Skin Inflammation Models
Atopic dermatitis is a chronic relapsing inflammatory skin disease. Several factors have been implicated in atopic dermatitis, and they include IgE-mediated sensitization to environmental and food allergens and abnormal reaction of the immune system against external antigens. Symptoms include itchiness, redness, and dryness of the skin.
Ovalbumin-Induced Atopic Dermatitis
The ovalbumin-induced atopic dermatitis model is induced either by a topical application or systemic administration of ovalbumin (sensitization) followed by topical application or intradermal injection of ovalbumin (challenge; usually seven days later) to the ear which will result in an inflammatory response. Ear swelling is measured using digital callipers to monitor the inflammatory response. Topical application of ovalbumin results in Th1 immune response while systemic ovalbumin administration induces a Th2 dominant inflammatory profile.
Ovalbumin-Induced Atopic Dermatitis Validation Data
Figure 1: Ovalbumin-induced model of atopic dermatitis. Efficacy of the Betamethasone-treated animals when compared to the Vehicle-treated animals at 15 minutes post challenge is shown. Ear swelling of the challenged and control animals is measured by ear thickness.
Figure 2 & 3: Histopathology image (H&E staining) of untreated control skin and skin post intra dermal injection with ovalbumin showing epidermal hyperplasia, dermal oedema and marked eosinophilic infiltration of the dermis next to the auricular cartilage
Oxazolone Induced Atopic Dermatitis
Recently it has been reported that multiple challenges with synthetic haptens, notably oxazolone, applied to the skin of mice over an extended period causes skin inflammation involving a shift from a typical Th1 dominated delayed-type hypersensitivity response to a chronic Th2 dominated inflammatory response like that observed in human atopic dermatitis. We have developed an oxazolone-induced atopic dermatitis-like skin condition in three different strains of mice:
- NC/Nga mutant mice
- SKH-1 hairless mice
- Balb/c albino mice
Combined with in-life clinical scoring, such as in-life ear measurements, histopathological evaluation, and optional cytokine analysis, these models offer an opportunity to conduct translational efficacy studies, furthering atopic dermatitis drug discovery programs.
Oxazolone Induced Atopic Dermatitis Validation Data
Figure 5: Histopathological changes in the skin of oxazolone-challenged NC/Nga mice in the Atopic Dermatitis Model. Note hyperkeratosis, acanthosis and infiltration of inflammatory cells and effects of clobetasol cream on these skin pathological changes.
Figure 6: Effects of commonly used anti-eczema steroidal agent clobetasol and dexamethasone on oxazolone-induced Atopic Dermatitis. Clobetasol cream applied topically on the affected skin and dexamethasone administered via oral gavage attenuated AD-like skin symptoms both in prophylactic and therapeutic dosing protocol.
Atopic Dermatitis Study Endpoints
- PK/PD blood collections
- Myeloperoxidase activity
- Cytokine/chemokine analysis
- Histopathological evaluation
- Ear thickness measurements
Symptoms in NC/Nga Mutant Mice
The Immune Response in Atopic Dermatitis Models
The ‘Hapten Atopy Hypothesis’ postulates that normally ‘harmless’ environmental and food allergens delivered via skin and mucosal membranes will initially stimulate a Th1 immune response, but repeated and prolonged exposure to such allergens in genetically predisposed individuals will likely shift the response from Th1 to Th2 leading to antibody class switch in B cells producing IgE antibodies which then tightly bind to peripheral mast cells and basophils.
Follow up exposure to the allergens will cause cross-linking of the IgEs and eventual degranulation of mast cells and basophils and release of histamine and other endogenous inflammatory pruritic agents. Animal models that recapitulate this cross-linking effect and inflammatory response are critically important in designing efficacy studies of new eczema treatments.
What models are available for Atopic Dermatitis?
There are 3 types of models for Atopic Dermatitis; sensitization models, transgenic mice models or mice that spontaneously develop Atopic Dermatitis-like skin lesions.
At Charles River we have developed several translational animal models to help our clients with their atopic dermatitis drug discovery programs. These include Oxazolone-induced Atopic Dermatitis, HDM-induced, VD3 analog induced (MC903) and Ovalbumin induced models in wild type or mutant mice. In vivo scoring for redness, scaling and/or skin thickness can be monitored daily. Tissues often are collected for further evaluation of immune system function
Should immunological endpoints be considered in studies of Atopic Dermatitis?
Atopic dermatitis is a chronic inflammatory skin disease with changes in skin barrier and imbalance in function of immune system. Recently it has been characterized as an autoimmune disease.
The exact etiology of the disease is not well understood, but it is likely multifactorial. AD onset is characterized by profound increases of Th2, Th17 and Th22 and their relevant cytokines and chemokines. These mediators have been demonstrated to play an important role in skin barrier function and skin integrity.
Recently, it has been demonstrated that group 2 innate lymphoid cells (ILC) can also produce Th2 cytokines. These cells have been found at increased levels in AD lesions compared to healthy control skin, thereby possibly further promoting Th2 response.
Based on the immune cells involved in pathogenesis of the disease, new therapeutic approaches are being developed, including those targeting IL-12/23, JAK kinase inhibitors, IL-31, IL-22, IL-17, thymic stromal lymphopoietin (TSLP) and Phosphodiesterase 4 inhibitors.