Mycobacterial heat shock protein 65 (mbHSP65)-induced atherosclerosis - Preventive oral tolerization and definition of atheroprotective and atherogenic mbHSP65-peptides

Grundtman, Cecilia; Onestingel, Elisabeth; Jakic, Bojana; Buszko, Maja; Almanzar, Giovanni; Demetz, Egon; Dietrich, Hermann; Wick, Georg

doi:10.1016/j.exger.2017.02.052

Cited by 4 publications

(17 citation statements)

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“…Several groups reported that immunization with HSP65 induces atherosclerotic lesions, [50][51][52] whereas others reported reduced atherosclerotic lesions. [53][54][55] The difference in outcomes could be attributed to the difference in the adjuvant used or the mode of antigen delivery.…”

Section: Other Lipid-related Antigensmentioning

confidence: 99%

Vaccine against arteriosclerosis: an update

Chyu

Dimayuga

Shah

2017

Therapeutic Advances in Vaccines

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Substantial data from experimental and clinical investigation support the role of immune-mediated mechanisms in atherogenesis, with immune systems responding to many endogenous and exogenous antigens that play either proatherogenic or atheroprotective roles. An active immunization strategy against many of these antigens could potentially alter the natural history of atherosclerosis. This review mainly focuses on the important studies on the search for antigens that have been tested in vaccine formulations to reduce atherosclerosis in preclinical models. It will also address the opportunities and challenges associated with potential clinical application of this novel therapeutic paradigm.

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Section: Other Lipid-related Antigensmentioning

confidence: 99%

Vaccine against arteriosclerosis: an update

Chyu

Dimayuga

Shah

2017

Therapeutic Advances in Vaccines

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“…Soluble Mammalian HSP60 Protein The concentration of soluble mammalian HSP60 (smHSP60) was assessed in serum samples from both WT and ApoE -/-mice by a sandwich enzyme-linked immunosorbent assay as described previously [15,23] . Results are indicated as nanograms of smH-SP60/mL and all values greater than the negative control (PBS) were considered as positive.…”

Section: Enzyme-linked Immunosorbent Assaymentioning

confidence: 99%

“…As proof, nasal and oral administration of mbHSP65 have been shown to reduce atherosclerosis in animals [14,[16][17][18][19][20][21] . We have recently shown that atherosclerosis is attenuated, pro-inflammatory cytokines are decreased and anti-inflammatory cytokines increased in the aorta in both wild-type (WT) and ApoE -/-mice after oral mbHSP65 administration [15] . This was accompanied by increased numbers of CD4 + CD25 + FoxP3 + T regulatory cells (Tregs) [15] .…”

Section: Introductionmentioning

confidence: 99%

“…We have recently shown that atherosclerosis is attenuated, pro-inflammatory cytokines are decreased and anti-inflammatory cytokines increased in the aorta in both wild-type (WT) and ApoE -/-mice after oral mbHSP65 administration [15] . This was accompanied by increased numbers of CD4 + CD25 + FoxP3 + T regulatory cells (Tregs) [15] . Taken together, these studies clearly suggest that mucosal administration with whole mbHSP65 and/or immunization with atherogenic mbHSP65 peptides may help prevent this disease.…”

Section: Introductionmentioning

confidence: 99%

“…mbHSP65 has immunologically mediated disease-promoting and protective roles. It can trigger innate and adaptive immune responses that initiate the earliest, still reversible inflammatory stage of atherosclerosis [10] and active immunization with mbHSP65 can accelerate atherosclerosis in animals [10][11][12][13][14][15] . On the other hand, mucosal immunization with mbHSP65 has recently been investigated in an effort to induce tolerance in atherosclerotic settings.…”

Section: Introductionmentioning

confidence: 99%

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Oral Tolerization with Mycobacterial Heat Shock Protein 65 Reduces Chronic Experimental Atherosclerosis in Aged Mice

Wick

Onestingel²,

Demetz³

et al. 2017

Gerontology

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Background: Atherosclerosis is a chronic inflammatory disease of the artery wall where both innate and adaptive immunity play important roles. Modulation of the immune response against the stress protein antigen, heat shock protein (HSP) 60, by administration of mycobacterial HSP65 (mbHSP65) orally and/or nasally shows promising therapeutic results in young animals in the sense of less severe experimental atherosclerosis; however, the case of aged animals with already established atherosclerosis has so far never been investigated. Objective: To investigate if mbHSP65 immunization would further accelerate atherosclerotic progression in aged ApoE^-/- mice (18 months old) with already long-established atherosclerosis and if these mice could be orally tolerized against mbHSP65. Methods: Aged wild-type (WT) and ApoE^-/- mice (65 weeks) were immunized and/or orally treated with mbHSP65 and then either kept on normal chow or changed to high-cholesterol diet (HCD). Atherosclerosis was assessed by en face analysis and the number of CD4⁺CD25⁺FoxP3⁺ T regulatory cells (Tregs) was assessed by flow cytometry in lymph node and spleen cells. Total cholesterol and triglyceride levels were determined. Soluble mammalian HSP60 and anti-mouse HSP60 (mHSP60) and anti-mbHSP65 antibodies were detected by enzyme-linked immunosorbent assay. Results: As expected, aged WT mice had only minor lesions in the aorta, which did not change under HCD for 14 weeks. Aged ApoE^-/- mice already had large complicated plaques, which increased in size under HCD. mbHSP65 immunization led to a significant aggravation of atherosclerosis in both WT and ApoE^-/- mice irrespective of the nature of their diet. This increase was accompanied by increased titers of both anti-mHSP60 and anti-mbHSP65 antibodies in the circulation. The increased plaque formation could be significantly diminished with oral mbHSP65 tolerization. An increased number of Tregs and lower or unchanged levels of cholesterol and triglycerides were associated with the reduced size of aortal lesions. Conclusion: Oral tolerization against mbHSP65 could be used both to prevent and to treat chronic atherosclerosis in aged individuals.

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Atherosclerosis: An Age-Dependent Autoimmune Disease

Henderson¹,

Rossmann²,

Cappellano³

et al. 2017

Handbook of Immunosenescence

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Age-dependent diseases are exponentially increasing due to the improvement of socio-economical perspective and the rapid increase of life expectancy in Western countries. Cardiovascular diseases (CVDs) represent the biggest cause of deaths worldwide. Among them, atherosclerosis is the most important representative leading to the known severe sequelae, i.e., myocardial infarction, stroke, and peripheral arterial occlusion. Evidence for an (auto)antigen-driven process at these sites of inflammation became available only recently. During the last decades, efforts have been done to identify exogenous and/or autologous antigens that may induce local cardiovascular immune reactions. Among them, the main candidates for such antigens are oxidized low-density lipoprotein (ox-LDL) and heat shock proteins (HSPs). Risk factors for CVDs (i.e., cigarette smoking, hypertension, diabetes, elevated lipid levels, and chronic infections) induce HSP60 and adhesion molecule expression in vascular endothelial cells (ECs), initiating the first inflammatory events. This chapter summarizes the involvment of innate and adpative immunity in atherosclerosis focusing on HSP60.

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Mycobacterial heat shock protein 65 (mbHSP65)-induced atherosclerosis - Preventive oral tolerization and definition of atheroprotective and atherogenic mbHSP65-peptides

Cited by 4 publications

References 0 publications

Vaccine against arteriosclerosis: an update

Vaccine against arteriosclerosis: an update

Oral Tolerization with Mycobacterial Heat Shock Protein 65 Reduces Chronic Experimental Atherosclerosis in Aged Mice

Atherosclerosis: An Age-Dependent Autoimmune Disease

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