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Li Z, Yang Y, Zong J, Zhang B, Li X, Qi H, Yu T, Li Y. Dendritic cells immunotargeted therapy for atherosclerosis. Acta Pharm Sin B 2025; 15:792-808. [PMID: 40177571 PMCID: PMC11959979 DOI: 10.1016/j.apsb.2024.12.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/15/2024] [Accepted: 11/20/2024] [Indexed: 04/05/2025] Open
Abstract
Atherosclerosis, a chronic inflammatory disease, is markedly influenced by both immune and inflammatory reactions throughout its progression. Dendritic cells, as pivotal antigen-presenting entities, play a crucial role in the initiation of immune responses and the preservation of immunological homeostasis. Accumulating data indicates that dendritic cells are present in healthy arteries and accumulate significantly in atherosclerotic plaques. Novel immunotherapeutic approaches and vaccination protocols have yielded substantial clinical advancements in managing chronic inflammatory diseases, with dendritic cell-centric modalities emerging for atherosclerotic management. In this review, we delineate the essential functions and underlying mechanisms of dendritic cells and their subsets in the modulation of atherosclerotic inflammation and immune responses. We underscore the immense promise of dendritic cell-based immunotherapeutic strategies, including vaccines and innovative combinations with nanotechnological drug delivery platforms for atherosclerosis treatment. We also discuss the challenges associated with dendritic cell immunotherapy and provide perspectives on the future direction of this field.
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Affiliation(s)
- Zhaohui Li
- Department of Vascular Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266400, China
| | - Yanyan Yang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Jinbao Zong
- Clinical Laboratory, Central Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, 266000, China
| | - Bei Zhang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xiaolu Li
- Department of Cardiac Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Hongzhao Qi
- Institute for Translational Medicine, the Affiliated Hospital of Qingdao University, Qingdao, 266021, China
| | - Tao Yu
- Department of Cardiac Ultrasound, the Affiliated Hospital of Qingdao University, Qingdao, 266000, China
- Institute for Translational Medicine, the Affiliated Hospital of Qingdao University, Qingdao, 266021, China
| | - Yongxin Li
- Department of Vascular Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266400, China
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Saini I, Joshi J, Kaur S. Unleashing the role of potential adjuvants in leishmaniasis. Int J Pharm 2025; 669:125077. [PMID: 39675537 DOI: 10.1016/j.ijpharm.2024.125077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/26/2024] [Accepted: 12/10/2024] [Indexed: 12/17/2024]
Abstract
Leishmaniasis is amongst one of the most neglected tropical disease, caused by an intracellular protozoan of genus Leishmania. Currently, the most promising strategy to combat leishmaniasis, relies on chemotherapy but the toxicity and increasing resistance of the standard drugs, presses the demand for new alternatives. Immunization is arguably the best strategy for cure because an individual once infected becomes immune to the disease. Yet, there is no efficient vaccine capable of providing enduring immunity against the parasite. Achieving the goal of developing highly efficacious and durable vaccine is limited due to lack of an appropriate adjuvant. Adjuvants are recognized as 'immune potentiators' which redirect or amplify the immune response. A number of adjuvants like alum, MPL-A, CpG ODN, GLA-SE, imiquimod, saponins etc. have been used in combination with various classes of Leishmania antigens. However, only few have reached clinical trials. Thus, the choice of an adjuvant is critically dependent on many factors such as the route of administration, the nature of antigen, formulation, the type of required immune response, their mode of action and the immunization schedule. This review provides an updated status on the types of adjuvants used in leishmaniasis so far and their mechanism of action if known.
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Affiliation(s)
- Isha Saini
- Parasitology Laboratory, Department of Zoology, Panjab University, Chandigarh, India
| | - Jyoti Joshi
- Goswami Ganesh Dutta Sanatan Dharma College, Sector-32C, Chandigarh, India
| | - Sukhbir Kaur
- Parasitology Laboratory, Department of Zoology, Panjab University, Chandigarh, India.
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Yin L, Bing Z, Zheng Y, Pan Y, Dong Y, Wang J, Luo R, Zhao Y, Dou H, Hou Y. Oroxylin A-induced Trained Immunity Promotes LC3-associated Phagocytosis in Macrophage in Protecting Mice Against Sepsis. Inflammation 2024; 47:2196-2214. [PMID: 38739341 DOI: 10.1007/s10753-024-02033-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/18/2024] [Accepted: 04/18/2024] [Indexed: 05/14/2024]
Abstract
Sepsis is defined as a dysregulated host response to infection that leads to multiorgan failure. Innate immune memory, i.e., "trained immunity", can result in stronger immune responses and provide protection against various infections. Many biological agents, including β-glucan, can induce trained immunity, but these stimuli may cause uncontrolled inflammation. Oroxylin A (OA) is an active flavonoid compound that is derived from Scutellaria baicalensis. OA is an agonist for inducing trained immunity in vivo and in vitro, and β-glucan was used as a positive control. The protective effects of OA-induced trained immunity were evaluated in mouse models that were established by either lipopolysaccharide (LPS) administration or caecal ligation and puncture (CLP). The expression of inflammatory factors and signaling pathway components involved in trained immunity was evaluated in vitro using qRT‒PCR, western blotting (WB) and enzyme-linked immunosorbent assay (ELISA). Flow cytometry and confocal microscopy were used to examine reactive oxygen species (ROS) levels and phagocytosis in trained macrophages. A PCR array was used to screen genes that were differentially expressed in trained macrophages. Here, we revealed that OA alleviated sepsis via trained immunity. OA-treated macrophages displayed increased glycolysis and mTOR phosphorylation, and mTOR inhibitors suppressed OA-induced trained immunity by effectively reprogramming macrophages. The PCR array revealed key genes in the mTOR signaling pathway in OA-treated macrophages. Furthermore, OA targeted the Dectin-1-syk axis to promote LC3-associated phagocytosis (LAP) by trained macrophages, thereby enhancing the ability of these macrophages to protect against infection. This ability could be transferred to a new host via the adoptive transfer of peritoneal macrophages. This study is the first to provide new insights into the potential of OA-induced trained immunity to be used as a strategy to protect mice against sepsis by promoting LAP by macrophages.
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Affiliation(s)
- Lijie Yin
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Ziqian Bing
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Yaojun Zheng
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Yuchen Pan
- Jiangsu International Laboratory of Immunity and Metabolism, The Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, China
| | - Yue Dong
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Jiali Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Renjie Luo
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China
| | - Yue Zhao
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China.
| | - Huan Dou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China.
| | - Yayi Hou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China.
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Ijaz MU, Vaziri F, Wan YJY. Effects of Bacillus Calmette-Guérin on immunometabolism, microbiome and liver diseases ⋆. LIVER RESEARCH 2023; 7:116-123. [PMID: 38223885 PMCID: PMC10786626 DOI: 10.1016/j.livres.2023.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 02/22/2023] [Accepted: 05/16/2023] [Indexed: 01/16/2024]
Abstract
Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries. Moreover, metabolic diseases increase the risk of having infectious diseases. The treatment of metabolic disease may require a long-term strategy of taking multiple medications, which can be costly and have side effects. Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest. A growing body of evidence indicates that Bacillus Calmette-Guérin (BCG) offers protection against non-infectious diseases. The non-specific effects of BCG occur likely due to the induction of trained immunity. In this regard, understanding how BCG influences the development of chronic metabolic health including liver diseases would be important. This review focuses on research on BCG, the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome, immunity, and metabolism.
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Affiliation(s)
- Muhammad Umair Ijaz
- Department of Medical Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Farzam Vaziri
- Department of Medical Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA
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Du J, Su Y, Wang R, Dong E, Cao Y, Zhao W, Gong W. Research progress on specific and non-specific immune effects of BCG and the possibility of BCG protection against COVID-19. Front Immunol 2023; 14:1118378. [PMID: 36798128 PMCID: PMC9927227 DOI: 10.3389/fimmu.2023.1118378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 01/20/2023] [Indexed: 02/04/2023] Open
Abstract
Bacille Calmette-Guérin (BCG) is the only approved vaccine for tuberculosis (TB) prevention worldwide. BCG has an excellent protective effect on miliary tuberculosis and tuberculous meningitis in children or infants. Interestingly, a growing number of studies have shown that BCG vaccination can induce nonspecific and specific immunity to fight against other respiratory disease pathogens, including SARS-CoV-2. The continuous emergence of variants of SARS-CoV-2 makes the protective efficiency of COVID-19-specific vaccines an unprecedented challenge. Therefore, it has been hypothesized that BCG-induced trained immunity might protect against COVID-19 infection. This study comprehensively described BCG-induced nonspecific and specific immunity and the mechanism of trained immunity. In addition, this study also reviewed the research on BCG revaccination to prevent TB, the impact of BCG on other non-tuberculous diseases, and the clinical trials of BCG to prevent COVID-19 infection. These data will provide new evidence to confirm the hypotheses mentioned above.
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Affiliation(s)
- Jingli Du
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
| | - Yue Su
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
| | - Ruilan Wang
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
| | - Enjun Dong
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
| | - Yan Cao
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
| | - Wenjuan Zhao
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
| | - Wenping Gong
- Tuberculosis Prevention and Control Key Laboratory/Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Senior Department of Tuberculosis, The 8th Medical Center of PLA General Hospital, Beijing, China
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Neonatal Subcutaneous BCG Vaccination Decreases Atherosclerotic Plaque Number and Plaque Macrophage Content in ApoE-/- Mice. BIOLOGY 2022; 11:biology11101511. [PMID: 36290415 PMCID: PMC9599032 DOI: 10.3390/biology11101511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/05/2022] [Accepted: 10/11/2022] [Indexed: 11/17/2022]
Abstract
Bacille-Calmette Guérin (BCG) modulates atherosclerosis development in experimental animals, but it remains unclear whether neonatal BCG vaccination is pro- or anti-atherogenic. Many animal models differ fundamentally from BCG administration to human infants in terms of age, vaccine preparation, dosing schedule, and route of administration. We aimed to elucidate the effect of neonatal subcutaneous BCG vaccination—analogous to human BCG vaccination—on atherosclerosis development in ApoE−/− mice. At 2 days of age, a total of 40 ApoE−/− mice received either a weight-equivalent human dose of BCG, or saline, subcutaneously. From 4 weeks onwards, the mice were fed a Western-type diet containing 22% fat. At 16 weeks of age, mice were sacrificed for the assessment of atherosclerosis. Body weight, plasma lipids, atherosclerosis lesion size and collagen content were similar in both groups. Atherosclerosis lesion number was lower in mice that received BCG. Macrophage content was 20% lower in the BCG-vaccinated mice (p < 0.05), whereas plaque lipid content was increased by 25% (p < 0.01). In conclusion, neonatal BCG vaccination reduces atherosclerosis plaque number and macrophage content but increases lipid content in a murine model of atherosclerosis. Human epidemiological and mechanistic studies are warranted to investigate whether neonatal BCG vaccination is potentially atheroprotective.
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7
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Funes SC, Rios M, Fernández-Fierro A, Di Genaro MS, Kalergis AM. Trained Immunity Contribution to Autoimmune and Inflammatory Disorders. Front Immunol 2022; 13:868343. [PMID: 35464438 PMCID: PMC9028757 DOI: 10.3389/fimmu.2022.868343] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/16/2022] [Indexed: 12/24/2022] Open
Abstract
A dysregulated immune response toward self-antigens characterizes autoimmune and autoinflammatory (AIF) disorders. Autoantibodies or autoreactive T cells contribute to autoimmune diseases, while autoinflammation results from a hyper-functional innate immune system. Aside from their differences, many studies suggest that monocytes and macrophages (Mo/Ma) significantly contribute to the development of both types of disease. Mo/Ma are innate immune cells that promote an immune-modulatory, pro-inflammatory, or repair response depending on the microenvironment. However, understanding the contribution of these cells to different immune disorders has been difficult due to their high functional and phenotypic plasticity. Several factors can influence the function of Mo/Ma under the landscape of autoimmune/autoinflammatory diseases, such as genetic predisposition, epigenetic changes, or infections. For instance, some vaccines and microorganisms can induce epigenetic changes in Mo/Ma, modifying their functional responses. This phenomenon is known as trained immunity. Trained immunity can be mediated by Mo/Ma and NK cells independently of T and B cell function. It is defined as the altered innate immune response to the same or different microorganisms during a second encounter. The improvement in cell function is related to epigenetic and metabolic changes that modify gene expression. Although the benefits of immune training have been highlighted in a vaccination context, the effects of this type of immune response on autoimmunity and chronic inflammation still remain controversial. Induction of trained immunity reprograms cellular metabolism in hematopoietic stem cells (HSCs), transmitting a memory-like phenotype to the cells. Thus, trained Mo/Ma derived from HSCs typically present a metabolic shift toward glycolysis, which leads to the modification of the chromatin architecture. During trained immunity, the epigenetic changes facilitate the specific gene expression after secondary challenge with other stimuli. Consequently, the enhanced pro-inflammatory response could contribute to developing or maintaining autoimmune/autoinflammatory diseases. However, the prediction of the outcome is not simple, and other studies propose that trained immunity can induce a beneficial response both in AIF and autoimmune conditions by inducing anti-inflammatory responses. This article describes the metabolic and epigenetic mechanisms involved in trained immunity that affect Mo/Ma, contraposing the controversial evidence on how it may impact autoimmune/autoinflammation conditions.
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Affiliation(s)
- Samanta C. Funes
- Instituto Multidisciplinario de Investigaciones Biológicas-San Luis (IMIBIO-SL), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de San Luis (UNSL), San Luis, Argentina
| | - Mariana Rios
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ayleen Fernández-Fierro
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - María S. Di Genaro
- Instituto Multidisciplinario de Investigaciones Biológicas-San Luis (IMIBIO-SL), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de San Luis (UNSL), San Luis, Argentina
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- *Correspondence: Alexis M. Kalergis,
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Tissue-resident immunity in the lung: a first-line defense at the environmental interface. Semin Immunopathol 2022; 44:827-854. [PMID: 36305904 PMCID: PMC9614767 DOI: 10.1007/s00281-022-00964-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 09/08/2022] [Indexed: 12/15/2022]
Abstract
The lung is a vital organ that incessantly faces external environmental challenges. Its homeostasis and unimpeded vital function are ensured by the respiratory epithelium working hand in hand with an intricate fine-tuned tissue-resident immune cell network. Lung tissue-resident immune cells span across the innate and adaptive immunity and protect from infectious agents but can also prove to be pathogenic if dysregulated. Here, we review the innate and adaptive immune cell subtypes comprising lung-resident immunity and discuss their ontogeny and role in distinct respiratory diseases. An improved understanding of the role of lung-resident immunity and how its function is dysregulated under pathological conditions can shed light on the pathogenesis of respiratory diseases.
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Shpilsky GF, Takahashi H, Aristarkhova A, Weil M, Ng N, Nelson KJ, Lee A, Zheng H, Kühtreiber WM, Faustman DL. Bacillus Calmette-Guerin 's beneficial impact on glucose metabolism: evidence for broad based applications. iScience 2021; 24:103150. [PMID: 34646988 PMCID: PMC8501688 DOI: 10.1016/j.isci.2021.103150] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/03/2021] [Accepted: 09/16/2021] [Indexed: 11/25/2022] Open
Abstract
Bacillus Calmette-Guerin (BCG) vaccinations improve glycemic control in juvenile-onset Type I diabetes (T1D), an effect driven by restored sugar transport through aerobic glycolysis. In a pilot clinical trial, T1D, but not latent autoimmune diabetes of adults (LADA), exhibited lower blood sugars after multidose BCG. Using a glucose transport assay, monocytes from T1D subjects showed a large stimulation index with BCG exposures; LADA subjects showed minimal BCG-induced sugar responsiveness. Monocytes from T1D, type 2 diabetes (T2D), and non-diabetic controls (NDC) were all responsive in vitro to BCG by augmented sugar utilization. Adults with prior neonatal BCG vaccination show accelerated glucose transport decades later. Finally, in vivo experiments with the NOD mouse (a T1D model) and obese db/db mice (a T2D model) confirm BCG's blood-sugar-lowering and accelerated glucose metabolism with sufficient dosing. Our results suggest that BCG's benefits for glucose metabolism may be broadly applicable to T1D and T2D, but less to LADA.
A pilot trial of BCG vaccinations to T1D showed reduced blood sugars but not in LADA Monocytes from T1D and to some degree T2D display stimulated glucose transport BCG vaccinations at birth show accelerated glucose transport decades later In vivo mouse models of both T1D and T2D demonstrate BCG-induced blood sugar lowering
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Affiliation(s)
- Gabriella F Shpilsky
- Massachusetts General Hospital, Immunobiology Laboratories, Boston, MA 02129, USA
| | - Hiroyuki Takahashi
- Massachusetts General Hospital, Immunobiology Laboratories, Boston, MA 02129, USA
| | - Anna Aristarkhova
- Massachusetts General Hospital, Immunobiology Laboratories, Boston, MA 02129, USA
| | - Michele Weil
- Massachusetts General Hospital, Diabetes Unit, Boston, MA 02129, USA
| | - Nathan Ng
- Massachusetts General Hospital, Immunobiology Laboratories, Boston, MA 02129, USA
| | - Kacie J Nelson
- Massachusetts General Hospital, Immunobiology Laboratories, Boston, MA 02129, USA
| | - Amanda Lee
- Massachusetts General Hospital, Immunobiology Laboratories, Boston, MA 02129, USA
| | - Hui Zheng
- Massachusetts General Hospital and Harvard Medical School, Statistics Department, Boston, MA 02129, USA
| | - Willem M Kühtreiber
- Massachusetts General Hospital, Immunobiology Laboratories, Boston, MA 02129, USA.,Massachusetts General Hospital and Harvard Medical School, Immunobiology Laboratories, Boston, MA 02129, USA
| | - Denise L Faustman
- Massachusetts General Hospital, Immunobiology Laboratories, Boston, MA 02129, USA.,Massachusetts General Hospital and Harvard Medical School, Immunobiology Laboratories, Boston, MA 02129, USA
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de Abajo FJ, Rodríguez-Martín S, Barreira D, Rodríguez-Miguel A, Fernández-Antón E, Gil M, García-Lledó A. Influenza vaccine and risk of acute myocardial infarction in a population-based case-control study. Heart 2021; 108:1039-1045. [PMID: 34645644 DOI: 10.1136/heartjnl-2021-319754] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 09/17/2021] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE To assess the relationship between influenza vaccination and risk of a first acute myocardial infarction (AMI) in the general population by different epidemic periods. METHODS This is a population-based case-control study carried out in BIFAP (Base de datos para la investigación farmacoepidemiológica en atención primaria), over 2001-2015, in patients aged 40-99 years. Per each incident AMI case, five controls were randomly selected, individually matched for exact age, sex and index date (AMI diagnosis). A patient was considered vaccinated when he/she had a recorded influenza vaccination at least 14 days before the index date within the same season. The association between influenza vaccination and AMI risk was assessed through a conditional logistic regression, computing adjusted ORs (AOR) and their respective 95% CIs. The analysis was performed overall and by each of the three time epidemic periods per study year (pre-epidemic, epidemic and postepidemic). RESULTS We identified 24 155 AMI cases and 120 775 matched controls. Of them, 31.4% and 31.2%, respectively, were vaccinated, yielding an AOR of 0.85 (95% CI 0.82 to 0.88). No effect modification by sex, age and background cardiovascular risk was observed. The reduced risk of AMI was observed shortly after vaccination and persisted over time. Similar results were obtained during the pre-epidemic (AOR=0.87; 95% CI 0.79 to 0.95), epidemic (AOR=0.89; 95% CI 0.82 to 0.96) and postepidemic (AOR=0.83; 95% CI 0.79 to 0.87) periods. No association was found with pneumococcal vaccine (AOR=1.10; 95% CI 1.06 to 1.15). CONCLUSIONS Results are compatible with a moderate protective effect of influenza vaccine on AMI in the general population, mostly in primary prevention, although bias due to unmeasured confounders may partly account for the results.
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Affiliation(s)
- Francisco José de Abajo
- Biomedical Sciences, Universidad de Alcalá de Henares Facultad de Medicina y Ciencias de la Salud, Alcalá de Henares, Spain .,Clinical Pharmacology Unit, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain
| | - Sara Rodríguez-Martín
- Biomedical Sciences, Universidad de Alcalá de Henares Facultad de Medicina y Ciencias de la Salud, Alcalá de Henares, Spain.,Clinical Pharmacology Unit, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain
| | - Diana Barreira
- Clinical Pharmacology Unit, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain
| | - Antonio Rodríguez-Miguel
- Clinical Pharmacology Unit, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain
| | | | - Miguel Gil
- Pharmacoepidemiology and Pharmacovigilance, Agencia Espanola de Medicamentos y Productos Sanitarios, Madrid, Spain
| | - Alberto García-Lledó
- Cardiology, Hospital Universitario Principe de Asturias, Alcalá de Henares, Spain.,Medicine, Universidad de Alcalá de Henares Facultad de Medicina y Ciencias de la Salud, Alcalá de Henares, Spain
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11
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Koeken VA, de Bree LCJ, Mourits VP, Moorlag SJ, Walk J, Cirovic B, Arts RJ, Jaeger M, Dijkstra H, Lemmers H, Joosten LA, Benn CS, van Crevel R, Netea MG. BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner. J Clin Invest 2021; 130:5591-5602. [PMID: 32692728 DOI: 10.1172/jci133935] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 07/14/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUNDInduction of innate immune memory, also termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases.METHODSWe investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis- and Staphylococcus aureus-induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity.RESULTSWhile BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in 3 smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination.CONCLUSIONThe capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications.FUNDINGNetherlands Organization for Scientific Research, European Research Council, and the Danish National Research Foundation.
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Affiliation(s)
- Valerie Acm Koeken
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - L Charlotte J de Bree
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.,Bandim Health Project, OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.,Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark
| | - Vera P Mourits
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Simone Jcfm Moorlag
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Jona Walk
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.,Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Branko Cirovic
- Quantitative Systems Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Rob Jw Arts
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Martin Jaeger
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Helga Dijkstra
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Heidi Lemmers
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Leo Ab Joosten
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Christine S Benn
- Bandim Health Project, OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.,Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark
| | - Reinout van Crevel
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Mihai G Netea
- Radboud Center for Infectious Diseases and.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.,Quantitative Systems Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
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12
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Sohrabi Y, Dos Santos JC, Dorenkamp M, Findeisen H, Godfrey R, Netea MG, Joosten LAB. Trained immunity as a novel approach against COVID-19 with a focus on Bacillus Calmette-Guérin vaccine: mechanisms, challenges and perspectives. Clin Transl Immunology 2020; 9:e1228. [PMID: 33363733 PMCID: PMC7755499 DOI: 10.1002/cti2.1228] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/03/2020] [Accepted: 11/29/2020] [Indexed: 12/13/2022] Open
Abstract
COVID-19 is a severe health problem in many countries and has altered day-to-day life in the whole world. This infection is caused by the SARS-CoV-2 virus, and depending on age, sex and health status of the patient, it can present with variety of clinical symptoms such as mild infection, a very severe form or even asymptomatic course of the disease. Similarly to other viruses, innate immune response plays a vital role in protection against COVID-19. However, dysregulation of innate immunity could have a significant influence on the severity of the disease. Despite various efforts, there is no effective vaccine against the disease so far. Recent data have demonstrated that the Bacillus Calmette-Guérin (BCG) vaccine could reduce disease severity and the burden of several infectious diseases in addition to targeting its primary focus tuberculosis. There is growing evidence for the concept of beneficial non-specific boosting of immune responses by BCG or other microbial compounds termed trained immunity, which may protect against COVID-19. In this manuscript, we review data on how the development of innate immune memory due to microbial compounds specifically BCG can result in protection against SARS-CoV-2 infection. We also discuss possible mechanisms, challenges and perspectives of using innate immunity as an approach to reduce COVID-19 severity.
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Affiliation(s)
- Yahya Sohrabi
- Department of Cardiology I – Coronary and Peripheral Vascular Disease, Heart FailureUniversity Hospital MünsterMünsterGermany
- Institute of Molecular Genetics of the Czech Academy of SciencesPragueCzech Republic
| | - Jéssica Cristina Dos Santos
- Department of Internal Medicine and Radboud Centre of Infectious Diseases (RCI)Radboud University Medical CentreNijmegenThe Netherlands
| | - Marc Dorenkamp
- Department of Cardiology I – Coronary and Peripheral Vascular Disease, Heart FailureUniversity Hospital MünsterMünsterGermany
| | - Hannes Findeisen
- Department of Cardiology I – Coronary and Peripheral Vascular Disease, Heart FailureUniversity Hospital MünsterMünsterGermany
| | - Rinesh Godfrey
- Department of Cardiology I – Coronary and Peripheral Vascular Disease, Heart FailureUniversity Hospital MünsterMünsterGermany
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Centre of Infectious Diseases (RCI)Radboud University Medical CentreNijmegenThe Netherlands
- Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES)University of BonnBonnGermany
| | - Leo AB Joosten
- Department of Internal Medicine and Radboud Centre of Infectious Diseases (RCI)Radboud University Medical CentreNijmegenThe Netherlands
- Núcleo de Pesquisa da Faculdade da Polícia Militar (FPM) do Estado de GoiásGoiâniaBrazil
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13
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Huaman MA, Qualls JE, Jose S, Schmidt SM, Moussa A, Kuhel DG, Konaniah E, Komaravolu RK, Fichtenbaum CJ, Deepe GS, Hui DY. Mycobacterium bovis Bacille-Calmette-Guérin Infection Aggravates Atherosclerosis. Front Immunol 2020; 11:607957. [PMID: 33391278 PMCID: PMC7775372 DOI: 10.3389/fimmu.2020.607957] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
Tuberculosis has been associated with increased risk of atherosclerotic cardiovascular disease. To examine whether mycobacterial infection exacerbates atherosclerosis development in experimental conditions, we infected low-density lipoprotein receptor knockout (Ldlr-/-) mice with Mycobacterium bovis Bacille-Calmette-Guérin (BCG), an attenuated strain of the Mycobacterium tuberculosis complex. Twelve-week old male Ldlr-/- mice were infected with BCG (0.3–3.0x106 colony-forming units) via the intranasal route. Mice were subsequently fed a western-type diet containing 21% fat and 0.2% cholesterol for up to 16 weeks. Age-matched uninfected Ldlr-/- mice fed with an identical diet served as controls. Atherosclerotic lesions in aorta were examined using Oil Red O staining. Changes induced by BCG infection on the immunophenotyping profile of circulating T lymphocytes and monocytes were assessed using flow cytometry. BCG infection increased atherosclerotic lesions in en face aorta after 8 weeks (plaque ratio; 0.021±0.01 vs. 0.013±0.01; p = 0.011) and 16 weeks (plaque ratio, 0.15±0.13 vs. 0.06±0.02; p = 0.003). No significant differences in plasma cholesterol or triglyceride levels were observed between infected and uninfected mice. Compared to uninfected mice, BCG infection increased systemic CD4/CD8 T cell ratio and the proportion of Ly6Clow non-classical monocytes at weeks 8 and 16. Aortic plaque ratios correlated with CD4/CD8 T cell ratios (Spearman’s rho = 0.498; p = 0.001) and the proportion of Ly6Clow non-classical monocytes (Spearman’s rho = 0.629; p < 0.001) at week 16. In conclusion, BCG infection expanded the proportion of CD4+ T cell and Ly6Clow monocytes, and aggravated atherosclerosis formation in the aortas of hyperlipidemic Ldlr-/- mice. Our results indicate that mycobacterial infection is capable of enhancing atherosclerosis development.
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Affiliation(s)
- Moises A Huaman
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Joseph E Qualls
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Shinsmon Jose
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Stephanie M Schmidt
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Anissa Moussa
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - David G Kuhel
- Metabolic Diseases Research Center, Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Eddy Konaniah
- Metabolic Diseases Research Center, Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Ravi K Komaravolu
- Metabolic Diseases Research Center, Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Carl J Fichtenbaum
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - George S Deepe
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - David Y Hui
- Metabolic Diseases Research Center, Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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14
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Adesanya OA, Uche-Orji CI, Adedeji YA, Joshua JI, Adesola AA, Chukwudike CJ. Expanded Scope of Bacillus Calmette-Guerin (BCG) Vaccine Applicability in Disease Prophylaxis, Diagnostics, and Immunotherapeutics. INFECTIOUS MICROBES & DISEASES 2020; 2:144-150. [PMID: 38630099 PMCID: PMC7769055 DOI: 10.1097/im9.0000000000000040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/02/2020] [Accepted: 10/06/2020] [Indexed: 11/29/2022]
Abstract
Following the discovery of the Bacillus Calmette-Guerin (BCG) vaccine, its efficacy against Mycobacterium tuberculosis was soon established, with several countries adopting universal BCG vaccination schemes for their populations. Soon, however, studies aimed to further establish the efficacy of the vaccine in different populations discovered that the vaccine has a larger effect in reducing mortality rate than could be explained by its effect on tuberculosis alone, which sparked suggestions that the BCG vaccine could have effects on other unrelated or non-mycobacterial pathogens causing diseases in humans. These effects were termed heterologous, non-specific or off-target effects and have been shown to be due to both innate and adaptive immune system responses. Experiments carried out in a bid to further understand these effects led to many more discoveries about the applicability of the BCG vaccine for the prevention, diagnosis, and treatment of certain disease conditions. As we approach the second century since the discovery of the vaccine, we believe it is timely to review these interesting applications of the BCG vaccine, such as in the prevention of diabetes, atherosclerosis, and leukemia; the diagnosis of Kawasaki disease; and the treatment of multiple sclerosis, non-muscle invading bladder cancer, and stage III melanoma. Furthermore, complications associated with the administration of the BCG vaccine to certain groups of patients, including those with severe combined immunodeficiency and HIV, have been well described in literature, and we conclude by describing the mechanisms behind these complications and discuss their implications on vaccination strategies, especially in low-resource settings.
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Affiliation(s)
- Oluwafolajimi A. Adesanya
- Institute for Advanced Medical Research and Training (IAMRAT), College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Yeshua A. Adedeji
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - John I. Joshua
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Adeniyi A. Adesola
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
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15
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Chai Q, Lu Z, Liu CH. Host defense mechanisms against Mycobacterium tuberculosis. Cell Mol Life Sci 2020; 77:1859-1878. [PMID: 31720742 PMCID: PMC11104961 DOI: 10.1007/s00018-019-03353-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/30/2019] [Accepted: 10/21/2019] [Indexed: 12/19/2022]
Abstract
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death worldwide from a single infectious pathogen. Mtb is a paradigmatic intracellular pathogen that primarily invades the lungs after host inhalation of bacteria-containing droplets via the airway. However, the majority of Mtb-exposed individuals can spontaneously control the infection by virtue of a robust immune defense system. The mucosal barriers of the respiratory tract shape the first-line defense against Mtb through various mucosal immune responses. After arriving at the alveoli, the surviving mycobacteria further encounter a set of host innate immune cells that exert multiple cellular bactericidal functions. Adaptive immunity, predominantly mediated by a range of different T cell and B cell subsets, is subsequently activated and participates in host anti-mycobacterial defense. During Mtb infection, host bactericidal immune responses are exquisitely adjusted and balanced by multifaceted mechanisms, including genetic and epigenetic regulation, metabolic regulation and neuroendocrine regulation, which are indispensable for maintaining host immune efficiency and avoiding excessive tissue injury. A better understanding of the integrated and equilibrated host immune defense system against Mtb will contribute to the development of rational TB treatment regimens especially novel host-directed therapeutics.
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Affiliation(s)
- Qiyao Chai
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Zhe Lu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Cui Hua Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
- Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
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16
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Zhong C, Yang X, Feng Y, Yu J. Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis. Front Immunol 2020; 11:284. [PMID: 32153588 PMCID: PMC7046758 DOI: 10.3389/fimmu.2020.00284] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 02/04/2020] [Indexed: 02/03/2023] Open
Abstract
Atherosclerosis, a chronic inflammatory disease of the arterial wall, is among the leading causes of morbidity and mortality worldwide. The persistence of low-grade vascular inflammation has been considered to fuel the development of atherosclerosis. However, fundamental mechanistic understanding of the establishment of non-resolving low-grade inflammation is lacking, and a large number of atherosclerosis-related cardiovascular complications cannot be prevented by current therapeutic regimens. Trained immunity is an emerging new concept describing a prolonged hyperactivation of the innate immune system after exposure to certain stimuli, leading to an augmented immune response to a secondary stimulus. While it exerts beneficial effects for host defense against invading pathogens, uncontrolled persistent innate immune activation causes chronic inflammatory diseases. In light of the above, the long-term over-activation of the innate immune system conferred by trained immunity has been recently hypothesized to serve as a link between non-resolving vascular inflammation and atherosclerosis. Here, we provide an overview of current knowledge on trained immunity triggered by various exogenous and endogenous inducers, with particular emphasis on its pro-atherogenic effects and the underlying intracellular mechanisms that act at both the cellular level and systems level. We also discuss how trained immunity could be mechanistically linked to atherosclerosis from both preclinical and clinical perspectives. This review details the mechanisms underlying the induction of trained immunity by different stimuli, and highlights that the intracellular training programs can be different, though partly overlapping, depending on the stimulus and the biological system. Thus, clinical investigation of risk factor specific innate immune memory is necessary for future use of trained immunity-based therapy in atherosclerosis.
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Affiliation(s)
- Chao Zhong
- Key Laboratory for Pharmacology and Translational Research of Traditional Chinese Medicine of Nanchang, Center for Translational Medicine, School of Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China.,Center for Metabolic Disease Research, Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Xiaofeng Yang
- Center for Metabolic Disease Research, Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Yulin Feng
- National Pharmaceutical Engineering Center, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Jun Yu
- Center for Metabolic Disease Research, Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
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17
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Yamazaki-Nakashimada MA, Unzueta A, Berenise Gámez-González L, González-Saldaña N, Sorensen RU. BCG: a vaccine with multiple faces. Hum Vaccin Immunother 2020; 16:1841-1850. [PMID: 31995448 DOI: 10.1080/21645515.2019.1706930] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BCG has been recommended because of its efficacy against disseminated and meningeal tuberculosis. The BCG vaccine has other mechanisms of action besides tuberculosis protection, with immunomodulatory properties that are now being discovered. Reports have shown a significant protective effect against leprosy. Randomized controlled trials suggest that BCG vaccine has beneficial heterologous (nonspecific) effects on mortality in some developing countries. BCG immunotherapy is considered the gold standard adjuvant treatment for non-muscle-invasive bladder cancer. BCG vaccine has also been tested as treatment for diabetes and multiple sclerosis. Erythema of the BCG site is recognized as a clinical clue in Kawasaki disease. BCG administration in the immunodeficient patient is associated with local BCG disease (BCGitis) or disseminated BCG disease (BCGosis) with fatal consequences. BCG administration has been associated with the development of autoimmunity. We present a brief review of the diverse facets of the vaccine, with the discovery of its new modes of action providing new perspectives on this old, multifaceted and controversial vaccine.
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Affiliation(s)
| | - Alberto Unzueta
- Gastroenterology and Transplant Hepatology, Geisinger Medical Center , Danville, PA, USA
| | | | | | - Ricardo U Sorensen
- Department of Pediatrics, Louisiana State University Health Sciences Center, Louisiana Primary Immunodeficiency Network , New Orleans, LA, USA.,Faculty of Medicine, University of La Frontera , Temuco, Chile
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18
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Liu Y, Liang S, Ding R, Hou Y, Deng F, Ma X, Song T, Yan D. BCG-induced trained immunity in macrophage: reprograming of glucose metabolism. Int Rev Immunol 2020; 39:83-96. [DOI: 10.1080/08830185.2020.1712379] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Yuntong Liu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun City, Jilin Province, China
| | - Shu Liang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun City, Jilin Province, China
| | - Ru Ding
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun City, Jilin Province, China
| | - Yuyang Hou
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun City, Jilin Province, China
| | - Feier Deng
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun City, Jilin Province, China
| | - Xiaohui Ma
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun City, Jilin Province, China
| | - Tiantian Song
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun City, Jilin Province, China
| | - Dongmei Yan
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun City, Jilin Province, China
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19
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Chistiakov DA, Kashirskikh DA, Khotina VA, Grechko AV, Orekhov AN. Immune-Inflammatory Responses in Atherosclerosis: The Role of Myeloid Cells. J Clin Med 2019; 8:jcm8111798. [PMID: 31717832 PMCID: PMC6912749 DOI: 10.3390/jcm8111798] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 10/24/2019] [Indexed: 01/28/2023] Open
Abstract
Inflammation plays a key role in the initiation and progression of atherosclerosis and can be caused by multiple agents, including increased concentration of circulating low-density lipoprotein (LDL) cholesterol. Areas of the arterial wall affected by atherosclerosis are enriched with lymphocytes and dendritic cells (DCs). Atherosclerotic plaques contain a variety of proinflammatory immune cells, such as macrophages, DCs, T cells, natural killer cells, neutrophils and others. Intracellular lipid accumulation in atherosclerotic plaque leads to formation of so-called foam cells, the cytoplasm of which is filled with lipid droplets. According to current understanding, these cells can also derive from the immune cells that engulf lipids by means of phagocytosis. Macrophages play a crucial role in the initial stages of atherogenesis by engulfing oxidized LDL (oxLDL) in the intima that leads to their transformation to foam cells. Dying macrophages inside the plaque form a necrotic core that further aggravates the lesion. Proinflammatory DCs prime differentiation of naïve T cells to proinflammatory Th1 and Th17 subsets. In this review, we discuss the roles of cell types of myeloid origin in atherosclerosis-associated inflammation.
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Affiliation(s)
- Dimitry A. Chistiakov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; (D.A.C.); (D.A.K.); (V.A.K.)
| | - Dmitry A. Kashirskikh
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; (D.A.C.); (D.A.K.); (V.A.K.)
| | - Victoriya A. Khotina
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; (D.A.C.); (D.A.K.); (V.A.K.)
| | - Andrey V. Grechko
- Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 109240 Moscow, Russia;
| | - Alexander N. Orekhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; (D.A.C.); (D.A.K.); (V.A.K.)
- Institute of Human Morphology, Tsyrupa st. 3, 117418 Moscow, Russia
- Correspondence: ; Tel.: +7-903-169-08-66
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20
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Lippens C, Garnier L, Guyonvarc'h PM, Santiago-Raber ML, Hugues S. Extended Freeze-Dried BCG Instructed pDCs Induce Suppressive Tregs and Dampen EAE. Front Immunol 2018; 9:2777. [PMID: 30555468 PMCID: PMC6281986 DOI: 10.3389/fimmu.2018.02777] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 11/12/2018] [Indexed: 12/31/2022] Open
Abstract
Several clinical observations have shown that Bacillus Calmette-Guérin (BCG) vaccine has beneficial impact on patients suffering from different chronic inflammatory diseases. Here we evaluated whether BCG inactivated by Extended Freeze-Drying (EFD) which circumvents all the side effects linked to the live bacteria, could influence the development of experimental autoimmune encephalomyelitis (EAE), a mouse model for Multiple Sclerosis. EFD BCG strongly attenuates inflammation, both systemically and at the central nervous system (CNS) level, alleviating EAE. Mechanistically, EFD BCG directly impacts the phenotype of plasmacytoid dendritic cells (pDCs), and promotes their ability to induce suppressive IL-10 secreting regulatory T cells (Tregs) that inhibit encephalitogenic CD4+ T cells. When co-cultured with human allogenic naive CD4+ T cells, EFD BCG exposed human pDCs similarly induce the differentiation of IL-10 producing Tregs. Our study provides evidence that EFD BCG could be used as an immunomodulator of encephalitogenic T cells in multiple sclerosis patients.
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Affiliation(s)
- Carla Lippens
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Laure Garnier
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
| | | | | | - Stéphanie Hugues
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland
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21
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van der Heijden CDCC, Noz MP, Joosten LAB, Netea MG, Riksen NP, Keating ST. Epigenetics and Trained Immunity. Antioxid Redox Signal 2018; 29:1023-1040. [PMID: 28978221 PMCID: PMC6121175 DOI: 10.1089/ars.2017.7310] [Citation(s) in RCA: 170] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
SIGNIFICANCE A growing body of clinical and experimental evidence has challenged the traditional understanding that only the adaptive immune system can mount immunological memory. Recent findings describe the adaptive characteristics of the innate immune system, underscored by its ability to remember antecedent foreign encounters and respond in a nonspecific sensitized manner to reinfection. This has been termed trained innate immunity. Although beneficial in the context of recurrent infections, this might actually contribute to chronic immune-mediated diseases, such as atherosclerosis. Recent Advances: In line with its proposed role in sustaining cellular memories, epigenetic reprogramming has emerged as a critical determinant of trained immunity. Recent technological and computational advances that improve unbiased acquisition of epigenomic profiles have significantly enhanced our appreciation for the complexities of chromatin architecture in the contexts of diverse immunological challenges. CRITICAL ISSUES Key to resolving the distinct chromatin signatures of innate immune memory is a comprehensive understanding of the precise physiological targets of regulatory proteins that recognize, deposit, and remove chemical modifications from chromatin as well as other gene-regulating factors. Drawing from a rapidly expanding compendium of experimental and clinical studies, this review details a current perspective of the epigenetic pathways that support the adapted phenotypes of monocytes and macrophages. FUTURE DIRECTIONS We explore future strategies that are aimed at exploiting the mechanism of trained immunity to improve the prevention and treatment of infections and immune-mediated chronic disorders.
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Affiliation(s)
| | - Marlies P Noz
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands
| | - Leo A B Joosten
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands
| | - Mihai G Netea
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands .,2 Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn , Bonn, Germany
| | - Niels P Riksen
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands
| | - Samuel T Keating
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands
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22
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TLR Agonists as Adjuvants for Cancer Vaccines. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1024:195-212. [PMID: 28921471 DOI: 10.1007/978-981-10-5987-2_9] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Toll-like receptors (TLRs) are one of the best characterised families of pattern recognition receptors (PRRs) and play a critical role in the host defence to infection. Accumulating evidence indicates that TLRs also participate in maintaining tissue homeostasis by controlling inflammation and tissue repair, as well as promoting antitumour effects via activation and modulation of adaptive immune responses. TLR agonists have successfully been exploited to ameliorate the efficacy of various cancer therapies. In this chapter, we will discuss the rationales of using TLR agonists as adjuvants to cancer treatments and summarise the recent findings of preclinical and clinical studies of TLR agonist-based cancer therapies.
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23
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van Dam AD, Bekkering S, Crasborn M, van Beek L, van den Berg SM, Vrieling F, Joosten SA, van Harmelen V, de Winther MPJ, Lütjohann D, Lutgens E, Boon MR, Riksen NP, Rensen PCN, Berbée JFP. BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice. Atherosclerosis 2016; 251:6-14. [PMID: 27232458 DOI: 10.1016/j.atherosclerosis.2016.05.031] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 05/03/2016] [Accepted: 05/18/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND AIMS Bacille-Calmette-Guérin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the main driver of atherosclerosis development, has remained underexposed in previous studies. Therefore, we aimed to elucidate the effect of BCG on cholesterol metabolism in addition to inflammation and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established model of human-like lipoprotein metabolism. METHODS Hyperlipidemic APOE*3-Leiden.CETP mice were fed a Western-type diet containing 0.1% cholesterol and were terminated 6 weeks after a single intravenous injection with BCG (0.75 mg; 5 × 10(6) CFU). RESULTS BCG-treated mice exhibited hepatic mycobacterial infection and hepatomegaly. The enlarged liver (+53%, p = 0.001) coincided with severe immune cell infiltration and a higher cholesterol content (+31%, p = 0.03). Moreover, BCG reduced plasma total cholesterol levels (-34%, p = 0.003), which was confined to reduced nonHDL-cholesterol levels (-36%, p = 0.002). This was due to accelerated plasma clearance of cholesterol from intravenously injected [(14)C]cholesteryl oleate-labelled VLDL-like particles (t½ -41%, p = 0.002) as a result of elevated hepatic uptake (+25%, p = 0.05) as well as reduced intestinal cholestanol and plant sterol absorption (up to -37%, p = 0.003). Ultimately, BCG decreased foam cell formation of peritoneal macrophages (-18%, p = 0.02) and delayed atherosclerotic lesion progression in the aortic root of the heart. BCG tended to decrease atherosclerotic lesion area (-59%, p = 0.08) and reduced lesion severity. CONCLUSIONS BCG reduces plasma nonHDL-cholesterol levels and delays atherosclerotic lesion formation in hyperlipidemic mice.
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Affiliation(s)
- Andrea D van Dam
- Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
| | - Siroon Bekkering
- Dept. of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Malou Crasborn
- Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands
| | - Lianne van Beek
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands; Dept. of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Susan M van den Berg
- Dept. of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands
| | - Frank Vrieling
- Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Simone A Joosten
- Dept. of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Vanessa van Harmelen
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands; Dept. of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Menno P J de Winther
- Dept. of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands
| | - Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, Bonn, Germany
| | - Esther Lutgens
- Dept. of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Prevention, Ludwig Maximilian's University Munich, Munich, Germany
| | - Mariëtte R Boon
- Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands
| | - Niels P Riksen
- Dept. of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Patrick C N Rensen
- Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands
| | - Jimmy F P Berbée
- Dept. of Medicine, Div. of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands
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24
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Allen S, Liu YG, Scott E. Engineering nanomaterials to address cell-mediated inflammation in atherosclerosis. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2016; 2:37-50. [PMID: 27135051 DOI: 10.1007/s40883-016-0012-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Atherosclerosis is an inflammatory disorder with a pathophysiology driven by both innate and adaptive immunity and a primary cause of cardiovascular disease (CVD) worldwide. Vascular inflammation and accumulation of foam cells and their products induce maturation of atheromas, or plaques, which can rupture by metalloprotease action, leading to ischemic stroke or myocardial infarction. Diverse immune cell populations participate in all stages of plaque maturation, many of which directly influence plaque stability and rupture via inflammatory mechanisms. Current clinical treatments for atherosclerosis focus on lowering serum levels of low-density lipoprotein (LDL) using therapeutics such as statins, administration of antithrombotic drugs, and surgical intervention. Strategies that address cell-mediated inflammation are lacking, and consequently have recently become an area of considerable research focus. Nanomaterials have emerged as highly advantageous tools for these studies, as they can be engineered to target specific inflammatory cell populations, deliver therapeutics of wide-ranging solubilities and enhance analytical methods that include imaging and proteomics. Furthermore, the highly phagocytic nature of antigen presenting cells (APCs), a diverse cell population central to the initiation of immune responses and inflammation, make them particularly amenable to targeting and modulation by nanoscale particulates. Nanomaterials have therefore become essential components of vaccine formulations and treatments for inflammation-driven pathologies like autoimmunity, and present novel opportunities for immunotherapeutic treatments of CVD. Here, we review recent progress in the design and use of nanomaterials for therapeutic assessment and treatment of atherosclerosis. We will focus on promising new approaches that utilize nanomaterials for cell-specific imaging, gene therapy and immunomodulation.
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Affiliation(s)
- Sean Allen
- Department of Biomedical Engineering, Northwestern University, Evanston IL, USA
| | - Yu-Gang Liu
- Department of Biomedical Engineering, Northwestern University, Evanston IL, USA
| | - Evan Scott
- Department of Biomedical Engineering, Northwestern University, Evanston IL, USA
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25
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Abstract
The immune reactions that regulate atherosclerotic plaque inflammation involve chemokines, lipid mediators and costimulatory molecules. Chemokines are a family of chemotactic cytokines that mediate immune cell recruitment and control cell homeostasis and activation of different immune cell types and subsets. Chemokine production and activation of chemokine receptors form a positive feedback mechanism to recruit monocytes, neutrophils and lymphocytes into the atherosclerotic plaque. In addition, chemokine signalling affects immune cell mobilization from the bone marrow. Targeting several of the chemokines and/or chemokine receptors reduces experimental atherosclerosis, whereas specific chemokine pathways appear to be involved in plaque regression. Leukotrienes are lipid mediators that are formed locally in atherosclerotic lesions from arachidonic acid. Leukotrienes mediate immune cell recruitment and activation within the plaque as well as smooth muscle cell proliferation and endothelial dysfunction. Antileukotrienes decrease experimental atherosclerosis, and recent observational data suggest beneficial clinical effects of leukotriene receptor antagonism in cardiovascular disease prevention. By contrast, other lipid mediators, such as lipoxins and metabolites of omega-3 fatty acids, have been associated with the resolution of inflammation. Costimulatory molecules play a central role in fine-tuning immunological reactions and mediate crosstalk between innate and adaptive immunity in atherosclerosis. Targeting these interactions is a promising approach for the treatment of atherosclerosis, but immunological side effects are still a concern. In summary, targeting chemokines, leukotriene receptors and costimulatory molecules could represent potential therapeutic strategies to control atherosclerotic plaque inflammation.
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Affiliation(s)
- M Bäck
- Translational Cardiology, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
| | - C Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, Germany.,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.,Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands
| | - E Lutgens
- Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, Germany.,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.,Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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26
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Ivanova EA, Bobryshev YV, Orekhov AN. Intimal pericytes as the second line of immune defence in atherosclerosis. World J Cardiol 2015; 7:583-93. [PMID: 26516412 PMCID: PMC4620069 DOI: 10.4330/wjc.v7.i10.583] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 08/31/2015] [Accepted: 09/07/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammation plays an essential role in the development of atherosclerosis. The initiation and growth of atherosclerotic plaques is accompanied by recruitment of inflammatory and precursor cells from the bloodstream and their differentiation towards pro-inflammatory phenotypes. This process is orchestrated by the production of a number of pro-inflammatory cytokines and chemokines. Human arterial intima consists of structurally distinct leaflets, with a proteoglycan-rich layer lying immediately below the endothelial lining. Recent studies reveal the important role of stellate pericyte-like cells (intimal pericytes) populating the proteoglycan-rich layer in the development of atherosclerosis. During the pathologic process, intimal pericytes may participate in the recruitment of inflammatory cells by producing signalling molecules and play a role in the antigen presentation. Intimal pericytes are also involved in lipid accumulation and the formation of foam cells. This review focuses on the role of pericyte-like cells in the development of atherosclerotic lesions.
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Affiliation(s)
- Ekaterina A Ivanova
- Ekaterina A Ivanova, Department of Development and Regeneration, Biomedical Sciences Group, KU Leuve, Leuven, Belgium
| | - Yuri V Bobryshev
- Ekaterina A Ivanova, Department of Development and Regeneration, Biomedical Sciences Group, KU Leuve, Leuven, Belgium
| | - Alexander N Orekhov
- Ekaterina A Ivanova, Department of Development and Regeneration, Biomedical Sciences Group, KU Leuve, Leuven, Belgium
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27
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Lagranderie M, Guyonvarc'h PM. The interplay between bacillus Calmette-Guérin and Treg cells and its role to prevent or cure inflammatory diseases. Expert Rev Clin Immunol 2015; 10:741-5. [PMID: 24837545 DOI: 10.1586/1744666x.2014.909286] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Clinical evidence indicates that Bacillus Calmette-Guérin (BCG) vaccination exerts anti-inflammatory effects in diseases such as asthma, multiple sclerosis or Type 1 diabetes. Although the exact mechanisms for this activity remain debated, the capacity of mycobacteria to induce regulatory T cells (Tregs) in vivo has been widely reported. However, adverse events associated with live BCG prevent its repeated use, especially in immunocompromised individuals. This article reviews the preclinical data showing a potent, systemic and long-term anti-inflammatory effect in animal models of allergic asthma, inflammatory bowel disease and atherosclerosis with a preparation of BCG inactivated by Extended Freeze-Drying (EFD BCG). It also presents the characteristics of EFD BCG-induced Tregs which play a crucial role in the immunomodulation of various inflammatory diseases. Finally, it compares EFD BCG with other approaches based on the therapeutic use of Tregs in humans.
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28
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Abstract
The view of atherosclerosis as an inflammatory disease has emerged from observations of immune activation and inflammatory signalling in human atherosclerotic lesions, from the definition of inflammatory biomarkers as independent risk factors for cardiovascular events, and from evidence of low-density lipoprotein-induced immune activation. Studies in animal models of hyperlipidaemia have also supported the beneficial effects of countering inflammation to delay atherosclerosis progression. Specific inflammatory pathways with relevance to human diseases have been identified, and inhibitors of these pathways are either already in use for the treatment of other diseases, or are under development and evaluation. These include 'classic' drugs (such as allopurinol, colchicine, and methotrexate), biologic therapies (for example tumour necrosis factor inhibitors and IL-1 neutralization), as well as targeting of lipid mediators (such as phospholipase inhibitors and antileukotrienes) or intracellular pathways (inhibition of NADPH oxidase, p38 mitogen-activated protein kinase, or phosphodiesterase). The evidence supporting the use of anti-inflammatory therapies for atherosclerosis is mainly based on either observational or small interventional studies evaluating surrogate markers of disease activity. Nevertheless, these data are crucial to understand the role of inflammation in atherosclerosis, and to design randomized controlled studies to evaluate the effect of specific anti-inflammatory strategies on cardiovascular outcomes.
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Affiliation(s)
- Magnus Bäck
- Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, L8:03, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
| | - Göran K Hansson
- Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, L8:03, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
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29
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Chistiakov DA, Orekhov AN, Sobenin IA, Bobryshev YV. Plasmacytoid dendritic cells: development, functions, and role in atherosclerotic inflammation. Front Physiol 2014; 5:279. [PMID: 25120492 PMCID: PMC4110479 DOI: 10.3389/fphys.2014.00279] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 07/08/2014] [Indexed: 12/21/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are a specialized subset of DCs that links innate and adaptive immunity. They sense viral and bacterial pathogens and release high levels of Type I interferons (IFN-I) in response to infection. pDCs were shown to contribute to inflammatory responses in the steady state and in pathology. In atherosclerosis, pDCs are involved in priming vascular inflammation and atherogenesis through production of IFN-I and chemokines that attract inflammatory cells to inflamed sites. pDCs also contribute to the proinflammatory activation of effector T cells, cytotoxic T cells, and conventional DCs. However, tolerogenic populations of pDCs are found that suppress atherosclerosis-associated inflammation through down-regulation of function and proliferation of proinflammatory T cell subsets and induction of regulatory T cells with potent immunomodulatory properties. Notably, atheroprotective tolerogenic DCs could be induced by certain self-antigens or bacterial antigens that suggests for great therapeutic potential of these DCs for development of DC-based anti-atherogenic vaccines.
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Affiliation(s)
- Dimitry A. Chistiakov
- Department of Medical Nanobiotechnology, Pirogov Russian State Medical UniversityMoscow, Russia
| | - Alexander N. Orekhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical SciencesMoscow, Russia
- Institute for Atherosclerosis Research, Skolkovo Innovative CenterMoscow, Russia
| | - Igor A. Sobenin
- Institute for Atherosclerosis Research, Skolkovo Innovative CenterMoscow, Russia
- Laboratory of Medical Genetics, Russian Cardiology Research and Production ComplexMoscow, Russia
| | - Yuri V. Bobryshev
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical SciencesMoscow, Russia
- Faculty of Medicine, University of New South WalesSydney, NSW, Australia
- School of Medicine, University of Western SydneyCampbelltown, NSW, Australia
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30
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Ait-Oufella H, Sage AP, Mallat Z, Tedgui A. Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis. Circ Res 2014; 114:1640-60. [PMID: 24812352 DOI: 10.1161/circresaha.114.302761] [Citation(s) in RCA: 155] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chronic inflammation in response to lipoprotein accumulation in the arterial wall is central in the development of atherosclerosis. Both innate and adaptive immunity are involved in this process. Adaptive immune responses develop against an array of potential antigens presented to effector T lymphocytes by antigen-presenting cells, especially dendritic cells. Functional analysis of the role of different T-cell subsets identified the Th1 responses as proatherogenic, whereas regulatory T-cell responses exert antiatherogenic activities. The effect of Th2 and Th17 responses is still debated. Atherosclerosis is also associated with B-cell activation. Recent evidence established that conventional B-2 cells promote atherosclerosis. In contrast, innate B-1 B cells offer protection through secretion of natural IgM antibodies. This review discusses the recent development in our understanding of the role of T- and B-cell subsets in atherosclerosis and addresses the role of dendritic cell subpopulations in the control of adaptive immunity.
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Affiliation(s)
- Hafid Ait-Oufella
- From INSERM UMR-S 970, Paris Cardiovascular Research Center (PARCC), Université Paris Descartes, Sorbonne Paris Cité, Paris, France (H.A.-O., Z.M., A.T.); Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Paris, France (H.A.-O.); and Department of Medicine, University of Cambridge, Cambridge, United Kingdom (A.P.S., Z.M.)
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31
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Talat Iqbal N, Hussain R. Non-specific immunity of BCG vaccine: A perspective of BCG immunotherapy. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.trivac.2014.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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