Hiromichi Yonekawa1, Toyoyuki Takada2, Hiroshi Shitara1, Choji Taya1, Yoshibumi Matsushima3, Kunie Matsuoka4 and Yoshiaki Kikkawa4

*1Center for Basic Technology Research* 

*Tokyo Metropolitan Institute of Medical Science, Tokyo 2Mammalian Genetics Laboratory, National Institute of Genetics, Mishima* 

*3Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama* 

*4Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo Japan* 

#### **1. Introduction**

20 Atopic Dermatitis – Disease Etiology and Clinical Management

Sybert, V. P., et al. (1985). Ichthyosis vulgaris: identification of a defect in synthesis of

Tokura, Y. (2010). Extrinsic and intrinsic types of atopic dermatitis. *J Dermatol Sci,* 58, 1,

Vasilopoulos, Y., et al. (2007). A nonsynonymous substitution of cystatin A, a cysteine

Vroling, A. B., et al. (2008). How epithelial cells detect danger: aiding the immune response.

Wang, B., et al. (2001). Insights into molecular mechanisms of contact hypersensitivity gained from gene knockout studies. *J Leukoc Biol,* 70, 2, (Aug), 185-191 Wang, I. J., et al. (2011). Filaggrin polymorphism P478S, IgE level, and atopic phenotypes. *Br* 

Weidinger, S., et al. (2008). Filaggrin mutations, atopic eczema, hay fever, and asthma in

Williams, H., et al. (1999). Worldwide variations in the prevalence of symptoms of atopic

Willis, C. M., et al. (2001). Sensitive skin: an epidemiological study. *Br J Dermatol,* 145, 2,

Wollenberg, A. &Bieber, T. (2000). Atopic dermatitis: from the genes to skin lesions. *Allergy,* 

Yamamoto, M., et al. (2007). A novel atopic dermatitis model induced by topical application

Yilmaz, M., et al. (2000). Correlation between atopic diseases and tuberculin responses.

Yoo, J., et al. (2005). Spontaneous atopic dermatitis in mice expressing an inducible thymic

Ziegler, S. F. (2010). The role of thymic stromal lymphopoietin (TSLP) in allergic disorders.

eczema in the International Study of Asthma and Allergies in Childhood. *J Allergy* 

with dermatophagoides farinae extract in NC/Nga mice. *Allergol Int,* 56, 2, (Jun),

stromal lymphopoietin transgene specifically in the skin. *J Exp Med,* 202, 4, (Aug

children. *J Allergy Clin Immunol,* 121, 5, (May), 1203-1209 e1201

3, (Mar), 191-194

*Allergy,* 63, 9, (Sep), 1110-1123

*J Dermatol,* 164, 4, (Apr), 791-796

*Clin Immunol,* 103, 1 Pt 1, (Jan), 125-138

*Curr Opin Immunol,* 22, 6, (Dec), 795-799

(Apr), 1-7

514-519

(Aug), 258-263

139-148

15), 541-549

55, 3, (Mar), 205-213

*Allergy,* 55, 7, (Jul), 664-667

filaggrin correlated with an absence of keratohyaline granules. *J Invest Dermatol,* 84,

protease inhibitor of house dust mite protease, leads to decreased mRNA stability and shows a significant association with atopic dermatitis. *Allergy,* 62, 5, (May),

> The term atopic dermatitis (AD) was first proposed by Wise & Sulzberger (Wise, 1993), who defined the condition as "confusing types of localized and generalized lichenification, generalized neurodermatitis or a manifestation of atopy." AD (or atopic eczema) is recognized as a very common disease that affects at least 15% of children and is strongly associated with cutaneous hyper-reactivity to environmental triggers (Geha, 2003, Leung and Bieber, 2003, Novak et al., 2003). AD is characterized by complex symptoms, including chronic relapsing, extreme pruritus and eczematous skin disease, all of which are frequently associated with IgE hyperresponsiveness to environmental allergens (Hanifin, 1980, Larsen et al., 1986, Schultz Larsen, 1993). The rapid increase in the prevalence of AD over the past three decades has resulted in an intense effort to elucidate the underlying pathogenesis and in the use of radical treatments for this disorder (Taylor et al., 1984, Larsen et al., 1986, Geha, 2003). The causative factors for AD generally fall into two categories: environmental and genetic factors. House dust mites and air pollution are included in the environmental category, and their involvement in the disease has been strongly suggested by epidemiological studies (Hanifin, 1982). Alternatively, genetic factors, including several different candidate regions, have been suggested from linkage studies on atopic and nonatopic phenotypes see Morar et al., (2006) and references therein). The fact that multiple linkage regions have been associated with the disease might be due to: 1) the disease is polygenic and many different genetic factors may be affected with the diseases, 2) the disease is clinically heterogeneous and different subphenotypes are influenced by different risk loci, which is not always followed by one-to-one correspondence, 3) different populations have a different genetic pool and may have different genetic factors for the disease, and consequently genetic studies are still not good enough to correspond to these situations. Additionally, there is a lack of appropriate animal models for human AD except for the flaky tail (*Flgft*) mouse. The *Flgft* mouse carries a loss-of-function (LOF) mutation in the gene encoding filaggrin (FLG), and this LOF mutation causes the barrier abnormality.

Mouse Models for Atopic Dermatitis Developed in Japan 23

Of the two models, the NC model has been more widely used to compare the phenotype between human AD patients and the mice, to explore causative genes (Ito et al., 2004, Ogawa et al., 2005, Fallon et al., 2009, Jung et al., 2011) and genetic loci (Kohara et al., 2001), and for drug development (Yamamoto et al., 2007, Shah et al., 2010, Tanaka and Matsuda, 2011) and the therapy of human AD (Takeda and Gelfand, 2009). Therefore, the immunological,

To perform preclinical trials or to survey potential drug targets for AD using mice, a high incidence of AD onset is required. Thus, there is a drawback to using NC mice, namely, that the NC mice exhibit a very low rate of the spontaneous onset of AD under specific pathogen-free (SPF) conditions. Even under conventional (non-SPF) conditions, the incidence rates of AD are variable and depend on the circumstances of the animal facility in which the NC mice have been bred (Kikkawa et al., unpublished results). Therefore, experimental conditions for the onset of AD are necessary for a high and stable incidence of AD. Although hypersensitivity to some environmental factors is suggested to cause dermatitis, the precise factor remains unclear. The breakthrough identification of conditions to induce AD in NC mice was made by Morita and colleagues, who discovered that fur mites induced dermatitis associated with IgE hyperproduction in a substrain of mice, NC/Kuj (Morita et al., 1999), and the mite antigen-induced dermatitis was subsequently confirmed (Sasakawa et al., 2001). These lines of evidence suggested a new model system for antigen-induced dermatitis. Alternatively, dermatitis can also be induced in NC mice by a hapten, such as 2,4-dinitrofluorobenzene (DNFB) (Tomimori et al., 2002, Tomimori et al., 2005), trinitrochlorobenzene (TNCB) (Taniguchi et al., 2003), or FITC (Hvid et al., 2009). Using these induced dermatitis models in NC mice, extensive surveys for therapeutic agents, both chemicals and herbal medicine, have been performed(Kobayashi et al., 2003, Lee et al., 2007, Jiang et al., 2009, Joo et al., 2009, Lee et al., 2010, Choi et al., 2011, Kim et al.,

pathological and genetic characteristics have been extensively examined in detail.

2011, Park et al., 2011, Sung et al., 2011a, Sung et al., 2011b, Wu et al., 2011).

**2.3 Establishment of hairless NC mice for the development of drugs and** 

such as the development of new ointment for the treatment of AD.

Although the NC model is a promising mouse model for AD, it has another serious drawback, namely the existence of dense hair on the body. The dense hair disturbs the pathological observation of the symptoms in the earlier stages of AD onset and without hair shaving also interferes with the painting of an ointment to test its efficacy. Hair shaving itself leads to another severe problem, laboratory animal allergy (LAA). LAA is a form of occupational allergic disease. The development of LAA is due to the presence of IgE antibodies directed against animal proteins, and incidence rates are rapidly increasing. Hair shaving increases the chance of direct exposure of the researcher to the animal proteins, and the worst possible outcome of LAA is death by anaphylactic shock (Pacheco et al., 2003, Schweitzer et al., 2003, Matsui et al., 2004, Curtin-Brosnan et al., 2010). Therefore, a hairless model on an AD-prone genetic background would be an ideal and powerful tool for basic research, such as the discovery of the genes responsible for AD, and for drug development,

We have generated a hairless mouse model for AD on the NC genetic background to study the pathophysiology of the disease and to screen ointment compounds as novel therapies for skin lesions. To generate the hairless mice, we applied a novel method that we recently developed for the ablation of specific cell lineages using diphtheria toxin (DT), also known

**comprehensive therapy for human AD** 

**2.2 Details of the NC model** 

The barrier abnormality is recently discovered to be linked to the incidence of AD (Oyoshi et al., 2009, Vercelli, 2009, Moniaga et al., 2010, O'Regan and Irvine, 2010).
