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The strategy of blocking the chemokine system to combat disease
A E Proudfoot1, C A Power, T N Wells
1Serono Pharmaceutical Research Institute, Geneva, Switzerland. Amanda.Proudfoot@serono.com
Abstract:
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.
Insights
Blocking chemokine receptors offers a novel anti-inflammatory therapy by preventing leukocyte recruitment. This approach targets upstream mechanisms, unlike current treatments, showing promise in reducing inflammation and potentially treating HIV-1 infection.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Inflammation involves leukocyte recruitment to affected sites.
- Current anti-inflammatory therapies act downstream, after cell migration.
- The chemokine system, comprising over 40 ligands and 18 receptors, presents a complex but promising therapeutic target.
Purpose of the Study:
- To propose a novel anti-inflammatory therapy by blocking chemokine receptor/ligand interactions.
- To explore specificity mechanisms within the complex chemokine system.
- To validate the chemokine system as a therapeutic target for inflammatory diseases.
Main Methods:
- Discussed specificity mechanisms of the chemokine system, including temporal regulation, glycosaminoglycan interactions, differential receptor/ligand binding, and receptor trafficking.
- Utilized a chemokine receptor antagonist in in vivo inflammation models.
- Reviewed the growing literature on small molecule inhibitors of chemokine receptors.
Main Results:
- Demonstrated successful reduction of inflammation in vivo using a chemokine receptor antagonist.
- Highlighted the potential of targeting the chemokine system for therapeutic benefit.
- Noted the increasing development of small molecule inhibitors for chemokine receptors, showing efficacy in inflammatory disease models and HIV-1 inhibition.
Conclusions:
- Preventing leukocyte recruitment via chemokine receptor blockade represents a novel, upstream anti-inflammatory strategy.
- The chemokine system's complexity is manageable through identified specificity mechanisms.
- Chemokine receptor antagonists are validated therapeutic agents with potential for treating inflammatory diseases and HIV-1 infection, with clinical trials imminent.