Abstract
Drug development involves pharmacometric experiments in animals. Such experiments should limit animal pain and stress. Conventional murine models of atopic dermatitis (AD) used in drug development are generated by weekly painting of hapten on dorsal skin for 5 weeks. The present study aimed to develop a protocol that involves less animal distress. The experiments focused on serum total IgE levels, which are a marker of AD. The conventional protocol induced ever rising IgE levels. Experiments with extended intervals between sensitizations showed that IgE peaked ~5 days after the second sensitization, after which it returned to the control level within 12–19 days. An additional third sensitization on day 28 further increased the serum IgE level. In the 4–5 days after the second sensitization, the dorsal skin exhibited typical AD-like lesions with edema, scabs, epithelial-cell hypertrophy, marked mast-cell and lymphocyte infiltration of dermis, and increased IL-4, IL-6, IL-10, IL-1β, IL-17A, IFN-γ and TNF-α expression. Thus, two 2,4-dinitrofluorobenzene sensitizations yield a murine AD model in less than 20 days. This study shows that animal model protocols used in drug development can be fine-tuned so that they remain effective yet cause animals less stress and pain.
Highlights
During drug discovery, it is necessary to use animals for various experiments, including for evaluating the efficacy and safety of the candidate drug
Current murine models of atopic dermatitis (AD) are generated by repeated painting of DNFB or DNCB on the dorsal skin and ears (Supplementary Fig. S1)
We started the present study with Protocol 1, which is a commonly used method for generating animal models of AD with a hapten
Summary
It is necessary to use animals for various experiments, including for evaluating the efficacy and safety of the candidate drug. Its key immunological feature is high levels of serum total IgE5,6 These high IgE levels are induced by some leukocytes; including T helper type 2 (Th2) cells that are specific for allergens such as certain foods and insect proteins. When these cells in the circulation encounter these allergens, they produce inflammatory cytokines such as interleukin (IL)-4. The binding of antigen by receptor-bound IgE induces the cells to secrete inflammatory cytokines, chemokines, histamine, and leukotriene These molecules in turn promote other inflammatory reactions that eventually lead to further exacerbation of the clinical manifestations of AD11.
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