Targeting T cells to treat atherosclerosis: odyssey from bench to bedside

Bullenkamp, Jessica; Dinkla, Sip; Kaski, Juan Carlos; Dumitriu, Ingrid E.

doi:10.1093/ehjcvp/pvw001

Cited by 32 publications

(26 citation statements)

References 60 publications

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“…The pathogenesis of ACS can be divided into plaque rupture with systemic inflammation and red thrombus, plaque rupture with low systemic inflammation, plaque erosion with white thrombus, and ACS without epicardial coronary artery thrombus or stenosis [ 2 ]. Usually, at the sites of plaque rupture, activated macrophages and T cells secrete cytokines that trigger a self-perpetuating vicious circle reaction, eventually leading to the fragile and thin fibrous cap as well as the accumulation of a central lipid core [ 7 , 8 ]. Therefore, systemic and local inflammatory responses are important causes of ACS.…”

Section: Current Status Of Inflammatory Risk In Acsmentioning

confidence: 99%

Immune and Inflammation in Acute Coronary Syndrome: Molecular Mechanisms and Therapeutic Implications

Wang

Liu

Shao

et al. 2020

Journal of Immunology Research

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Acute coronary syndrome (ACS) is a major cause of acute death worldwide. Both innate and adaptive immunity regulate atherosclerosis progression, plaque stability, and thrombus formation. Immune and inflammation dysfunction have been indicated in the pathogenesis of ACS. The imbalance in the proatherogenic and antiatherogenic immune networks promotes the transition of plaques from a stable to unstable state and results in the occurrence of acute coronary events. The residual inflammatory risk (RIR) has received increasing attention in recent years, and lowering RIR has been expected to improve the outcomes of ACS patients. The CANTOS, COLCOT, and LoDoCo trials verified the benefits of reducing cardiovascular events using anti-inflammation therapies; however, most of the other studies focusing on lowering RIR produced negative or contradicting results. Therefore, restoring the balance in autoimmune regulation is essential because proatherogenic and antiatherogenic immunomodulatory effects are equally important in the complex human immune network. In this review, we summarized the recent evidence of the roles of proatherogenic and antiatherogenic immune networks in the pathogenesis of ACS and discussed how immune and inflammation contribute to atherosclerosis progression, plaque instability, and adverse cardiovascular events. We also provide a “from bench to bedside” perspective of a novel and promising personalized strategy in RIR intervention and therapeutic approaches for the treatment of ACS.

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Section: Current Status Of Inflammatory Risk In Acsmentioning

confidence: 99%

Immune and Inflammation in Acute Coronary Syndrome: Molecular Mechanisms and Therapeutic Implications

Wang

Liu

Shao

et al. 2020

Journal of Immunology Research

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“…This is particularly observable in older people 2 , 3 . Moreover, there is good evidence that terminally differentiated T-cells may cause vascular damage, to the extent that therapies specifically targeting T-cells in advanced atherosclerosis are being developed 4 - 7 . Among activated CD4 T-cells, cardiologists are particularly interested in CD28 null CD4 T-cells 8 - 10 .…”

Section: Introductionmentioning

confidence: 99%

CD28^null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death

Pera¹,

Caserta²,

Albanese³

et al. 2018

Theranostics

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An increased risk of cardiovascular death in Cytomegalovirus (CMV)-infected individuals remains unexplained, although it might partly result from the fact that CMV infection is closely associated with the accumulation of CD28null T-cells, in particular CD28null CD4 T-cells. These cells can directly damage endothelium and precipitate cardiovascular events. However, the current paradigm holds that the accumulation of CD28null T-cells is a normal consequence of aging, whereas the link between these T-cell populations and CMV infection is explained by the increased prevalence of this infection in older people. Resolving whether CMV infection or aging triggers CD28null T-cell expansions is of critical importance because, unlike aging, CMV infection can be treated.Methods: We used multi-color flow-cytometry, antigen-specific activation assays, and HLA-typing to dissect the contributions of CMV infection and aging to the accumulation of CD28null CD4 and CD8 T-cells in CMV+ and CMV- individuals aged 19 to 94 years. Linear/logistic regression was used to test the effect of sex, age, CMV infection, and HLA-type on CD28null T-cell frequencies.Results: The median frequencies of CD28null CD4 T-cells and CD28null CD8 T-cells were >12-fold (p=0.000) but only approximately 2-fold higher (p=0.000), respectively, in CMV+ (n=136) compared with CMV- individuals (n=106). The effect of CMV infection on these T-cell subsets was confirmed by linear regression. Unexpectedly, aging contributed only marginally to an increase in CD28null T-cell frequencies, and only in CMV+ individuals. Interestingly, the presence of HLA-DRB1*0301 led to an approximately 9-fold reduction of the risk of having CD28null CD4 T-cell expansions (OR=0.108, p=0.003). Over 75% of CMV-reactive CD4 T-cells were CD28null.Conclusion: CMV infection and HLA type are major risk factors for CD28null CD4 T-cell-associated cardiovascular pathology. Increased numbers of CD28null CD8 T-cells are also associated with CMV infection, but to a lesser extent. Aging, however, makes only a negligible contribution to the expansion of these T-cell subsets, and only in the presence of CMV infection. Our results open up new avenues for risk assessment, prevention, and treatment.

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“…Thus, we do not know the contribution of T cell subpopulations producing MPs in AMI. Expectedly, experimental targets for T lymphocyte modulation are required to relieve the inflammatory response in atherosclerosis [26]. Hence, these evidences confirm that T cell activation in AMI encourages MICA/B expression in the cells.…”

Section: Discussionmentioning

confidence: 61%

Association of Major Histocompatibility Complex Class I Related Chain A/B Positive Microparticles with Acute Myocardial Infarction and Disease Severity

et al. 2020

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Background: Various cell types undergo activation and stress during atherosclerosis resulting in the development of acute myocardial infarction (AMI) in coronary artery disease (CAD). Major histocompatibility complex class I related chain A and B (MICA/B) can be expressed on the surface of activated and stressed cells and released into blood circulation in several forms including microparticles (MICA/B+ MPs) from various cell types. We aimed to investigate the association of these MICA/B+ MPs with the presence of AMI. Fifty-one AMI and 46 age-matched control subjects were recruited. Methods: Levels of MICA/B+ MPs derived from various parent cells including endothelial cells, platelets, monocytes, neutrophils, and T lymphocytes were determined by flow cytometry. Results: The levels and proportion of MICA/B+ MPs from all types of cell origin were significantly increased in AMI patients compared to those of the controls. A multivariate regression model showed an independent association between MICA/B+ MPs and AMI (OR = 11.6; 95% CI = 2.8, 47.3). Interestingly, based on the disease severity, we found that the levels of MICA/B+ MPs were significantly elevated in the ST-segment elevation myocardial infarction (STEMI) compared to the non-STEMI (NSTEMI) patients. Moreover, an independent association of MICA/B+ MPs with the occurrence of STEMI was also demonstrated (OR = 4.1; 95% CI = 1.5, 16.7). Conclusions: These results suggest that MICA/B+ MPs are associated with AMI and disease severity. They may act as mediators contributing to the pathological process of AMI. Alternatively, they are the results of various cell activations contributing to AMI.

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Targeting T cells to treat atherosclerosis: odyssey from bench to bedside

Cited by 32 publications

References 60 publications

Immune and Inflammation in Acute Coronary Syndrome: Molecular Mechanisms and Therapeutic Implications

Immune and Inflammation in Acute Coronary Syndrome: Molecular Mechanisms and Therapeutic Implications

CD28^null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death

Association of Major Histocompatibility Complex Class I Related Chain A/B Positive Microparticles with Acute Myocardial Infarction and Disease Severity

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Targeting T cells to treat atherosclerosis: odyssey from bench to bedside

Cited by 32 publications

References 60 publications

Immune and Inflammation in Acute Coronary Syndrome: Molecular Mechanisms and Therapeutic Implications

Immune and Inflammation in Acute Coronary Syndrome: Molecular Mechanisms and Therapeutic Implications

CD28null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death

Association of Major Histocompatibility Complex Class I Related Chain A/B Positive Microparticles with Acute Myocardial Infarction and Disease Severity

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CD28^null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death