- Dr Simi Ali, Principal Investigator
- Dr Isabel J. Crane, Co-Investigator
- University of Newcastle, Newcastle-upon-Tyne, UK
- Non-Glycosaminoglycan-Binding Chemokine Receptor Agonists: A Novel Route to Anti-Rejection Therapy?
Solid organ transplantation is often complicated by rejection; this is manifested by vigorous inflammation. The early events in rejection are controlled by small proteins, termed “chemokines”, which recruit immune cells from the blood and direct them into the transplanted organ. Recent evidence suggests that chemokines anchor themselves to molecules called proteoglycans, which exist on the surface of cells lining the blood vessels. In addition, they also bind to their specific receptors.
Initial hope that targeting of chemokines may result in the attenuation of inflammation is hampered by the redundancy in chemokine activity. A series of small molecule chemokine receptor antagonists has been created. However, as immune cells can express multiple chemokine receptors, it seems likely that blockade of any single receptor will have an incomplete potential to prevent migration of immune cells promoted by a physiological range of chemokines.
We have recently engineered a chemokine variant which can bind to its receptor but cannot anchor to proteoglycans. Importantly, this molecule can inhibit the recruitment of all white blood cells. In this project we will define the mechanism of action of this new anti-inflammatory molecule and will also determine whether related molecules produce the same effect. In this study we will use a wide range of experiments including in vivo experiments and a mouse model of organ transplantation. We anticipate that our work will lead to the development of novel agents for anti-inflammatory therapy.
Significance: These molecules should contribute to the rational design of therapeutic agents to selectively block graft-damaging lymphocytes following transplantation.