**8. References**

Acosta-Rodriguez, E. V., Rivino, L., Geginat, J., Jarrossay, D., Gattorno, M., Lanzavecchia, A., Sallusto, F., & Napolitani, G. (2007). Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. *Nat. Immunol.* 8, 639–646.

Because of the crucial role of chemokine/chemokine-receptor interactions in the pathogenesis of allergic responses, it seems very attractive to use specific inhibitors, like neutralizing antibodies or small molecule antagonists, as therapeutic drugs to prevent or dampen the inflammatory reaction. Many inhibitors of chemokines and their receptors have already been developed and are currently tested in various disease models and in clinical studies (for recent reviews see (Garin & Proudfoot, 2011; Mackay, 2008; Pease, 2011)) However, the pleiotropic action of many chemokines and the frequent redundancies in the system hamper the development of efficient drugs and their approval for clinical use. Nevertheless, there is still optimism that chemokines and their receptors are promising

In the case of CCR4 at least four different small molecule inhibitors have been developed and successfully tested *in vitro* as well as in T cell migration models in mice (Nakagami et al., 2010; Pease, 2011; Sato et al., 2009). As indicated by the fact that CCR4 knockout mice develop AD-like symptoms (Islam et al., 2011; Stutte et al., 2010) and OVA-induced lung inflammation (Chvatchko et al., 2000) comparable to wild-type mice, blockade of CCR4 alone may not be sufficient to prevent these allergic reactions. In two studies addressing skin inflammation, simultaneous blockade of CCR4- and CCR10-ligands, or of CCR4 and the CCR10 ligand CCL27 was shown to be required for efficient inhibition of contact hypersensitivity at the time of challenge, or for homing of allergen-specific T cells to the skin (Mirshahpanah et al., 2008; Reiss et al., 2001). In another study, however, treatment with anti-CCL27 alone led to a significant inhibition of CHS and development of AD-like symptoms (Homey et al., 2002). As discussed above the amelioration of AD symptoms in CCL17-deficient mice but not CCR4-deficient mice indicates the presence of an additional receptor for CCL17, in particular with relevance for the emigration of LC from the skin. In addition, differences in the function of CCL17 and CCL22 regarding the attraction of Treg versus T helper cells may limit the usefulness of CCR4 antagonists in the treatment of allergic reactions. In fact, CCR4 blockade has also been proposed as a means to reduce attraction of tumor infiltrating Treg in cancer therapy (Yang et al., 2011). Therefore, it may be reasonable to also consider neutralization of certain chemokine ligands like CCL17 and

CCL27 for therapy of AD, as an alternative to the blockade of chemokine receptors.

We are grateful to Heike Weighardt, Sonja Didovic and Theresa Globisch for comments on the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft

Acosta-Rodriguez, E. V., Rivino, L., Geginat, J., Jarrossay, D., Gattorno, M., Lanzavecchia,

A., Sallusto, F., & Napolitani, G. (2007). Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. *Nat.* 

**6. Perspectives on chemokines and chemokine receptors as therapeutic** 

**targets in AD** 

**7. Acknowledgment** 

*Immunol.* 8, 639–646.

through SFB 704.

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**Part 2** 

**Microorganisms in Atopic Dermatits** 

