Inducing Autoreactivity to Control Cholesterol Metabolism
Cholesterol ester transfer protein (CETP) mediates the transfer of neutral lipids between HDL and the lower density lipoproteins VLDL and LDL. Elevated serum HDL, which is a negative risk factor for atherosclerosis is associated with lower levels of CETP activity. CETP-deficient humans have been identified and described as generally free of atherosclerosis and prone to longevity. The objective of this sutdy is to determine whether anti-CETP autoantibodies could be induced in experimental animals by vaccination as a novel approach to the reduction of CETP activity and thereby alter the cell helper epitope of tetanus toxoid, a B cell epitope derived from the C-terminus of CETP, and an N-terminal cysteine was synthesized and used to immunize transgenic mice expressing human CETP (CETP mice) and New Zealand white rabbits after primary vaccination and two booster injections. The anti CETP autoantibodies were directed against the neutral lipid binding site since they competed with monoclonal antibody TP2, known to inhibit CETP activity, for binding to recombinant human CETP. In a small study using a hyper-cholesteremia rabbit model, the vaccinated group has significantly reduced aortic atherosclerotic lesions compared to non-vaccinated controls (p<.01).