Numerous lines of evidence indicates that the adaptive immune response is involved in the development of atherosclerosis. Significantly, several studies have shown that the vaccination of atherosclerosis prone animals with autologous oxidized low density lipoprotein (LDL) can reduce the incidence of atherosclerosis. This opens up the exciting possibility of therapeutic intervention for cardiovascular disease. The long-term aims of our research are to define pro- and anti-atherogenic immune responses and to develop specific vaccines that could be used prophylactically in high risk individuals or therapeutically in aged individuals. The current experimental systems in which atherosclerosis prone mice are immunized with mouse LDL in the presence of Complete Freunds Adjuvants are limited in their ability to provide this information. Mouse LDL is difficult to obtain in sufficiently large amounts for thorough immune dissection studies. Furthermore such findings have limited applications for human therapy in which immunization with human LDL is necessary and CFA can not be used as a adjuvant. Genetically altered mice expressing human ApoB, the main protein component of LDL are available. These have been bred onto an atherosclerosis prone strain, the LDLR-/- mouse, to generate hybrids which rapidly develop atherosclerosis and for which human ApoB is a self protein. In this proposal we wish to determine the feasibility of using huApoBxLDLR-/- mice for both immune dissection and vaccine development. We hypothesize that immunization of these mice with human MDA-LDL in the presence of CFA should reduce atherosclerosis in the same way as immunization of LDLR-/- with mouse MDA/LDL.
Our first aim i s to test this hypothesis. If proven correct, we plan as our second aim to determine whether immunization with human MDA-LDL in the presence of alternative adjuvants, which have the potential for human user, can also reduce atherosclerosis Our final aim is to dissect the phenotype and antigen specificity of the cellular and humoral autoimmune response to human LDL. The propose experiments will allow us to determine the feasibility of this system. By correlating the effect on atherosclerosis with the type of immune response induced, we can hypothesize which components of the immune response are responsible for mediating the anti or pro-atherogenic effects of vaccination. Our future studies will test these hypotheses and use this information as the basis for the logical development of future vaccines.
