Rosanna Marsella

Canine Models of Atopic Dermatitis: A Useful Tool with Untapped Potential

Animal models have contributed greatly to the expansion of knowledge in the field of atopic dermatitis (AD). Some species, such as the dog, naturally and commonly develop a pruritic dermatitis that is clinically and immunologically extremely similar to human AD. Recently, canine models of AD have been validated. In one of these models (Beagles), AD can be reliably reproduced upon allergen challenge, providing a tool with which to study effectively how AD is affected by allergen exposure. Interestingly, decreased epidermal filaggrin expression and disturbed extrusion of lamellar bodies by keratinocytes are present in these dogs, as well as increased transepidermal water loss, particularly in sites characteristically affected by AD. Owing to the remarkable similarity with the human disease, these dog models not only can help answer questions relative to the pathogenesis of the disease but also can be used as tools for rapid screening of drugs with potential clinical application, including those aimed at restoring epidermal barrier dysfunction.

Current evidence of skin barrier dysfunction in human and canine atopic dermatitis

Atopic dermatitis (AD) is a multifaceted disease resulting from a complex interaction between environmental and genetic factors. Both of these factors can shape skin barrier function and the immunological response of predisposed patients. There is increasing evidence that an impaired skin barrier plays a role in both human and canine AD. Although many primary skin barrier defects had already been documented in the past in humans, the recent identification of the filaggrin mutations and the fact that such mutations are now considered the most important risk factor for development of AD have further emphasized the relevance of epidermal dysfunction in human AD. Much less is known in veterinary medicine, but evidence is rapidly building to support a role for skin barrier dysfunction in canine AD. Canine AD shares many clinical and immunological similarities with its human counterpart. The similar distribution of clinical lesions and the importance of the epicutaneous route of allergen exposure provided the incentive to investigate the role of skin barrier impairments in canine AD. The purpose of this comparative review is to present the current evidence of barrier dysfunction in both human and canine AD.

The ACVD task force on canine atopic dermatitis (XII): the relationship of cutaneous infections to the pathogenesis and clinical course of canine atopic dermatitis

Dogs and human beings with atopic dermatitis (AD) frequently exhibit concurrent skin infections with Staphylococcus sp. bacteria or Malassezia yeast, and treatment of such infections is an important facet of managing these patients. Staphylococci appear to colonize atopic skin readily, and bacterial products on the skin could augment cutaneous inflammation via immediate hypersensitivity responses to the bacteria, by superantigen-mediated lymphocyte activation, or other non-specific mechanisms. Similarly, skin colonization by Malassezia yeast could contribute to clinical signs of AD; yeast components could induce inflammation via non-specific mechanisms, such as alteration in mediator release, or via antigen-specific hypersensitivity reactions. Clinical and experimental evidence exists that secondary microbial infections can both initiate and perpetuate episodes of AD in dogs and humans, and could even participate in promotion of pro-allergic immunologic responses. Mechanistic details of these complex interactions are under extensive investigation in human beings; only a few observations have been extended to include dog with AD.

The ACVD task force on canine atopic dermatitis (II): genetic factors

Canine atopic dermatitis is commonly diagnosed in pruritic animals. Many studies have attempted to determine the inheritance pattern of both atopic dermatitis and of elevated allergen-specific IgE production. Despite many clinical, laboratory and breeding studies, the mode of inheritance and genetic mutations underlying this disease currently remain elusive.

Animal models of atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting over 10% of human (sic) children, and it is the most common cause of occupational disability in adults. Atopic dermatitis also is seen commonly in companion animals, especially in dogs, in which its prevalence has been estimated to be about 10% of the canine population. Numerous similarities exist between canine AD and its human counterpart, suggesting the possibility that canine AD could be used as a model for the human disease. Dogs have been used in the past as model for human allergic diseases. The most popular model has been the Basenji–Greyhound, which develops a recurrent, nonseasonal, pruritic dermatitis and asthma. Skin lesions include lichenified plaques and inflammatory papules and nodules. These dogs also display airway hyper-reactivity, with changes in pulmonary mechanics similar to those of symptomatic, human asthma, and they exhibit a variety of immunologic abnormalities analogous to the human disease. Cats also have been reported to develop AD, but our understanding of the condition in this species currently is limited. Certain similarities appear to exist between feline and human AD; however, the feline condition has some peculiar clinical features, and for this reason it will be described separately. Finally, AD recently has been described in laboratory animals, notably the NC/ Nga mouse, which is thought by some authors to be a promising animal model for AD. The purpose of this article is to review the latest information available on AD in companion animals and in mice and describe how these spontaneously arising diseases might serve as models to improve our understanding of human AD.

The ACVD task force on canine atopic dermatitis (XXIII): are essential fatty acids effective?

Essential fatty acids (EFAs) exhibit the potential to affect allergic inflammation through the modulation of prostaglandin and leukotriene production, the inhibition of cellular activation and cytokine secretion as well as the alteration of the composition and function of the epidermal lipid barrier. Because of these multi-faceted effects, EFA have been proposed for treatment of canine atopic dermatitis (AD) since 1987. To date, more than 20 trials have been performed, reporting the efficacy of either oral EFA supplements or EFA-rich diets. Unfortunately, most of these studies were found to exhibit one or more of the following deficiencies: heterogeneity of diagnoses used as inclusion criteria, short duration of supplementation, lack of randomization of treatment allocation, lack of blinding of investigators and/or owners, lack of placebo or active controls, lack of documentation of plasma or skin EFA profiles during supplementation, as well as lack of standardization of the basal diets or supplements which could have provided additional EFA. Consequently, there is presently insufficient evidence to recommend for or against the use of EFA to control clinical signs of canine AD. Evidence of efficacy must await the performance of blinded, randomized and controlled trials of at least 3 months duration in which diets are identical for all of study subjects. In these trials, clinical efficacy should be evaluated in relation to plasma and cutaneous EFA treatment-induced alterations.

Transmission electron microscopy studies in an experimental model of canine atopic dermatitis

Impairment of skin barrier function has been hypothesized in canine atopic dermatitis (AD). In this prospective, controlled study, the ultrastructure of the upper epidermal layers was investigated using an experimental model of canine AD. Seven atopic Beagles sensitized to Dermatophagoides farinae and four healthy Beagles were used as controls. Both normal and atopic dogs were challenged with D. farinae for 3 days. Clinical signs were scored and skin biopsies were taken from the inguinal area before and 3 days after allergen exposure. Samples were processed to enhance lipid visibility and evaluated by Transmission Electron Microscopy. Emphasis was placed on evaluation of the lipid lamellae (LL), and lamellar bodies (LB) of the stratum corneum.After allergen challenge, atopic Beagles developed severe pruritic dermatitis while no skin lesions were noted in the controls. Ultrastructurally, before allergen challenge, atopic Beagles displayed focally severe abnormalities in LL organization and wider intercellular spaces containing abnormal lipid material. In atopic Beagles, LBs were frequently found inside corneocytes while this finding was not observed in the controls. After allergen challenge, further increase of intercellular spaces was observed in the stratum corneum of atopic Beagles while no appreciable changes were observed in the normal dogs. Intercellular spaces in atopic Beagles were filled with abundant amounts of abnormal lipid material and highly disorganized LL. It is concluded that baseline differences in the ultrastructure of the skin exist between normal and experimentally sensitized atopic Beagles and that these changes are aggravated by allergen challenge and the resulting flare-up of dermatitis.

Assessment of cross‐reactivity among five species of house dust and storage mites

In vitro cross-reactivity among two house dust (Dermatophagoides farinae, D. pteronyssinus) and three storage (Acarus siro, Tyrophagus putrescentiae, Lepidoglyphus destructor) mites was examined in 20 mite-sensitive dogs with natural occurring atopic dermatitis (group A), 13 high-IgE beagles experimentally sensitized to D. farinae (group B), and five healthy beagles (group C). Intradermal testing (IDT) and serology for allergen-specific IgE demonstrated that co-sensitization for all possible pairs of the five mites was generally 45% or higher among group A dogs. In the same dogs, enzyme-linked immunosorbent assay cross-inhibition results indicated that each one of D. farinae, A. siro and T. putrescentiae was a strong inhibitor of all the remaining mites, whereas D. pteronyssinus was a strong inhibitor of L. destructor. A high number of positive IDT and serology test results for D. pteronyssinus, A. siro, T. putrescentiae and L. destructor were recorded among group B dogs. No conclusive evidence of exposure to these mites was found upon analysis of dust samples from their environment and their food for the presence of mites and guanine. Also, the number of positive test results was generally higher among group B than among group C dogs. Enzyme-linked immunosorbent assay cross-inhibition revealed that D. farinae was a strong inhibitor of D. pteronyssinus, A. siro and T. putrescentiae. Collectively, these results demonstrated extensive in vitro cross-reactivity among house dust and/or storage mites that can explain false-positive results upon testing of dust mite-sensitive dogs with atopic dermatitis.

Immunohistochemical evaluation of filaggrin polyclonal antibody in atopic and normal beagles.

In human atopic dermatitis (AD), impairments in skin barrier function are emphasized and hypothesized to increase risk of allergic sensitization. Filaggrins, crucial proteins for keratinization, are decreased in lesional and nonlesional human atopic skin. As canine AD shares numerous similarities with the human counterpart, this study aimed to evaluate a polyclonal antibody against human filaggrin in atopic beagles sensitized to house dust mites (HDM) and normal healthy dogs. The effects of HDM exposure on immunostaining and clinical signs were evaluated in both groups. Positive immunohistochemical staining with anti-filaggrin antibody was evaluated both objectively and subjectively by two blinded investigators. Pearson correlation test showed significant correlation between objective and subjective scores, both at baseline and after allergen exposure (r = 0.80; P = 0.0017 and r = 0.75; P = 0.013 respectively). Analysis of variance showed significant effect of time (P = 0.01) with immunostaining being higher in baseline samples than after HDM exposure. It also showed a significant group x time interaction (P = 0.02) with immunostaining not changing significantly over time in atopic dogs, while decreasing in normal dogs after HDM exposure. An independent t-test showed that, at baseline, atopic beagles had significantly less positive immunostaining than controls (P = 0.009) and that, after HDM exposure, there was no significant difference between groups. No correlation existed between clinical scores and immunostaining. In atopic dogs immunostaining was characterized by faint granular staining, while normal samples showed discrete intense staining. Moreover, immunostaining was present in all epidermal layers in many samples, suggesting cross-reactivity of the antibody used with other epidermal proteins besides filaggrin.

The ACVD task force on canine atopic dermatitis (XXII): nonsteroidal anti-inflammatory pharmacotherapy

The pharmacotherapy of canine atopic dermatitis has relied primarily on the use of glucocorticoids and anti-histamines. During the last decade, other anti-inflammatory drugs have been investigated in clinical trials. This paper will review the studies using misoprostol, cyclosporine, tacrolimus, phosphodiesterase inhibitors, capsaicin, leukotriene inhibitors and serotonin-reuptake inhibitors for treatment of dogs with atopic dermatitis. For each drug the mechanism of action, the rationale for use in atopic dermatitis, the clinical efficacy, reported adverse effects and strength of recommendation for treatment of canine atopic dermatitis are described. At the time of this writing, there is fair evidence to support the recommendation for using cyclosporine, misoprostol and pentoxifylline for treatment of canine atopic dermatitis. This recommendation can be strengthened by the performance of additional blinded randomized controlled trials with larger number of dogs. In contrast, there is insufficient evidence to recommend for or against treatment with tacrolimus, leukotriene inhibitors, serotonin-reuptake antagonists and capsaicin.