Research Group
- Dr. Simi Ali, Principal Investigator
- Dr. John A. Kirby, Co-Investigator
Location
- University of Newcastle, Newcastle-Upon-Tyne, UK
Title
- Anti-Rejection Therapy: Modifying Intragraft Immunity by Specific Blockade of Th1 Cell Recruitment
Solid organ transplantation is often complicated by rejection, which is manifested by vigorous inflammation. The Th1 cytokines stimulate the acute rejection process whilst Th2 cytokines tend to downregulate this process. It is also known that Th1 and Th2 lymphocytes produce different chemokine receptors. For example, Th1 lymphocytes express chemokine receptor CCR5. One of the major ligands for CCR5 is the chemokine RANTES. Significantly, lymphocytes expressing CCR5 are known to predominate during acute renal rejection.
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.
We will address the possibility that this anchorage is essential for functional activation of chemokines and that disruption of this process might offer a possibility for anti-inflammatory therapy. Data from our group suggests that a chemokine called RANTES contributes to the process of graft rejection. In this study we will use molecular biology methods to produce several versions of RANTES with variable abilities to bind proteoglycans. We will then use these constructs in a range of assays designed to assess the biological activity. The potential anti-inflammatory activity of these molecules will be evaluated by selectively blocking the movement of CCR5-expressing Th1 lymphocytes in laboratory experiments. These molecules should contribute to the rational design of therapeutic agents to selectively block graft-damaging Th1 lymphocytes following transplantation.
