Regulation of the adaptive immune response by chemokine scavenging receptors

When our bodies are invaded by foreign organisms such as bacteria or viruses, we mount what is called an immune response. This requires the careful orchestration of cell movement throughout the body, without which the immune response would not be properly developed. Much of the movement of the immune cells is regulated by specialised proteins which are called Chemokines. It is with these proteins that we work. We have identified molecules that can degrade some of the chemokines and therefore remove them from the area surrounding cells. We believe that this is important for the proper working of the immune system. The current proposal aims to study these molecules, which we call scavengers, in much more detail and to carefully examine their roles in helping the development of immune responses. The data we generate will therefore help us to understand the regulation of the immune response in much more detail and will have implications for our ability to therapeutically manipulate this process. In addition, sometimes chemokines can play deleterious roles and can be at the root cause of diseases such as arthritis and psoriasis. We believe that we might be able to use these scavenger molecules in disease contexts to switch off inflammation. We will therefore try to develop anti-inflammatory agents based on our knowledge of these scavenger molecules and will partner with a large Pharmaceutical company to help develop their therapeutic potential.

Over the past 20 years much has been learnt about the fundamental roles played by chemokines and their receptors in regulating immune responses. We have been particularly interested in a subfamily of chemokine receptors which are characterised by promiscuous ligand binding and by an apparent inability to signal following ligand binding. Currently there are 4 members of this atypical chemokine receptor family and we have been instrumental in the identification and characterisation of 2 of these namely D6 and CCXCKR. Essentially, both are scavenger receptors, binding and internalising chemokine ligands and targeting them for intracellular degradation. D6 binds all the inflammatory CC chemokines and CCXCKR, in a complementary manner, binds the key homeostatic CC chemokines. These are therefore negative regulators of CC chemokine biology the identification of which has marked a major shift in our understanding of chemokine biology. Our studies on D6 indicate that it plays a strong role in regulating inflammatory responses in vivo. However, our more recent data suggest broader roles for D6 specifically in the context of regulation of adaptive immune responses. The ligand binding profile of CCXCKR immediately implicates it in adaptive immunity and thus we propose that these 2 atypical receptors represent a novel and important axis in the orchestration of the in vivo immune response. We now propose to unify our studies into D6 and CCXCKR under a single programme. We will use shared technologies to carefully investigate their roles in regulating chemokine availability, leukocyte migration and movement and the impact of this on adaptive immune responses. In addition, we have seen that an N terminal fragment of D6 retains the ability to bind chemokines. Given the promiscuity of D6 and its ability to bind all inflammatory CC chemokines, this N terminal peptide may represent a valuable therapeutic agent. We therefore also propose to initiate studies into the usefulness of chemokine scavenger receptor derived peptides as therapeutic agents. In the first instance, this will involve a biochemical analysis of the D6 N-terminal peptide as well as in vivo analyses of its ability to block inflammation in murine models. In addition, we will partner with colleagues at Novartis to develop the therapeutic potential of the D6 N-terminal peptide.