Recombinant Antibodies to an Oxidized Low-Density Lipoprotein Epitope Induce Rapid Regression of Atherosclerosis in Apobec-1−/−/Low-Density Lipoprotein Receptor−/−Mice

Schiopu, Alexandru; Frendéus, Björn; Jansson, Bo; Söderberg, Ingrid; Ljungcrantz, Irena; Araya, Zufan; Shah, Prediman K.; Carlsson, Roland; Nilsson, Jan; Fredrikson, Gunilla Nordin

doi:10.1016/j.jacc.2007.07.081

Cited by 155 publications

(106 citation statements)

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“…26 A human recombinant IgG specific for the MDA-modified apo B peptide p45 inhibits the development of atherosclerosis in hypercholesterolemic mice and induces regression of lesions when combined with cholesterol lowering. 27,28 Studies performed on cultured cells have shown that immune complexes of this antibody and oxidized LDL inhibit cytokine release from monocytes through interaction with the inhibitory FcγIIb receptor. 29 Treatment of obese, hypercholesterolemic non-human primates with this antibody resulted in lower plasma levels of pro-inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

Asciutto¹,

Dias²,

Edsfeldt³

et al. 2015

Atherosclerosis

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Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy.Asciutto, Giuseppe; Dias, Nuno; Edsfeldt, Andreas; Alm, Ragnar; Nordin Fredrikson, Gunilla; Goncalves, Isabel; Nilsson, Jan Link to publication Citation for published version (APA): Asciutto, G., Dias, N., Edsfeldt, A., Alm, R., Nordin Fredrikson, G., Goncalves, I., & Nilsson, J. (2015). Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy. Atherosclerosis, 239(2), 289-294. DOI: 10.1016289-294. DOI: 10. /j.atherosclerosis.2015 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Methods: Native (nat) and malondialdehyde (MDA)-modified apoB p210 autoantibodies (IgM-p210nat, IgG-p210nat, IgM-p210MDA and IgG-p210MDA) were analyzed by ELISA from plasma samples of 351 patients at the time they underwent CEA. The incidence of postoperative CV events was assessed using national registers.Results: A total of 52 non-fatal and 15 fatal CV events were registered during the follow-up period (35.1 ± 16.7 months). Patients who suffered from a fatal CV event had significantly lower plasma levels of IgG-p210nat and IgG-p210MDA. Kaplan-Meier curves of event-free survival showed increased CV mortality in patients with levels of IgG-p210nat and IgGp210MDA below the median (Log Rank 7.813, p .005 and 9.105, p .003 respectively). The association between low levels of p210 IgG and fatal post-operative CV events remained significant when adjusting for age, sex, total cholesterol, HDL cholesterol, smoking habits and hypertension in a Cox Proportional Hazard model (hazard ratios (HR) IgG-p210nat below median: HR 6.7 (95% C.I. 1.5-30.6, p .013) and IgG-p210MDA below median: HR 7.8 (95% C.I. 1.7-35.5, p .008).Conclusions: The present findings support the notion that autoantibodies against LDL antigens are involved in the atherosclerotic disease process and suggest that CEA patients with low levels of IgG-p210nat and IgG-p210MDA have an increased risk of post-operative CV death.

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Section: Discussionmentioning

confidence: 99%

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

Asciutto¹,

Dias²,

Edsfeldt³

et al. 2015

Atherosclerosis

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“…Oxidized LDL cholesterol (oxLDL) is generally accepted as an Ag that activates the adaptive immune system after recognition by APCs such as macrophages and dendritic cells (DCs) (8). Although, Ab treatment against a specific epitope of oxLDL, ApoB100, has been shown to induce regression of atherosclerosis, the effect of modulating immune responses on regression has not been explored (9). T cells are important in the process of atherosclerosis and affect all stages of the disease process.…”

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confidence: 99%

Interruption of the OX40–OX40 Ligand Pathway in LDL Receptor–Deficient Mice Causes Regression of Atherosclerosis

Foks

Puijvelde

Bot

et al. 2013

The Journal of Immunology

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Patients suffering from cardiovascular disease have well-established atherosclerotic lesions, rendering lesion regression of therapeutic interest. The OX40 (TNFRSF4)–OX40 ligand (OX40L; TNFSF4) pathway is important for the proliferation and survival of T cells, stimulates B cells, and is associated with cardiovascular disease. We hypothesized that interference with the OX40–OX40L pathway, in combination with decreases in cholesterol, may induce regression of atherosclerosis. LDLr−/− mice were fed a Western-type diet for 10 wk, after which they received chow diet and were treated with anti-OX40L or PBS for 10 wk. A significant regression of lesions was observed in the aorta and aortic arch of anti-OX40L–treated mice compared with control mice. Interference of the OX40–OX40L pathway reduced Th2 responses, as shown by decreases in GATA-3 and IL-4 levels. Also, IgE levels were decreased, as demonstrated by reduced mast cell presence and activation. Notably, IL-5 production by T and B1 cells was increased, thus enhancing atheroprotective oxidized low-density lipoprotein–specific IgM production. The increase in IL-5 production and IgM was mediated by IL-33 production by APCs upon OX40L blockade. We conclude that interruption of the OX40–OX40L signaling pathway, combined with decreases in dietary cholesterol, induces the regression of atherosclerosis through induction of IL-5–producing T cells and oxidized low-density lipoprotein–specific IgM and reductions in Th2 and mast cells.

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“…However, we have recently presented an independent association between high levels of IgG antibodies to apoB-100 peptides and a low degree of carotid stenosis ), lower risk of myocardial infarction (Sjogren et al 2008), and a lower risk for progression of coronary disease in diabetic patients ). The atheoprotective effect of IgG has also been shown in experimental studies using human IgG1 specific for a malondialdehyde-modified apoB-100 peptide (Schiopu et al 2004;Schiopu et al 2007). In accordance, we found in the present study increased levels of Th2-induced apoB/IgG1 immune complexes in the circulation of cBSA immunized mice, indicating a capture of oxidized LDL antigens at the injection site and a subsequent presentation by APCs, resulting in atheroprotection.…”

Section: Discussionmentioning

confidence: 82%

Immunization with cationized BSA inhibits progression of disease in ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis

et al. 2011

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Recombinant Antibodies to an Oxidized Low-Density Lipoprotein Epitope Induce Rapid Regression of Atherosclerosis in Apobec-1−/−/Low-Density Lipoprotein Receptor−/−Mice

Cited by 155 publications

References 15 publications

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy

Interruption of the OX40–OX40 Ligand Pathway in LDL Receptor–Deficient Mice Causes Regression of Atherosclerosis

Immunization with cationized BSA inhibits progression of disease in ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis

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