Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques

Li, Shijie; Kievit, Paul; Robertson, Anna Karin; Kolumam, Ganesh; Li, Xiumin; Wachenfeldt, Karin von; Valfridsson, Christine; Bullens, Sherry; Messaoudi, Ilhem; Bader, Lindsay; Cowan, Kyra J.; Kamath, Amrita V.; Bruggen, Nicholas van; Bunting, Stuart; Frendéus, Björn; Grove, Kevin L.

doi:10.1016/j.molmet.2013.06.001

Cited by 39 publications

(35 citation statements)

References 85 publications

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“…Exposure of human PBMCs to anti-MDA-p45 IgG reduced expression of TNF-α and enhanced the secretion of the anti-inflammatory cytokine IL-10. These observations are in line with previous studies by Li et al, 8 demonstrating that anti-MDA-p45 IgG inhibits the release of proinflammatory cytokines. The in vivo relevance of this finding was supported by the observation that treatment of non-human primates with anti-MDA-p45 IgG reduced circulating levels of TNF-α and IL-1β.…”

Section: Discussionsupporting

confidence: 93%

“…7 The mechanism through which anti-p45 IgG inhibits atherosclerosis involves inhibition of inflammation by binding of immune complexes to the inhibitory FcγRII. 8 In accordance, administration of this antibody (MLDL1278a) to diet-induced obese non-human primates resulted in a significant decrease in circulating proinflammatory cytokines. 8 However, treatment with MLDL1278a failed to decrease carotid plaque inflammation, as assessed by positron emission tomography with 18-F-fluorodeoxyglucose, in the randomized, double-blind Goal of Oxidized LDL and Activated Macrophage Inhibition by Exposure to a Recombinant Antibody (GLACIER) study in subjects with stable CVD.…”

mentioning

confidence: 83%

“…8 In accordance, administration of this antibody (MLDL1278a) to diet-induced obese non-human primates resulted in a significant decrease in circulating proinflammatory cytokines. 8 However, treatment with MLDL1278a failed to decrease carotid plaque inflammation, as assessed by positron emission tomography with 18-F-fluorodeoxyglucose, in the randomized, double-blind Goal of Oxidized LDL and Activated Macrophage Inhibition by Exposure to a Recombinant Antibody (GLACIER) study in subjects with stable CVD. 9 The reasons for this remain to be fully understood but may reflect an incomplete understanding of the role of antibodies targeting MDA-modified apo B-100 in clinically manifest CVD.…”

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confidence: 83%

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Apolipoprotein B-100 Antibody Interaction With Atherosclerotic Plaque Inflammation and Repair Processes

Asciutto

Wigren

Fredrikson

et al. 2016

Stroke

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Background and Purpose-Treatment with IgG against the malondialdehyde (MDA)-modified apolipoprotein B-100 epitope p45 reduces atherosclerosis in experimental models. This study investigated the association between p45 IgG autoantibodies and plaque inflammation in subjects with advanced cardiovascular disease. Methods-Native and MDA-p45 IgG levels were analyzed by ELISA in 349 carotid endarterectomy patients. In a subcohort of 195 subjects, endarterectomy samples were analyzed by immunohistochemistry and ELISA to determine plaque constituents and inflammation. Peripheral blood mononuclear cells were isolated from healthy donors. Results-Patients with preoperative events of neurological ischemia had lower levels of native p45 IgG. Low levels of MDA-p45 IgG were associated with increased risk of postoperative cardiovascular death during a mean follow-up of 54 months. High plasma levels of native p45 IgG were associated with increased plaque content of collagen and smooth muscle cell growth factors, as well as with lower levels of proinflammatory cytokines. Exposure of peripheral blood mononuclear cells from healthy donors to recombinant MDA-p45 IgG in presence of oxidized low-density lipoprotein reduced the expression of tumor necrosis factor-α and stimulated release of smooth muscle cell growth factors. Conclusions-This study confirms previous experimental findings of anti-inflammatory properties of apolipoprotein B-100 p45 antibodies and provides the first clinical evidence of associations between p45 IgG autoantibody levels and atherosclerotic plaque inflammation, plaque repair as well as prevalent and incident cardiovascular events in carotid endarterectomy patients. These findings suggest the possibility that treatment with anti-p45 antibodies may have beneficial effects in advanced cardiovascular disease.

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Section: Discussionsupporting

confidence: 93%

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confidence: 83%

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confidence: 83%

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Apolipoprotein B-100 Antibody Interaction With Atherosclerotic Plaque Inflammation and Repair Processes

Asciutto

Wigren

Fredrikson

et al. 2016

Stroke

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“…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. 29 The association between antibodies against oxLDL and CV disease has been extensively studied.…”

Section: Discussionmentioning

confidence: 99%

“…29 Treatment of obese, hypercholesterolemic non-human primates with this antibody resulted in lower plasma levels of pro-inflammatory cytokines. 29 The association between antibodies against oxLDL and CV disease has been extensively studied. Results from studies analyzing antibodies against the intact oxLDL particle have provided inconclusive and partly contradictive results possible due to difficulties in obtained standardized antigens in the detection assays used.…”

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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Obesity as an immune-modifying factor in cancer immunotherapy

Canter

Beerthuijzen

et al. 2018

Journal of Leukocyte Biology

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Immunotherapy has achieved breakthrough status in many advanced stage malignancies and is rapidly becoming the fourth arm of cancer treatment. Although cancer immunotherapy has generated significant excitement because of the potential for complete and sometimes durable responses, there is also the potential for severe and occasionally life-threatening toxicities, including cytokine release syndrome and severe autoimmunity. A large body of work also points to a "metainflammatory" state in obesity associated with impairment of immune responses. Because immune checkpoint blockade (and other cancer immunotherapies) have altered the landscape of immunotherapy in cancer, it is important to understand how immune responses are shaped by obesity and how obesity may modify both immunotherapy responses and potential toxicities.

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Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques

Cited by 39 publications

References 85 publications

Apolipoprotein B-100 Antibody Interaction With Atherosclerotic Plaque Inflammation and Repair Processes

Apolipoprotein B-100 Antibody Interaction With Atherosclerotic Plaque Inflammation and Repair Processes

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

Obesity as an immune-modifying factor in cancer immunotherapy

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