ApoB-100–Related Peptide Vaccine Protects Against Angiotensin II–Induced Aortic Aneurysm Formation and Rupture

Honjo, Tomoyuki; Chyu, Kuang‐Yuh; Dimayuga, Paul C.; Yano, Juliana; Lio, Wai Man; Trinidad, Portia; Zhao, Xiaoning; Zhou, Jianchang; Chen, Shuang; Cercek, Bojan; Arditi, Moshe; Shah, Prediman K.

doi:10.1016/j.jacc.2014.11.054

Cited by 22 publications

(18 citation statements)

References 31 publications

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“…Our study shows that (1) CD8+ T‐cell activation and memory generation occurs in response to atherogenic diet feeding in apoE −/− mice; (2) A small fraction of these activated CD8+ T cells in apoE −/− mice are antigen‐specific that are reactive to the p210 peptide fragment of apoB‐100, supporting the notion that p210 is a self‐antigen; and (3) Immunization of apoE −/− mice with the p210 peptide fragment altered the immune‐dominant epitopes, concurrent with reduced atherosclerosis. This has significant implications in our efforts to characterize immune functions in atherosclerosis and develop potential apoB‐100 peptide‐based vaccine candidates …”

Section: Discussionmentioning

confidence: 99%

“…Male apoE −/− mice fed normal chow were subcutaneously immunized with p210/cBSA/Alum in the dorsal area at 7 weeks of age, followed by a booster at 10 and 12 weeks of age . Each injection contained 100 μg of p210 peptide conjugated to the carrier cBSA (cationized BSA) according to the manufacturer's protocol (ThermoFisher Scientific) and with Alum (containing 1.38 mg aluminum per administration, ThermoFisher Scientific) as adjuvant.…”

Section: Methodsmentioning

confidence: 99%

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Identification of apoB‐100 Peptide‐Specific CD8+ T Cells in Atherosclerosis

Dimayuga

Zhao

Yano

et al. 2017

JAHA

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BackgroundT cells are found in atherosclerotic plaques, with evidence supporting a potential role for CD8+ T cells in atherogenesis. Prior studies provide evidence of low‐density lipoprotein and apoB‐100 reactive T cells, yet specific epitopes relevant to the disease remain to be defined. The current study was undertaken to identify and characterize endogenous, antigen‐specific CD8+ T cells in atherosclerosis.Methods and ResultsA peptide fragment of apoB‐100 that tested positive for binding to the mouse MHC‐I allele H2Kb was used to generate a fluorescent‐labeled H2Kb pentamer and tested in apoE−/− mice. H2Kb pentamer(+)CD8+ T cells were higher in apoE−/− mice fed an atherogenic diet compared with those fed a normal chow. H2Kb pentamer (+)CD8+ T cells in atherogenic diet–fed mice had significantly increased effector memory phenotype with a shift in Vβ profile. H2Kb pentamer blocked lytic activity of CD8+ T cells from atherogenic diet–fed mice. Immunization of age‐matched apoE−/− mice with the apoB‐100 peptide altered the immune‐dominant epitope of CD8+ T cells and reduced atherosclerosis.ConclusionsOur study provides evidence of a self‐reactive, antigen‐specific CD8+ T‐cell population in apoE−/− mice. Immune modulation using the peptide antigen reduced atherosclerosis in apoE−/− mice.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Identification of apoB‐100 Peptide‐Specific CD8+ T Cells in Atherosclerosis

Dimayuga

Zhao

Yano

et al. 2017

JAHA

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“…Recently, PD‐1 and TIM‐3 have been implicated in regulating CD8+ T cell function in atherosclerosis in humans, by affecting TNF‐α and IFN‐γ production (Qiu et al, ). In contrast to these pro‐atherogenic effects of CD8+ T cells, CD8 T cell cytotoxicity increased by ApoB‐100 targeted immunisation modulates the functions of dendritic cells, monocytes and macrophages (Chyu et al, ; Honjo et al, ; Cochain and Zernecke, ), suggesting a possible favourable effect in atherosclerosis, but their relative relevance in vivo is uncertain.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges

Kyaw

Peter

et al. 2017

British J Pharmacology

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Cytotoxic lymphocytes encompass natural killer lymphocytes (cells) and cytotoxic T cells that include CD8+ T cells, natural killer (NK) T cells, γ, δ (γδ)-T cells and human CD4 + CD28À T cells.These cells play critical roles in inflammatory diseases and in controlling cancers and infections. Cytotoxic lymphocytes can be activated via a number of mechanisms that may involve dendritic cells, macrophages, cytokines or surface proteins on stressed cells. Upon activation, they secrete pro-inflammatory cytokines as well as anti-inflammatory cytokines, chemokines and cytotoxins to promote inflammation and the development of atherosclerotic lesions including vulnerable lesions, which are strongly implicated in myocardial infarctions and strokes. Here, we review the mechanisms that activate and regulate cytotoxic lymphocyte activity, including activating and inhibitory receptors, cytokines, chemokine receptors-chemokine systems utilized to home to inflamed lesions and cytotoxins and cytokines through which they affect other cells within lesions. We also examine their roles in human and mouse models of atherosclerosis and the mechanisms by which they exert their pathogenic effects. Finally, we discuss strategies for therapeutically targeting these cells to prevent the development of atherosclerotic lesions and vulnerable plaques and the challenge of developing highly targeted therapies that only minimally affect the body's immune system, avoiding the complications, such as increased susceptibility to infections, which are currently associated with many immunotherapies for autoimmune diseases. LINKED ARTICLESThis article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/ 10.1111/bcp.v82.4/issuetoc Abbreviation TCR, T cell receptor; MHC, major histocompablity complex; NKG2D, natural-killer group 2, member D; TRAIL, TNF-related apoptosis-inducing ligand; DNAM-1, DNAX accessory molecule-1; Clec9A, C-type lectin domain family 9 member A

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“…Additionally, a peptide derived from human ApoB-100, p210 (ApoB-100 3136–3155 ) was found to bind to IgM and IgG antibodies from human sera 177 . Vaccination with p210 protected mice from atherosclerosis and aortic aneurysm formation 178, 179 . While the efficacy of immunization strategies against different antigens, such as naïve and modified LDL, ApoB-100 or peptides derived from ApoB-100, has been demonstrated in various species and animal models 110 (table 1), the functional properties of antigen recognition and its exact cellular and functional consequences, as required for the ultimate goal of defining a clinical vaccination strategy in humans, remain enigmatic.…”

Section: A Vaccine Against Atherosclerosismentioning

confidence: 99%

“…For instance, it has been shown that vaccination against some peptides, e.g. p210, conferred atheroprotection in mice, an effect linked to T cell responses in some studies 142, 143, 179–181 . However, the tested peptide does not bind to mouse MHC-II (I-A b ), thus excluding a CD4 + T cell restricted mode of action.…”

Section: A Vaccine Against Atherosclerosismentioning

confidence: 99%