RESULTS: Dogs that were enrolled in the study were client-owned, ranged from 1 to 14 years of age, weighed 3.7 to 60.7 kg, and required twice daily treatment with Apoquel for allergic or atopic dermatitis for 7 days. One hundred and twenty-one (121) dogs with 1673 total dose administrations successfully completed the study and were included in the data summary. Out of a total number of 1673 administrations, 1533 (91.6%) were accepted voluntarily within 5 min, 134 (8%) were consumed with assistance (with food treats or by pilling) outside of the 5 min offering time and 6 (0.4%) doses were not consumed. The per dose percent acceptance rate for the 14 offered doses showed minimal variation ranging from 89.9 to 93.3%. CONCLUSIONS: Client-owned dogs from the general veterinary patient population that required treatment with oclacitinib found the chewable tablets to be very palatable and no aversion occurred with repeated dosing. Oclacitinib chewable tablets were well tolerated and are a palatable alternative to the film-coated tablet.

Pharmacokinetics of a single dose of oclacitinib maleate as a top dress in adult horses.

The objective of this study was to determine the pharmacokinetic parameters of oclacitinib maleate as a top dress given to adult horses. Six adult horses with a mean weight of 528 kg were administered a single dose of 0.5 mg/kg oclacitinib maleate. Blood was collected prior to drug administration and at 15 min, 30 min, 45 min, 1, 2, 4, 6, 8, 12, 24, 48, and 72 h after treatment. Oclacitinib maleate plasma concentrations were measured by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were found best to fit a one-compartment model. Mean Cmax was 486 ng/ml (range 423-549 ng/ml), and Tmax was estimated to be 1.7 h (range 0.3-3.1 h). The estimated T1/2 was 7.5-8 h.