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A common feature of the eotaxins, the MCPs, and CCL5 is their ability to mediate chemotaxis via CCR3, which is shown to be expressed on eosinophils (14), mast cells (15), basophils (16), and Th2 cells (17, 18). The involvement of other chemokines was demonstrated in vivo, showing that different chemokines, mostly activators of CCR3, contribute to the complex pathophysiology of asthma (19). A major breakthrough, showing the impact of CCR3 in asthma, was achieved recently (20). Targeted disruption of CCR3 was successfully performed, demonstrating that eosinophils and other inflammatory cells are arrested in the subendothelial space of pulmonary vessels after bronchial allergen challenge in OVA-sensitized mice (20), suggesting that the local inflammatory response is abolished, targeting CCR3 already in the circulation. However, airway hyper-responsiveness (AHR) is enhanced in i.p. sensitized mice, which correlates to increased intraepithelial mast cells in the airways (20), whereas AHR is abrogated in CCR3-deficient mice sensitized by the epicutaneous route (21). Therefore, CCR3 appears to be particularly attractive as a drug target; its blockade has been proposed as a tool for the therapy of asthma (22).

The therapeutic use of chemokines or their derivatives with antagonistic or agonistic properties, such as Met-RANTES, AOP-RANTES, or NNY-RANTES, has been intensively discussed in the literature, particularly for the inhibition of HIV infection (44). The treatment of asthma is one rationale for the development of CCR3 antagonists such as I-TAC-eotaxin hybrid-1 (55). Besides peptides, small m.w. antagonists are also considered potential drugs for the blockade of chemokine receptors. Because the latter compounds, derived from piperazine and piperidine, may exhibit unexpected side effects (particularly in the heart and CNS), peptide ligands inactivating chemokine receptors may represent an alternative due to better tolerance. There are already agonistic drugs, which are applied to induce inhibitory effects, such as luteinizing hormone-releasing hormone analogues, which are used to down-regulate hormone release (58). Hence, we propose the concept of an agonistic receptor inactivator mediating its effects through desensitization and internalization, thereby rendering target cells insensitive to further activation through the inactivated receptors.

We suggest from the presented study that the blood represents an ideal compartment for application of such an agonistic receptor inactivator, as generated toxic substances such as reactive oxygen species accumulate much more slowly than in inflamed tissues. Therefore, peptides would be interesting candidates because they are mainly administered parenterally, are usually highly specific, and consequently have relatively low systemic toxicity (66). Finally, we speculate that CD26/DPP IV-resistant agonists, such as NNY-CCL14, which is able to efficiently internalize its receptors, can be given at significantly lower doses than antagonists such as Met-RANTES to inhibit extravasation of effector cells (19). Additional studies are necessary to demonstrate the proposed mechanism in vivo of NNY-CCL14 and to exclude an involvement of other receptors. 2351a5e196