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


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.


CONCLUSIONS
These data indicate that vaccination with oxLDL-pulsed mDCs provides a novel and powerful strategy for the immunomodulation of atherosclerosis.
Habets
Kim L L
KL
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands. k.habets@lacdr.leidenuniv.nl
van Puijvelde
Gijs H M
GH
van Duivenvoorde
Leonie M
LM
van Wanrooij
Eva J A
EJ
de Vos
Paula
P
Tervaert
Jan-Willem Cohen
JW
van Berkel
Theo J C
TJ
Toes
Rene E M
RE
Kuiper
Johan
J
D000818:Animals; D050197:Atherosclerosis / Q000628:therapy*; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D008077:Lipoproteins, LDL / Q000276:immunology* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000172:deficiency*; D014611:Vaccination
D016207:Cytokines; D007074:Immunoglobulin G; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol