Multi-faceted strategies to combat disease by interference with the chemokine system

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Inappropriate cell recruitment is a hallmark of all autoimmune, allergic and inflammatory diseases. The prevention of inflammation by interfering with cellular recruitment through the neutralization of cytokines and adhesion molecules has proven to be successful in the clinic. Chemokines are important potential targets owing to their central role in the cell recruitment process. Chemokines are unique among cytokines because they signal through seven transmembrane receptors, thus enabling the identification of small molecule inhibitors through high throughput screening. The object of this Review is to discuss the validity and feasibility of targeting several points of therapeutic intervention offered by the chemokine system and to assess the state of play within the field to date.

Section snippets

Chemokines and disease

The holy grail of many biotechnology and pharmaceutical companies is to find the key targets that control pathologies and to develop appropriate therapeutics to control them. Recently, there have been several success stories, through the targeting of key proteins that are involved in autoimmune diseases with therapeutic antibodies. Antibody neutralization of the cytokine tumor necrosis factor-α (TNF-α) represents one such successful therapeutic platform, and attempts to inhibit specific

Modes of intervention

There are several approaches to interfering with identified targets (Figure 2), which are described in more detail in later sections. The approach taken depends on several factors, including whether the target is intracellular or extracellular, exemplified by the traditional division of anti-inflammatory strategies by the biotechnology companies and the pharmaceutical companies as ‘outside the cell’ and ‘inside the cell’ intervention, respectively. Interference with the activity of cytokines,

Small molecules

The most widely adopted approach to block the interaction of the chemokine with its receptor is using small molecule antagonists (Figure 3a). It has been an exciting and instructive experience to see the field evolve, from the identification of the first chemokine receptors in 1991 8, 9, until today, where several small molecule chemokine receptor antagonists are being evaluated in advanced human clinical trials. In the pioneering days, the main challenge consisted of designing small molecules

Modified chemokines

A second approach to block the chemokine–receptor interaction is by using chemokines that have been modified in such a way that they retain high affinity for their receptor but have abrogated signaling properties, thereby producing a receptor antagonist (Figure 3b). Traditionally, these have been chemokines modified at their N-terminus, the region, which in most chemokines, is responsible for signaling. The approach of producing N-terminally truncated chemokines was particularly suitable to

Antibodies

The use of neutralizing mAbs (Figure 3c), principally against the chemokines themselves, has been used extensively in animal models of disease, although surprisingly, few are being developed for therapeutic use – perhaps a reflection of the worry that orally available small molecule receptor inhibitors would supersede the use of antibodies. Therefore, the use of neutralizing antibodies against specific chemokines has, for the moment, been of more use in proving that inhibition of chemokine

Binding proteins

An interesting conundrum exists in the human system: the human genome has evolved several endogenous strategies to combat inflammation, in the guise of binding proteins that neutralize proinflammatory cytokines (Figure 3d). Examples of these are, IL-1 receptor α (IL-1Rα) [29], TNF-binding protein-I (TBP-I) and TBP-II [30], interferon receptor α (IFNRα) [31] and IL-18-binding protein (IL-18BP) [32]. Similarly, viruses have evolved to produce such proteins and their genomes encode binding

Perspectives

The initial discovery of chemokines led to the perhaps naïve hope that each leukocyte subtype would express a specific chemokine receptor, which would facilitate therapeutic intervention in an unprecedented manner. However, our knowledge of the system as it is today indicates that this is not the case. The chemokine system is highly complex. It is often described as redundant – this is certainly evident from in vitro studies, although we believe that there are certainly levels of control and

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