ApoB-100 Antigens Reduce Atherosclerosis in Mice
Studies have also found that the transfer of splenocytes could replicate the atheroprotective effect in nonimmunized mice.
Active immunization using vaccines made from selected apolipoprotein B-100 (ApoB-100)-related peptide-based antigens is feasible and effective in reducing atherosclerosis in murine models, according to Prediman K. Shah, MD, Director of the Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.
In a presentation on the concept of an antiatherosclerotic vaccine, Shah also said that passive immunization with high-affinity monoclonal antibody to the P45 epitope of human ApoB-100 induces rapid regression of atherosclerosis in a murine model.
Vaccine development
Shah and colleagues formulated a library of 302 peptides to cover the complete sequence of ApoB-100. Each peptide was 20 amino acids long with a 5-amino-acid overlap, Shah said. IgG and IgM antibodies were identified against 102 such peptide epitopes in pooled human plasma.
Reduction in atherosclerosis
These antigenic peptides were used to immunize ApoE-null mice. One of the peptides, called peptide 2, reduced aortic atherosclerosis and plaque inflammation, and increased collagen content in immunized mice.
Shah said he was also able to confirm in a mouse study that the adoptive transfer of splenocytes from peptide 2-immunized mice could decrease atherosclerosis in recipient ApoE-null mice that had not been immunized (Figure).
“We were able to show that the atheroprotective effects could be passively transferred through splenocytes,” he said.
Another study confirmed that vaccination with specific ApoB-related peptide antigens in mice with high cholesterol reduces plaque buildup.
High-affinity human antibody
A high-affinity human monoclonal antibody against the P45 unit of ApoB-100 was also studied.
A panel of antibodies was selected against malondialdehyde (MDA)-modified, Apo-derived peptide sequences. They were tested for affinity, specificity and in vivo activity and transferred to an IgG format. The human recombinant antibody induced rapid plaque regression in a mouse model.
Early studies
Shah cited an earlier study in which cholesterol-fed rabbits were given homologous LDL.
LDL is involved in the oxidation of phospholipids, the fragmentation of Apo-100, the formulation of covalent aldehyde (MDA and 4-HNE) and amino acid (lysine and histidine) adducts.
The immunized rabbits showed a one third reduction in atherosclerosis compared with the control group, despite hypercholesterolemia.
In another study, LDL receptor-deficient rabbits were immunized with homologous MDA-modified LDL. These rabbits showed a 35% reduction in atherosclerosis compared with the control group.
Shah also cited a 1998 mouse study in which immunization of LDL-R null mice with homologous native or MDA-LDL reduced atherosclerosis. Another study found that immunization of ApoE-null mice with homologous MDA-LDL reduced atherosclerosis, Shah said.