One of the key characteristics of
inflammation is the recruitment of leukocytes to the site of
inflammation. Most anti-inflammatory strategies act intracellularly on the target cells, but after the cells have migrated to the site. We therefore propose that the prevention of cellular recruitment by blockade of the relevant
chemokine receptor/
ligand pair would present a novel
therapy in that it would act upstream of the
therapies currently in use. The
chemokine system is a complex family of over 40
ligands and 18 receptors and as such may appear difficult to inhibit selectively. In the first part of the article we discuss the specificity mechanisms that are beginning to be unraveled which we believe occur at multiple levels. These levels of control of specificity include the temporal regulation of both the
ligands and their receptors, which are under the control of pro-inflammatory
cytokines; the localization of
chemokines on cell surfaces through their interactions with
glycosaminoglycans; differential receptor/
ligand interactions; and different patterns of receptor trafficking, to name but a few. The
chemokine system has been validated as providing good therapeutic targets by several approaches. In our laboratory, we have used a
chemokine receptor antagonist in models of
inflammation in vivo to demonstrate that this approach is successful in reducing
inflammation.
Chemokine receptors belong to the class of seven transmembrane spanning receptors, which have proven to be excellent targets by the pharmaceutical industry for many diseases. The number of small molecule inhibitors of
chemokine receptors is rapidly growing in the patent literature, and reports both in the literature as well as conferences in the field have shown them to be effective in inflammatory disease models, as well as inhibiting HIV-1
infection. Since clinical trials will begin this year with some of these molecules, hopefully we will fairly soon have the answer of the efficacy of this therapeutic approach.