{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T07:05:38Z","timestamp":1761807938834,"version":"3.38.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2015,3,1]],"date-time":"2015-03-01T00:00:00Z","timestamp":1425168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 (apopox-DCs) and, as a control, unpulsed apoptotic DCs could modulate atherosclerosis by inducing tolerance. Adoptive transfer of apopox-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-6Chi monocyte numbers and a 50% decrease in circulating CCL2 levels, but only apopox-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 apopox-DC treatment prevented lesion progression by 28%. Moreover, progressed lesions of apopox-DC\u2013treated 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 apopox-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 apopox-DCs.<\/jats:p>","DOI":"10.4049\/jimmunol.1401843","type":"journal-article","created":{"date-parts":[[2015,2,5]],"date-time":"2015-02-05T03:14:06Z","timestamp":1423106046000},"page":"2208-2218","source":"Crossref","is-referenced-by-count":18,"title":["Oxidized Low-Density Lipoprotein\u2013Induced Apoptotic Dendritic Cells as a Novel Therapy for Atherosclerosis"],"prefix":"10.1093","volume":"194","author":[{"given":"Vanessa","family":"Frodermann","sequence":"first","affiliation":[{"name":"Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gijs H M","family":"van Puijvelde","sequence":"additional","affiliation":[{"name":"Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Wierts","sequence":"additional","affiliation":[{"name":"Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H Maxime","family":"Lagraauw","sequence":"additional","affiliation":[{"name":"Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda C","family":"Foks","sequence":"additional","affiliation":[{"name":"Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J","family":"van Santbrink","sequence":"additional","affiliation":[{"name":"Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilze","family":"Bot","sequence":"additional","affiliation":[{"name":"Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johan","family":"Kuiper","sequence":"additional","affiliation":[{"name":"Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saskia C A","family":"de Jager","sequence":"additional","affiliation":[{"name":"Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University , 2333 CC Leiden ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,3,1]]},"reference":[{"key":"2025030705105724700_r1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/ni.2001","article-title":"The immune system in atherosclerosis","volume":"12","author":"Hansson","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030705105724700_r2","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.immuni.2004.09.003","article-title":"Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization","volume":"21","author":"Angeli","year":"2004","journal-title":"Immunity"},{"key":"2025030705105724700_r3","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/S0008-6363(97)00229-0","article-title":"Mapping of vascular dendritic cells in atherosclerotic arteries suggests their involvement in local immune-inflammatory reactions","volume":"37","author":"Bobryshev","year":"1998","journal-title":"Cardiovasc. Res."},{"key":"2025030705105724700_r4","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1038\/15200","article-title":"Natural adjuvants: endogenous activators of dendritic cells","volume":"5","author":"Gallucci","year":"1999","journal-title":"Nat. Med."},{"key":"2025030705105724700_r5","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nri11308","article-title":"Death-defying immunity: do apoptotic cells influence antigen processing and presentation?","volume":"4","author":"Albert","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"2025030705105724700_r6","doi-asserted-by":"crossref","first-page":"3277","DOI":"10.4049\/jimmunol.181.5.3277","article-title":"Apoptotic cells induce immunosuppression through dendritic cells: critical roles of IFN-gamma and nitric oxide","volume":"181","author":"Ren","year":"2008","journal-title":"J. Immunol."},{"key":"2025030705105724700_r7","doi-asserted-by":"crossref","first-page":"4663","DOI":"10.1074\/jbc.M508342200","article-title":"Apoptotic cells, at all stages of the death process, trigger characteristic signaling events that are divergent from and dominant over those triggered by necrotic cells: Implications for the delayed clearance model of autoimmunity","volume":"281","author":"Patel","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2025030705105724700_r8","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/37022","article-title":"Immunosuppressive effects of apoptotic cells","volume":"390","author":"Voll","year":"1997","journal-title":"Nature"},{"key":"2025030705105724700_r9","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1172\/JCI1112","article-title":"Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine\/paracrine mechanisms involving TGF-beta, PGE2, and PAF","volume":"101","author":"Fadok","year":"1998","journal-title":"J. Clin. Invest."},{"key":"2025030705105724700_r10","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.immuni.2004.09.009","article-title":"Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells","volume":"21","author":"Kim","year":"2004","journal-title":"Immunity"},{"key":"2025030705105724700_r11","doi-asserted-by":"crossref","first-page":"7104","DOI":"10.4049\/jimmunol.0900824","article-title":"Apoptotic dendritic cells induce tolerance in mice through suppression of dendritic cell maturation and induction of antigen-specific regulatory T cells","volume":"183","author":"Kushwah","year":"2009","journal-title":"J. Immunol."},{"key":"2025030705105724700_r12","doi-asserted-by":"crossref","first-page":"5403","DOI":"10.1182\/blood-2010-11-320028","article-title":"Marginal zone macrophages suppress innate and adaptive immunity to apoptotic cells in the spleen","volume":"117","author":"McGaha","year":"2011","journal-title":"Blood"},{"key":"2025030705105724700_r13","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1084\/jem.20021215","article-title":"Immune tolerance after delivery of dying cells to dendritic cells in situ","volume":"196","author":"Liu","year":"2002","journal-title":"J. Exp. Med."},{"key":"2025030705105724700_r14","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1084\/jem.188.11.2163","article-title":"Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells","volume":"188","author":"Inaba","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025030705105724700_r15","doi-asserted-by":"crossref","first-page":"5589","DOI":"10.4049\/jimmunol.168.11.5589","article-title":"Uptake of apoptotic antigen-coupled cells by lymphoid dendritic cells and cross-priming of CD8(+) T cells produce active immune unresponsiveness","volume":"168","author":"Ferguson","year":"2002","journal-title":"J. Immunol."},{"key":"2025030705105724700_r16","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1084\/jem.187.10.1555","article-title":"CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigen-presenting cells","volume":"187","author":"Adler","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025030705105724700_r17","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nm1749","article-title":"CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells","volume":"14","author":"Perruche","year":"2008","journal-title":"Nat. Med."},{"key":"2025030705105724700_r18","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1083\/jcb.201004096","article-title":"Clearance of apoptotic cells: implications in health and disease","volume":"189","author":"Elliott","year":"2010","journal-title":"J. Cell Biol."},{"key":"2025030705105724700_r19","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1161\/CIRCULATIONAHA.106.662080","article-title":"Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice","volume":"115","author":"Ait-Oufella","year":"2007","journal-title":"Circulation"},{"key":"2025030705105724700_r20","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1161\/ATVBAHA.108.169078","article-title":"Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis","volume":"28","author":"Ait-Oufella","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2025030705105724700_r21","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1161\/ATVBAHA.108.167197","article-title":"Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-\/- mice","volume":"28","author":"Thorp","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2025030705105724700_r22","doi-asserted-by":"crossref","first-page":"416","DOI":"10.2353\/ajpath.2007.060406","article-title":"Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice","volume":"170","author":"Bhatia","year":"2007","journal-title":"Am. J. Pathol."},{"key":"2025030705105724700_r23","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1161\/ATVBAHA.113.301879","article-title":"T-cell immunoglobulin and mucin domain 3 acts as a negative regulator of atherosclerosis","volume":"33","author":"Foks","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2025030705105724700_r24","doi-asserted-by":"crossref","first-page":"4978","DOI":"10.4049\/jimmunol.180.7.4978","article-title":"Apoptotic cells protect mice against lipopolysaccharide-induced shock","volume":"180","author":"Ren","year":"2008","journal-title":"J. Immunol."},{"key":"2025030705105724700_r25","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.4049\/jimmunol.178.4.2212","article-title":"Peripheral tolerance induction using ethylenecarbodiimide-fixed APCs uses both direct and indirect mechanisms of antigen presentation for prevention of experimental autoimmune encephalomyelitis","volume":"178","author":"Turley","year":"2007","journal-title":"J. Immunol."},{"key":"2025030705105724700_r26","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/0003-2697(75)90488-1","article-title":"Separation of plasma lipoproteins by density-gradient ultracentrifugation","volume":"65","author":"Redgrave","year":"1975","journal-title":"Anal. Biochem."},{"key":"2025030705105724700_r27","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1016\/S0021-9258(18)52241-9","article-title":"Different fate in vivo of oxidatively modified low density lipoprotein and acetylated low density lipoprotein in rats. Recognition by various scavenger receptors on Kupffer and endothelial liver cells","volume":"266","author":"Van Berkel","year":"1991","journal-title":"J. Biol. Chem."},{"key":"2025030705105724700_r28","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1084\/jem.191.3.435","article-title":"A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes","volume":"191","author":"Huang","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025030705105724700_r29","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1161\/CIRCULATIONAHA.110.973222","article-title":"Immunotherapy with tolerogenic apolipoprotein B-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice","volume":"123","author":"Hermansson","year":"2011","journal-title":"Circulation"},{"key":"2025030705105724700_r30","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1084\/jem.20070885","article-title":"The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions","volume":"204","author":"Nahrendorf","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025030705105724700_r31","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.4049\/jimmunol.0803172","article-title":"Ly6C(low) monocytes differentiate into dendritic cells and cross-tolerize T cells through PDL-1","volume":"182","author":"Peng","year":"2009","journal-title":"J. Immunol."},{"key":"2025030705105724700_r32","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1084\/jem.20052119","article-title":"Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery","volume":"203","author":"Tacke","year":"2006","journal-title":"J. Exp. Med."},{"key":"2025030705105724700_r33","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.4049\/jimmunol.180.5.3019","article-title":"Blood monocyte subsets differentially give rise to CD103+ and CD103\u2212 pulmonary dendritic cell populations","volume":"180","author":"Jakubzick","year":"2008","journal-title":"J. Immunol."},{"key":"2025030705105724700_r34","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1172\/JCI29950","article-title":"Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata","volume":"117","author":"Swirski","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2025030705105724700_r35","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1172\/JCI29919","article-title":"Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites","volume":"117","author":"Tsou","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2025030705105724700_r36","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1161\/CIRCULATIONAHA.107.745091","article-title":"Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice","volume":"117","author":"Combadi\u00e8re","year":"2008","journal-title":"Circulation"},{"key":"2025030705105724700_r37","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/29788","article-title":"Decreased lesion formation in CCR2\u2212\/\u2212 mice reveals a role for chemokines in the initiation of atherosclerosis","volume":"394","author":"Boring","year":"1998","journal-title":"Nature"},{"key":"2025030705105724700_r38","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1161\/01.ATV.0000163181.40896.42","article-title":"Repopulation of apolipoprotein E knockout mice with CCR2-deficient bone marrow progenitor cells does not inhibit ongoing atherosclerotic lesion development","volume":"25","author":"Guo","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2025030705105724700_r39","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/nm.3258","article-title":"Local proliferation dominates lesional macrophage accumulation in atherosclerosis","volume":"19","author":"Robbins","year":"2013","journal-title":"Nat. Med."},{"key":"2025030705105724700_r40","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1161\/01.RES.85.8.e17","article-title":"Protective role of interleukin-10 in atherosclerosis","volume":"85","author":"Mallat","year":"1999","journal-title":"Circ. Res."},{"key":"2025030705105724700_r41","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1161\/01.ATV.0000134378.86443.cd","article-title":"Leukocyte-derived interleukin 10 is required for protection against atherosclerosis in low-density lipoprotein receptor knockout mice","volume":"24","author":"Potteaux","year":"2004","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2025030705105724700_r42","doi-asserted-by":"crossref","first-page":"37324","DOI":"10.1074\/jbc.M004732200","article-title":"Large scale gene expression analysis of cholesterol-loaded macrophages","volume":"275","author":"Shiffman","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2025030705105724700_r43","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1016\/j.cub.2006.09.043","article-title":"Apoptotic cells induce a phosphatidylserine-dependent homeostatic response from phagocytes","volume":"16","author":"Kiss","year":"2006","journal-title":"Curr. Biol."},{"key":"2025030705105724700_r44","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.immuni.2009.06.018","article-title":"Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR","volume":"31","author":"A-Gonzalez","year":"2009","journal-title":"Immunity"},{"key":"2025030705105724700_r45","doi-asserted-by":"crossref","first-page":"4288","DOI":"10.1182\/blood-2006-08-043422","article-title":"Liver X receptors regulate dendritic cell phenotype and function through blocked induction of the actin-bundling protein fascin","volume":"109","author":"Geyeregger","year":"2007","journal-title":"Blood"},{"key":"2025030705105724700_r46","doi-asserted-by":"crossref","first-page":"32336","DOI":"10.1074\/jbc.M109.047472","article-title":"The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor","volume":"284","author":"Tang","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2025030705105724700_r47","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1084\/jem.20090847","article-title":"PD-L1 regulates the development, maintenance, and function of induced regulatory T cells","volume":"206","author":"Francisco","year":"2009","journal-title":"J. Exp. Med."},{"key":"2025030705105724700_r48","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1097\/01.tp.0000267785.52567.9c","article-title":"Extracorporeal photochemotherapy is accompanied by increasing levels of circulating CD4+CD25+GITR+Foxp3+CD62L+ functional regulatory T-cells in patients with graft-versus-host disease","volume":"84","author":"Biagi","year":"2007","journal-title":"Transplantation"},{"key":"2025030705105724700_r49","doi-asserted-by":"crossref","first-page":"88ra75","DOI":"10.1126\/scitranslmed.3006168","article-title":"Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis","volume":"5","author":"Lutterotti","year":"2013","journal-title":"Sci. Transl. Med."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/194\/5\/2208\/62232667\/1401843.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/194\/5\/2208\/62232667\/1401843.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T06:32:21Z","timestamp":1741329141000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/194\/5\/2208\/7972835"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,1]]},"references-count":49,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,3,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1401843","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"type":"print","value":"0022-1767"},{"type":"electronic","value":"1550-6606"}],"subject":[],"published-other":{"date-parts":[[2015,3]]},"published":{"date-parts":[[2015,3,1]]}}}