**4. Th2-type cytokine – Targeted treatment for AD**

Because of the importance of Th2-type cytokines in the pathogenesis of AD, it has been thought that Th2-type cytokines have the potential to be targeted to develop novel agents against AD. A clinical trial to administer a humanized anti–IL-5 monoclonal Ab (mepolizumab) to AD patients was performed, with a disappointing result (46). To the best of our knowledge, no trial targeting IL-4 or IL-13 for AD patients has thus far been performed.

#### **4.1 Antagonist of IL-5 for treatment of AD**

AD patients received 750 mg of humanized anti–IL-5 monoclonal Abs (mepolizumab) intravenously twice (at day 0 and 7) (46). Efficacy assessed by SCORAD was observed at

The Roles of Th2-Type Cytokines in the Pathogenesis of Atopic Dermatitis 47

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and TH2 cytokines in a murine model of allergic dermatitis. *J Clin Invest,* 103,

transgenic mice results in a pruritic inflammatory skin disease: an experimental

Early up-regulation of Th2 cytokines and late surge of Th1 cytokines in an atopic

(2005). Correlation of disease evolution with progressive inflammatory cell activation and migration in the IL-4 transgenic mouse model of atopic dermatitis.

progression in the keratin 14 IL-4-transgenic mouse model of atopic dermatitis parallels the up-regulation of B cell activation molecules, proliferation and surface

expression of interleukin-13 in the skin induces a pruritic dermatitis and skin

E., Schou, C., Krishnaswamy, G. & Beaty, T. H. (1994). Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E

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quiz 666.

153.

9, pp.461-466.

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pp.1103-1111.

day 14 but was not statistically significant. There was no difference in pruritis score between mepolizumab- and placebo-administered groups. Even when efficacy was assessed by PGA (the Physician's Global Assessment of Improvement), the numbers showing 'marked improvement' were not statistically significant. However, it is of note that 4 of 18 (22.2%) patients receiving mepolizumab showed 'marked improvement'. These results can be interpreted two ways: one is that the overall efficacy of mepolizumab is not as good as expected. The other is that mepolizumab is effective only for limited patients. The latter is likely when mepolizumab is administered to patients with bronchial asthma. In the first clinical trial, mepolizumab yielded a disappointing result (47, 48). However, it turned out that mepolizumab is quite effective for the patients with sputa containing large numbers of eosinophils (49, 50). It is important to select patients who are sensitive to certain molecular target drugs by so-called 'companion diagnostics': in this case, numbers of eosinophils in sputum. A companion diagnostic should be found to treat AD effectively with mepolizumab.

#### **5. Conclusion**

In this chapter, we summarized the studies concerned with Th2-type cytokines in the pathogenesis of AD from the standpoint of the model mice and genetic association. Furthermore, we mentioned a trial in which AD patients were treated by administration of neutralizing Abs against IL-5. We hope the information in this review will be useful in developing new treatments for AD patients in the future.

#### **6. Acknowledgement**

We thank Dr. Dovie R. Wylie for critical review of this manuscript. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.

#### **7. References**


day 14 but was not statistically significant. There was no difference in pruritis score between mepolizumab- and placebo-administered groups. Even when efficacy was assessed by PGA (the Physician's Global Assessment of Improvement), the numbers showing 'marked improvement' were not statistically significant. However, it is of note that 4 of 18 (22.2%) patients receiving mepolizumab showed 'marked improvement'. These results can be interpreted two ways: one is that the overall efficacy of mepolizumab is not as good as expected. The other is that mepolizumab is effective only for limited patients. The latter is likely when mepolizumab is administered to patients with bronchial asthma. In the first clinical trial, mepolizumab yielded a disappointing result (47, 48). However, it turned out that mepolizumab is quite effective for the patients with sputa containing large numbers of eosinophils (49, 50). It is important to select patients who are sensitive to certain molecular target drugs by so-called 'companion diagnostics': in this case, numbers of eosinophils in sputum. A companion diagnostic should be found to treat AD effectively

In this chapter, we summarized the studies concerned with Th2-type cytokines in the pathogenesis of AD from the standpoint of the model mice and genetic association. Furthermore, we mentioned a trial in which AD patients were treated by administration of neutralizing Abs against IL-5. We hope the information in this review will be useful in

We thank Dr. Dovie R. Wylie for critical review of this manuscript. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the

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effect of the R110Q *IL13* genetic variant alone and in combination with *IL4RA*


**4** 

Ulf Meyer-Hoffert

*Germany* 

*Department Dermatology* 

**Epidermal Serine Proteases and Their** 

The skin and its appendages protect the body from water loss, chemical and physical damages, UV-radiation and infection by pathogenic as well as non-pathogenic microbes. The protective function of both, the physical and the chemical barrier, is provided from epidermal keratinocytes, which are continuously dividing in the *stratum basale* and differentiating towards the surface (Candi et al. 2005). Cells of the uppermost living epidermis layer, the stratum granulosum, are loosing their nuclei and other organelles at the transition zone to the stratum corneum (SC), forming now flattened polyhedrons, called corneocytes. These corneocytes contain instead of a cell membrane the cornified envelope (CE) consisting of structural proteins, which are crosslinked by glutaminases (Candi et al. 2005). The intercellular space of the corneocytes is filled with lamellar bodyderived lipids, which make the SC more hydrophobous. This mechanism protects skin

Finally, in a tightly regulated process termed desquamation that abolishes the cohesion between corneocytes, these cells are shed into the environment by proteolysis of corneodesmosomal proteins. The formation of stratified epithelia requires a specific differentiation program, which includes a timely and spatially well coordinated proteolytic system to detach the corneocytes from each other without any disturbance of the barrier function. During the last years it became evident that this proteolytic balance is not only important for the physical barrier function of the skin but is also paving the way for immunological responses. In this chapter we want to look at the various proteases in the epidermis, their inhibitors and how they might contribute to the pathogenesis of

A number of different proteases and their inhibitors have been involved in the desquamation process and to contribute to the skin's barrier function. On the basis of the catalytic domain, proteases are classified into aspartate-, cysteine-, glutamate-, metallo-, serine- and threonine proteases. Particularly serine proteases (SP) have a prominent role in epidermal permeability barrier homeostasis, as acute barrier disruption increases SP-activity

**1. Introduction** 

from water loss and other insults.

atopic dermatitis (AD).

**2. Proteases** 

**Inhibitors in Atopic Dermatitis** 

*University Hospital Schleswig-Holstein, Campus Kiel* 

