HMG-CoA Reductase Inhibitors as Immunomodulators: Potential Use in Transplant Rejection

The benefit of HMG-CoA reductase inhibitors (statins) to the cardiovascular system is now well established and these drugs are being used extensively to treat hypercholesterolaemia clinically. However, as clinical outcomes become available it appears that statins are proving more beneficial than expected and thus it is being proposed that the actions of statins go beyond their ability to lower serum cholesterol levels. The report that statins can interact directly with lymphocyte function-associated antigen (LFA)-1 and prevent it engaging with the intracellular adhesion molecule (ICAM)-1 receptor on T cells is a novel mechanism of statin action and provides convincing evidence that these compounds can regulate biological systems other than by the cholesterol synthesis pathway. Immunosuppression to prevent organ transplant rejection is one application for which statins are currently being assessed. The clinical evidence is conflicting and does not convincingly reflect whether statins are beneficial as immunomodulators. However, in vivo studies investigating the cellular actions of statins have identified two mechanisms by which statins can potentially modulate an in vivo immune response. Firstly, statins regulate inducible class II major histocompatibility complex (MHC) expression on macrophages and endothelial cells. Secondly, statins can inhibit LFA-1 adhesion to ICAM-1 and thus regulate T cell activation. These findings suggest that statins have the potential to regulate an immune response in vivo and that more investigation is essential in order to explain the opposing clinical data