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Cardiovascular Research Advance Access first published online on October 9, 2009
This version [Corrected Proof] published online on November 12, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp338
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Vaccination using oxidized low-density lipoprotein-pulsed dendritic cells reduces atherosclerosis in LDL receptor-deficient mice

Kim L.L. Habets1,*,{dagger}, Gijs H.M. van Puijvelde1,{dagger}, Leonie M. van Duivenvoorde2, Eva J.A. van Wanrooij1, Paula de Vos1, Jan-Willem Cohen Tervaert3, Theo J.C. van Berkel1, Rene E.M. Toes2 and Johan Kuiper1

1 Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands
2 Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
3 Department of Clinical and Experimental Immunology, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands

* Corresponding author. Tel: +31 71 5276051, Fax: +31 71 5276032, Email: k.habets{at}lacdr.leidenuniv.nl

Aims: Modification of lipoproteins plays an important role in the development of atherosclerosis. Oxidatively modified low-density lipoprotein (oxLDL) has a number of pro-inflammatory effects, whereas immunization with various forms of oxLDL is able to reduce atherosclerosis. The uptake of modified LDL by dendritic cells (DCs) and the presentation of epitopes thereof may form an important step in the immunomodulatory effects of LDL. In this study, we transferred oxLDL-pulsed mature DCs (mDCs) to LDL receptor-null (LDLr–/–) mice and examined the effects on atherosclerosis.

Methods and results: Bone marrow-derived DCs were cultured for 10 days in the presence of granulocyte-macrophage colony-stimulating factor. Immature DCs were matured by lipopolysaccharide and pulsed with copper-oxidized LDL. These mDCs were transferred three times to LDLr–/– mice before the induction of atherosclerosis by Western-type diet feeding. The transfer of oxLDL-pulsed mDCs resulted in an 87% reduction in carotid artery lesion size (P < 0.001) with a concurrent increase in plaque stability, whereas treatment using mDCs pulsed with the atherosclerosis-irrelevant antigen, ovalbumin, did not influence lesion size or stability. Furthermore, the vaccination procedure resulted in the induction of oxLDL-specific T cells with a reduced Th1 profile and an increase in oxLDL-specific IgG levels, which contributed to a reduction in foam cell formation.

Conclusion: These data indicate that vaccination with oxLDL-pulsed mDCs provides a novel and powerful strategy for the immunomodulation of atherosclerosis.

KEYWORDS Atherosclerosis; Immunotherapy; Dendritic cells; Antigen-presenting cells

Time for primary review: 23 days

{dagger} These authors have contributed equally to this study.


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