title: Oxidized low-density lipoprotein-induced apoptotic dendritic cells as a novel therapy for atherosclerosis.
abstract: Modulation of immune responses may form a powerful approach to treat atherosclerosis. It was shown that clearance of apoptotic cells results in tolerance induction to cleared Ags by dendritic cells (DCs); however, this seems impaired in atherosclerosis because Ag-specific tolerance is lacking. This could result, in part, from decreased emigration of DCs from atherosclerotic lesions because of the high-cholesterol environment. Nonetheless, local induction of anti-inflammatory responses by apoptotic cell clearance seems to dampen atherosclerosis, because inhibition of apoptotic cell clearance worsens atherosclerosis. In this study, we assessed whether i.v. administration of oxLDL-induced apoptotic DCs (apop(ox)-DCs) and, as a control, unpulsed apoptotic DCs could modulate atherosclerosis by inducing tolerance. Adoptive transfer of apop(ox)-DCs into low-density lipoprotein receptor knockout mice either before or during feeding of a Western-type diet resulted in increased numbers of CD103(+) tolerogenic splenic DCs, with a concomitant increase in regulatory T cells. Interestingly, both types of apoptotic DCs induced an immediate 40% decrease in Ly-6C(hi) monocyte numbers and a 50% decrease in circulating CCL2 levels, but only apop(ox)-DC treatment resulted in long-term effects on monocytes and CCL2 levels. Although initial lesion development was reduced by 40% in both treatment groups, only apop(ox)-DC treatment prevented lesion progression by 28%. Moreover, progressed lesions of apop(ox)-DC-treated mice showed a robust 45% increase in collagen content, indicating an enhanced stability of lesions. Our findings clearly show that apoptotic DC treatment significantly decreases lesion development, but only apop(ox)-DCs can positively modulate lesion progression and stability. These findings may translate into a safe treatment for patients with established cardiovascular diseases using patient-derived apop(ox)-DCs.
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
authors: Vanessa
authors: V
authors: Frodermann
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
authors: Gijs H M
authors: GH
authors: van Puijvelde
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
authors: Laura
authors: L
authors: Wierts
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
authors: H Maxime
authors: HM
authors: Lagraauw
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
authors: Amanda C
authors: AC
authors: Foks
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
authors: Peter J
authors: PJ
authors: van Santbrink
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
authors: Ilze
authors: I
authors: Bot
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands j.kuiper@lacdr.leidenuniv.nl.
authors: Johan
authors: J
authors: Kuiper
authors: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
authors: Saskia C A
authors: SC
authors: de Jager
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D003094:Collagen / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D005786:Gene Expression Regulation; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D061251:Primary Cell Culture; D011973:Receptors, LDL; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D000950:Antigens, Ly; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008077:Lipoproteins, LDL; C494192:Ly-6C antigen, mouse; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D003094:Collagen