2017 Cardiovascular Research Day Abstract Book

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Anti-ApoA-I antibodies induced using an epitope-specific immunostimulatory liposomal
formulation exacerbate atherosclerosis in dyslipidemic mice
David Henson 1 • Robert Kline IV, MS 1 • Vincent Venditto, PhD 1
1Pharmaceutical Sciences, University of Kentucky
Graduate Student
Autoantibodies targeting apolipoprotein A-I (ApoA-I) have been identified in patients with chronic
inflammatory diseases including rheumatoid arthritis, lupus and obesity and correlate with
cardiovascular disease progression. Although correlated, the exact role of these antibodies has not
been fully elucidated. Induction of antibodies in mice through immunization, rather than passive
administration of antibodies derived from other species, offers a unique opportunity to explore the
impact of anti-ApoA-I antibodies in the context of atherosclerosis. Furthermore, the ability to
modulate epitope-specific immune responses offers a strategy to study the impact of antibody
responses toward specific domains within the full protein. To achieve these objectives, we prepared
an immunostimulatory liposomal formulation containing peptides derived from the LCAT domain
of ApoA-I. We first determined that mice immunized with the complete formulation induce robust
antibody responses toward the epitope, as well as the full-length protein. These data suggest that
antibody responses toward ApoA-I are either not controlled by immunological tolerance
mechanisms or our formulation was capable of breaking tolerance. Although successful at inducing
a robust immune response, the antibodies alone failed to induce atherosclerosis in wild-type mice.
We then studied the role of antibodies in the context of dyslipidemia utilizing the AAV-PCSK9 gainof-function
mutant and western diet. After establishment of dyslipidemia, mice were immunized
with the immunostimulatory liposomal formulations. Once again, mice immunized with the
complete formulation achieved robust antibody responses, which persisted for 150 days.
Furthermore, mice immunized with the complete formulation had a statistically significant
elevation in atherosclerosis over control mice. These data highlight our ability to modulate the anti-
ApoA-I antibody response using epitope-specific liposomal formulations and provides a platform to
study the role of these antibodies in an immunologically intact system.
This work was supported by a pilot grant through the Center for Research in Obesity &
Cardiovascular Disease COBRE, NIH (P20GM103527) and a Scientist Development Grant from the
American Heart Association (17SDG32670001). DH is supported by a UK Center for Clinical and
Translational Science training grant from the National Center for Advancing Translational Sciences,
NIH (TL1TR001996).
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