Suppression of early atherosclerosis in LDL-receptor deficient mice by oral tolerance with $beta;2-glycoprotein I

George, Jacob; Yacov, Niva; Breitbart, Eyal; Bangio, Livnat; Shaish, Aviv; Gilburd, Boris; Shoenfeld, Yehuda; Harats, Dror

doi:10.1016/j.cardiores.2004.01.028

Cited by 71 publications

(30 citation statements)

References 29 publications

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“…In preclinical models, nasal or oral administration of HSP65 reduced atherosclerosis in Ldlr -/-mice (146,147). Similar findings are reported for nasal administration of oxLDL (148,149) or β2-glycoprotein I (150). Another approach is to deliver the relevant antigens via tolerogenic DCs that have suppressed costimulatory functions but maintain antigen-presenting functions.…”

Section: Regulation Of Proatherogenic Adaptive Immune Responsessupporting

confidence: 58%

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Lichtman¹,

Binder²,

Tsimikas³

et al. 2013

J. Clin. Invest.

172

171

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Many remarkable advances have improved our understanding of the cellular and molecular events in the pathogenesis of atherosclerosis. Chief among these is the accumulating knowledge of how the immune system contributes to all phases of atherogenesis, including well-known inflammatory reactions consequent to intimal trapping and oxidation of LDL. Advances in our understanding of the innate and adaptive responses to these events have helped to clarify the role of inflammation in atherogenesis and suggested new diagnostic modalities and novel therapeutic targets. Here we focus on recent advances in understanding how adaptive immunity affects atherogenesis.

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Section: Regulation Of Proatherogenic Adaptive Immune Responsessupporting

confidence: 58%

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Lichtman¹,

Binder²,

Tsimikas³

et al. 2013

J. Clin. Invest.

172

171

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“…In previous studies, intranasal inoculation with HSP65 or an apolipoprotein B-100 peptide or oral feeding with ␤2-glycoprotin I resulted in some degree of amelioration of atherosclerosis that correlated with indications of increased IL-10 expression (9,(12)(13)(14). However, none of these studies demonstrated a causative role for IL-10 in the induction of immune tolerance.…”

Section: Discussionmentioning

confidence: 94%

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

Park¹,

Huang²,

Jankowska‐Gan

et al. 2016

Journal of Biological Chemistry

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We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe ؊/؊ mouse model. We have also shown sensitization of Apoe ؊/؊ mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr ؊/؊ mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the ␣1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr ؊/؊ mice, suggesting future courses of experimentation for the characterization of such epitopes.Atherosclerosis underlies coronary artery disease (CAD) 3 and stroke, major global causes of death (1), and is a chronic inflammatory disease that is modulated by both innate and adaptive immune pathways. It is increasingly accepted that autoimmunity constitutes some portion of the pathological processes underlying atherosclerosis, with oxidized LDLs, native lipoproteins, and heat shock proteins identified as autoantigens involved in atherogenesis (1-8). Recognition of the autoimmune aspects of atherosclerosis has suggested the possibility of employing immunomodulatory approaches to ameliorate symptoms. That such an approach is feasible has been borne out in studies in which blockage of T cells reactive to native lipoprotein ApoB100 (4) or mucosal or subcutaneous immunization with HSP65 (9, 10), oxidized LDL (11), native ␤2-glycoprotein I (12), or apolipoprotein B-100 peptide (13, 14) have been shown to be atheroprotective. Collagens can compose up to 60% of the total protein content in atherosclerotic plaques (15) and stimulate the growth and inflammation of atheromas (16). We have shown previously that interleukin 17-dependent autoimmunity to type V collagen col(V)) is a consistent feature of atherosclerosis in advanced CAD in humans and in Apoe Ϫ/Ϫ mice on a high-fat diet (17). Moreover, the same study provided evidence of a causative role for col(V) autoimmunity in the pathogenesis of atherosclerosis because sensitization of Apoe Ϫ/Ϫ mice on normal chow to col(V) has been shown to markedly increase the ...

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“…Targets for tolerance induction have included ox-LDL (with decreased atherosclerosis after an oral tolerance protocol), malondialdehyde treated LDL (no effect) (1859), HSP60 (reduced atherosclerosis) (1860), HSP65 (reduced atherosclerosis) (1142), and ␤2-glycoprotein I (reduced atherosclerosis) (606) in addition to the APOB-100 studies above. In addition to these "self" targets which had been hypothesized to be involved in the atherogenic sensitization of Th1 cells, mucosal tolerance protocols directed against pneumococcus, or even measles virus envelope resulted in reduced atherosclerosis, suggesting there may be multiple, unsuspected potential antigenic targets as well the possibility of nonspecific effects from simply increasing Treg numbers with increased secretion of IL-10 (30, 241).…”

Section: Evidence For the Atheroprotective Effects Of Tregmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Suppression of early atherosclerosis in LDL-receptor deficient mice by oral tolerance with $beta;2-glycoprotein I

Abstract: Thus, oral administration of beta 2GPI is an effective means of suppressing atherogenesis in mice and should further be investigated.

Cited by 71 publications

References 29 publications

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

Molecular Biology of Atherosclerosis

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