BMB Reports 2024; 57(10): 431-440  https://doi.org/10.5483/BMBRep.2024-0045
Multifaceted roles of trained immunity in diverse pathological contexts
Hyo Jin Park1,#, Su Min Kim1,#, Un Yung Choi2,3,* & Lark Kyun Kim1,*
1Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06230, 2Department of Microbiology, Konkuk University School of Medicine, Chungju 27478, 3KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju 27478, Korea
Correspondence to: Lark Kyun Kim, Tel: +82-2-2019-5402; Fax: +82-2-2019-5210; E-mail: LKKIM@yuhs.ac; Un Yung Choi, Tel: +82-43-840-3752; Fax: +82-43-840-3048; E-mail: uychoi@kku.ac.kr
#These authors contributed equally to this work.
Received: March 20, 2024; Revised: April 23, 2024; Accepted: May 13, 2024; Published online: June 17, 2024.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Trained immunity, an innate immune response characterized by enhanced cellular responsiveness, exhibits a profound memory akin to adaptive immunity. This phenomenon involves intricate metabolic and epigenetic reprogramming triggered by stimuli such as β-glucan and BCG, shaping innate immune memory. Following elucidation of the background on trained immunity, it is important to explore its multifaceted roles in various pathological contexts. In this review, we delve into the specific contributions of trained immunity in the intricate landscape of viral infections, tumorigenesis, and diverse inflammatory diseases, shedding light on its potential as a therapeutic target, and offering comprehensive understanding of its broader immunological implications.
Keywords: Autoimmune disease, Cancer, Trained immunity, Virus infection
INTRODUCTION

Trained immunity is a process through which innate immune cells develop a form of immunological memory, which memory was previously thought to be unique to adaptive immunity. Following exposure to specific stimuli, innate immune cells can adapt their responses to subsequent challenges, leading to a more robust response when encountering previously experienced infectious agents, or even nonspecific pathogens (1). This phenomenon is not exclusive to vertebrates, as it is found in plants and invertebrates lacking an adaptive immune system (2). Notably, Rag2−/− mice, lacking adaptive immunity, displayed a heightened protection against reinfection, challenging the traditional concept (3). The exploration of trained immunity in human has gained momentum, especially with vaccinations like Bacillus Calmette-Guérin vaccine (BCG), Oral Polio Vaccin (OPV), and smallpox. These vaccines, originally designed for specific infections, have shown nonspecific protective effects against various infections, introducing the concept of “trained immunity” (4-6).

MECHANISMS OF TRAINED IMMUNITY

Triggers and signaling pathways in the induction of trained immunity

Trained immunity, which was initially identified in monocytes and macrophages, has been discovered to also exist in dendritic cells (DCs), neutrophils, natural killer (NK) cells, innate lymphoid cells (ILCs), and non-immune cells like epithelial and endothelial cells, and even in hematopoietic precursor cells in the bone marrow (7-14). Innate immune memory in monocytes and macrophages is initiated by the activation of pattern recognition receptors (PRRs) responding to pathogen-associated or damage-associated molecular patterns (PAMPs/DAMPs) (15). Among the various PAMPs known to induce trained immunity, the most extensively researched are β-glucan and BCG ligands (16). Additionally, monocytes have been shown to exhibit nonspecific immune responses when exposed to ligands from parasites or viral pathogens (17). DAMPs, such as oxidized Low-density Lipoprotein (oxLDL), lipoprotein (a), catecholamines, aldosterone, uric acid, and heme, are also recognized inducers of trained immunity (18-21).

These triggers activate PRR signaling pathways, resulting in the rewiring of several metabolic, epigenetic, and transcriptional processes. For example, β-glucan engages C-type lectin receptor known as dectin-1 (22), initiating a signaling cascade through PI3K/AKT/mTOR pathway activation, stimulating HIF1A, and enhancing glycolysis via the modulation of gene expression and epigenetic status (8). On the other hand, BCG activates trained immunity via NOD2 receptors, leading to Akt/mTOR pathway activation, which facilitates the metabolic shift toward glycolysis (8, 23). Metabolites like mevalonate, and lipids, such as oxLDL, are also known to be inducers of trained immunity, initiating diverse signaling pathways through IGF1R and TLR2/4, respectively (24, 25).

PAMPs and DAMPs activate diverse signaling pathways that converge on a common mechanism of the formation of trained immunity through metabolic and epigenetic reprogramming—the fundamental molecular processes underlying trained immunity. Initial stimulation leads to enhanced responses, facilitated by histone modifications in genes associated with inflammation and antimicrobial defense, causing alterations in chromatin accessibility. Additionally, trained immunity triggers metabolic shifts in glycolysis, the TCA cycle, and fatty acid metabolism. The resultant metabolites serve as cofactors for epigenetic enzymes, showing a profound link between metabolic reprogramming and epigenetic regulation (26).

Epigenetic reprogramming in trained immunity

Epigenetic remodeling, including histone tail modification, epigenetic changes involving long noncoding RNA, and DNA methylation, play a pivotal role in trained immunity (27). In unstimulated cells, the promoter and enhancer regions of proinflammatory genes, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) are typically in a state of highly condensed chromatin (Fig. 1). However, upon acute stimulation by the initial stimulus, such as β-glucan, activating histone modifications, including H3K4 monomethylation (H3K4me1), H3K4 trimethylation (H3K4me3), and H3K27 acetylation (H3K27ac) increase. This leads to the opening of chromatin in the promoter and enhancer regions of proinflammatory genes, resulting in increased gene expression. Some epigenetic markers do not revert to the unstimulated state after the stimulus subsides, leaving chromatin in a mildly condensed state in trained monocytes, the enhanced response upon subsequent exposure is facilitated by the rapid conversion of activating histone modifications to open chromatin (Fig. 1) (3, 7). Likewise, the study conducted on individuals vaccinated with BCG showed that the vaccine’s training effect is associated with an increase in H3K4me3 and H3K27ac at the promoter regions of genes encoding TNF-α and IL-6 (16).

Epigenetic remodeling is also mediated by long noncoding RNAs (lncRNAs), which contribute to the formation of chromosomal loops within Topologically Associating Domains (TADs) (28). A TAD is a three-dimensional structure formed by the clustering of functionally related genes and their regulatory elements. This arrangement facilitates the proximity of distantly located gene regulatory elements to their target genes (29). Specifically, immune priming lncRNA (IPLs) regulates a histone modifying enzyme called MLL1, which in turn induces histone modification at the gene promoters within the TAD. IPLs, via MLL1, induce H3K4me3 at immune gene promoters, enhancing chromatin accessibility for swifter gene expression upon a second stimulus (30). A notable example is observed after BCG vaccination, where human neutrophils demonstrate a heightened level of certain IPLs directing H3K4me3 at the promoters of IL-1β and IL-8 (31).

Another facet of epigenetic remodeling in trained immunity involves changes in DNA methylation. It is recognized that in trained immunity, DNA methylation can be modulated by an increase in metabolites in monocytes trained with β-glucan, which in turn regulates the expression of proinflammatory genes (32). However, further research is needed for more comprehensive understanding of this area.

Metabolic reprogramming in trained immunity

The cells that form trained immunity undergo metabolic reprogramming upon initial exposure to a pathogen, ensuring that upon subsequent encounters with the pathogen, they produce energy more rapidly, and respond more robustly (33). This metabolic rewiring induces the production of intermediate metabolites that serve as substrates for epigenetic enzymes, emphasizing the collaborative role of metabolic and epigenetic changes in innate immune memory formation (26).

Glycolysis emerges as a crucial metabolic pathway in trained immunity, converting glucose into pyruvate for further utilization in the tricarboxylic acid (TCA) cycle or lactate synthesis. Even under normal oxygenation conditions, activated immune cells can undergo aerobic glycolysis where there is an urgent need for significant energy (34). Elevated aerobic glycolysis is a hallmark of trained immunity induced by β-glucan, BCG, and oxLDL in various cell types (35, 36). β-glucan trained cells exhibit a shift from oxidative phosphorylation to aerobic glycolysis, increasing lactate production, and redirecting TCA cycle for lipid synthesis through an Akt-mTOR-HIF-1α pathway (8). Recent studies propose that training with β-glucan induces both glycolysis and oxidative phosphorylation (OXPHOS) (37). Moreover, the increase in IL-6 induced by β-glucan training was reversed upon treatment with an OXPHOS inhibitor. These studies highlight the crucial role of glycolysis and OXPHOS in the formation of the trained phenotype.

The heightened TCA cycle activity fueled by acetyl-CoA transformed from pyruvate produced through glycolysis results in increased energy and metabolites production. This metabolic enhancement enables trained cells to exhibit a proinflammatory phenotype, including increased cytokine production, enhanced phagocytic capacity, and elevated reactive oxygen species (ROS) production. Moreover, TCA cycle intermediates, such as acetyl-CoA, fumarate, and itaconate, exert a significant influence on trained immunity by inducing epigenetic changes (32). Increased acetyl-CoA contributes to acetyl groups formation by histone acetyltransferases, an essential process in innate immune memory. Fumarate inhibits the histone demethylase enzyme KDM5, increasing histone trimethylation in the promoters of proinflammatory genes, making them more accessible for transcription factors (38). On the other hand, itaconate induces immune tolerance by inhibiting succinate dehydrogenase (SDH) activity and suppressing the TCA cycle, while β-glucan inhibits the immune repressive gene 1 (IRG1), counteracting the immune tolerance induced by LPS and restoring SDH expression (39). These processes contribute to increased energy production through metabolic reprogramming, while also highlighting the intricate involvement of reprogrammed intermediate metabolites in governing epigenetic regulation during trained immunity (Fig. 2). In the subsequent sections of this review, we delve into its intricate workings across various pathological contexts (Table 1).

TRAINED IMMUNITY IN VARIOUS PATHOLOGIC DISEASE

Trained immunity in virus infectious disease

Research into trained immunity has extensively covered its role in enhanced resistance to nonspecific pathogens through accelerated secondary responses (1). Nevertheless, the dynamics of trained immunity in viral infection and its underlying mechanisms remain a relatively recent research area. However, even before the concept of trained immunity was developed, studies demonstrated its protective role against various viral infections. A 2005 case study found that BCG vaccination protects against acute lower respiratory tract infection, particularly those caused by respiratory syncytial virus (RSV) (40). BCG vaccines expressing N or M2 antigens of RSV enhance helper T cell activation, leading to heightened resistance against RSV infection (41, 42). Subsequent mouse model studies extended this protection to influenza A (IVA), herpes simplex virus type 2 (HSV-2), and other viral infections (43-45), supporting the concept that enhanced responsiveness by trained immunity results in less severe viral infections.

Further insights into the mechanisms of trained immunity have revealed how trained innate immune cells contribute to an anti-viral role. For example, BCG enhances efferocytosis response by alveolar phagocytes, protecting against lethal IVA pneumonia (46). BCG-vaccinated mice exhibited reduced mortality when exposed to ectromelia virus, accompanied by a significant increase in interferon (IFN) production (47). Epigenetic reprogramming induced by BCG vaccination in monocytes leads to functional changes that are indicative of the induction of IL-1β and IL-6 production. These epigenetic and functional changes by trained immunity protected against yellow fever virus infection, emphasizing the key role of IL-1β in responses to unrelated viral infections (48). In mouse macrophages trained with Candida albicans and β-glucan, heightened expression of IFN-β and IL-6 mitigates lung pathology induced by vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) (49). Further mechanistic investigations into the anti-viral role of trained immunity are anticipated in the future.

The global spread of COVID-19 due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has sparked investigations into the link between disease severity and BCG vaccine-trained immunity. Several studies have suggested that universal BCG vaccination policies correlate with lower case fatality rates and reduced morbidity and mortality (50, 51). Experimental studies on the direct evidence of trained immunity induced by BCG vaccination on SARS-CoV-2 have so far produced mixed results. One study emphasized that only intravenous BCG administration, in human-ACE2 transgenic mice, offers resistance against lethal SARS-CoV-2 challenge (52). The ability of trained immunity induced by BCG vaccine was primarily linked to heightened proinflammatory responses; however, this study showed that augmented resistance to SARS-CoV-2 was associated with reduced viral titers, diminished proinflammatory cytokine production, and a concurrent decrease in pulmonary pathology. In contrast, another study suggests that BCG vaccination, while inducing protective innate immune memory responses against heterologous pathogens like influenza A virus (IAV), does not confer protection against SARS-CoV-2 (53). Notably, both studies employed K18-hACE2 transgenic mice and administered the BCG vaccine intravenously, but there were discrepancies in the timing of intranasal infection with SARS-CoV2 post-vaccination (6 weeks versus 4 weeks) and the type of BCG vaccine used (Pasteur versus TICE, respectively). Consequently, while the two vaccines are presumed to have minimal differences in terms of tuberculosis vaccine efficacy, further investigations are needed to discern potential variations in innate immune cell training between the two vaccine types.

Viruses themselves can induce trained immunity, as evidenced by latent infections with murine gamma herpesvirus 68 or murine cytomegalovirus (MCMV), providing resistance to bacterial pathogens, Listeria monocytogenes, and Yersinia pestis (54). Protection is attributed to prolonged TNF-α and IFN-γ production, and systemic activation of macrophages, suggesting that herpesvirus latency functions as a training mechanism for immune cells. In addition to herpesvirus, individuals previously infected with the yellow fever virus, upon subsequent infection with dengue virus, demonstrated reduced severity (55). The quadrivalent inactivated IVA vaccine induces trained immunity, enhancing innate immune responses against viral stimuli, and fine-tuning the anti-SARS-CoV-2 response. In a Dutch hospital, individuals who received a previous IVA vaccination had a lower risk of SARS-CoV-2 infection during both the first and second COVID-19 waves (56). Another critical aspect is understanding how SARS-CoV-2 trains innate immune cells. Recovery from severe COVID-19 leads to enduring epigenetic changes in monocytes, indicative of “trained immunity”, likely originating from hematopoietic stem and progenitor cells (HSPC) (57). IL-6 plays a pivotal role in imprinting these modifications, suggesting potential contributions to chronic inflammation and post-acute sequelae of COVID-19. Furthermore, the identification of an increase in CD9+ monocytes associated with COVID-19 severity provides valuable insights into the immune response and potential markers for severity assessment (58). Further investigations are needed to map epigenetic and metabolic remodeling, and alterations in the composition of innate immune cells induced by SARS-CoV-2, offering insights into how trained immunity influences disease progression in long COVID.

Trained immunity in cancer

Trained immunity, extending beyond infectious agents, enhances the responsiveness of innate immune cells, with implications in cancer pathology and treatment (59). BCG and β-glucan mediate anti-tumor immunity, including the induction of trained immunity, which has been evaluated in bladder cancers, pancreatic cancer, melanoma, and various tumor metastasis (9, 60, 61).

Bladder cancer, treated with BCG recognized for intrinsic immunotherapy, exhibits a connection to trained immunity (62). BCG injections in non-muscle invasive bladder cancer (NMIBC) patients increased H3K4me3 modifications in monocytes, elevating serum IFN-γ levels (63). This BCG-induced epigenetic reprogramming was impaired in patients with autophagy gene polymorphisms, while inhibiting autophagy blocked BCG-induced trained immunity, potentially influencing tumor recurrence (60). In pancreatic ductal adenocarcinoma, β-glucan treatment enhances phagocytosis and ROS-mediated cytotoxicity in infiltrating monocytes and macrophages, exhibiting trained cell characteristics. These CCR2-dependent trained cells migrate to the pancreas, playing a pivotal role in reducing tumor burden (61). Moreover, β-glucan-induced trained immunity inhibits melanoma tumor proliferation by the remodeling of granulopoiesis and training neutrophils via transcriptomic and epigenetic rewiring, which is associated with increased ROS production and type I IFN signaling pathway (9). This study showed that administering neutrophils trained with β-glucan inhibited tumor growth significantly in mouse model, suggesting the therapeutic potential of trained granulopoiesis in anti-tumor strategies.

In the lung metastatic microenvironment, myeloid cells, trained by β-glucan, inhibit tumor metastasis and extended survival in mouse models, mediated by sphingosine-1-phosphate metabolism (64). Blocking sphingosine-1-phosphate synthesis and mitochondrial fission negates β-glucan-induced trained immunity, highlighting the significance of the metabolic sphingolipid-mitochondrial fission pathway in metastasis control. Similarly, IVA-trained alveolar macrophages (AMs) enhance phagocytic and tumor cell cytotoxic functions via epigenetic, transcriptional, and metabolic rewiring in mouse lung metastatic model (64). Both studies demonstrate that the adoptive transfer of β-glucan-trained bone marrow-derived macrophages or IAV-trained AM reduces tumor lung metastasis, indicating the potential of trained innate immune cell therapy.

As the understanding of trained immunity mechanisms deepens, there is growing realization of its therapeutic potential in training innate immune cells to mount effective and durable responses against malignancies, akin to conventional CAR-T cell therapy (65). This concept is verified by the potential of trained immunity to induce long-lasting and broader specificity in recognizing and attacking pathogens or tumor cells (66). The production and administration of trained innate immune cells may be more cost-effective, compared to the complex processes involved in generating chimeric antigen receptor CAR-T cell. This paradigm shift opens avenues for innovative immunotherapeutic strategies that harness the mechanisms of trained immunity. Additionally, there is a focus on developing anti-cancer vaccines to enhance the trained immune response. For example, the re-engineered BCG releasing high levels of cyclic-di-AMP significantly augment trained immunity and enhanced in vivo efficacy in urothelial cancer models (67). Beyond BCG vaccine modifications, a personalized cancer vaccine utilizing engineered Escherichia coli, loaded with tumor antigens and β-glucan, induced trained immunity, fostering potent adaptive anti-tumor responses, and preventing postoperative recurrence (68). Moreover, a nanovaccine employing a “two-phase release” system, which encapsulates HPV16 E7 peptide and muramyl dipeptide (MDP) in nanoparticles and integrates β-glucan into a hydrogel, enhanced trained immunity both in vitro and in vivo (68). Subsequent pre-immunization of mice with this nanovaccine demonstrated significant anti-tumor effects on tumor cells transformed by HPV16 and Ras oncogene. Moreover, nanomaterials, called MDP10-high-density lipoprotein (HDL) suppresses tumor growth by inducing trained immunity through the epigenetic rewiring of multipotent progenitors in mouse bone marrow (69). The researchers further validated that combining MTP10-HDL with checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4, enhances therapeutic outcomes. Based on these studies, a vaccine formulation that combines trained immunity inducers such as β-glucan with pathogen- or cancer-specific antigens holds promise. This approach represents a promising strategy for leveraging trained immunity to enhance personalized cancer immunotherapy, potent vaccines, and therapy. While trained immunity demonstrates favorable effects in stimulating host defense mechanisms, it is important to carefully consider the possibility of triggering or exacerbating autoimmune disorders. Further research is needed to fully understand the benefits and limitations of a vaccine formulation that combines trained immunity inducers.

Trained immunity in autoimmune disorder

The concept of “Trained Immunity” is actively researched both in cancer and infectious diseases, and in various inflammatory disorders of different organs. One of the disease entities where the trained immunity is actively applied to understand pathophysiology is autoimmune diseases.

Macrophages are implicated in the pathogenesis of Multiple Sclerosis (MS), a chronic neurological autoimmune disorder that is characterized by neurodegeneration in the white matter of the central nervous system (CNS) (70). The application of trained immunity concepts in MS has been evident in studies involving experimental autoimmune encephalomyelitis (EAE) (71). For example, β-glucan exacerbates disease progression in EAE-induced mice, but reduces clinical scores in Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a model dependent on persistent viral infection (71). This underscores the dichotomous nature of trained immunity stimuli like β-glucan, which can be beneficial in viral contexts, but detrimental in autoimmune conditions. Additionally, BCG administration in EAE models has shown promise in reducing symptoms and CNS lesions by decreasing Th17 cell levels (72). Given that Th17 cells producing IL-17 contribute to the inflammatory cascade leading to demyelination and neurodegeneration in the CNS, mimicking aspects of MS pathology, this study suggests its potential effectiveness in MS patients. Building on this understanding, macrophage from mice treated with helminth extract exhibits reduced antigen-presenting cell function and inhibits IL-17 production, while curtailing the encephalitogenic activity of T cells in the EAE model (73).

Systemic Lupus Erythematosus (SLE) is marked by the secretion of proinflammatory cytokines (74). In particular, IL-1β plays a pivotal role in SLE progression, as evidenced by milder symptoms in IL-1β-deficient mice models and elevated cytokine levels in SLE patients (75). The disease may induce a trained immunity in the innate immune system, promoting a persistent inflammatory environment that exacerbates SLE (76). In lupus murine models, β-glucan accelerates disease progression by inducing a proinflammatory state (77), while BCG vaccination offers some benefits, possibly by inducing TNF-α and promoting Treg expansion, thus moderating autoreactive T cells (16, 35). Additionally, a metabolic shift toward aerobic glycolysis, a pivotal mechanism in trained immunity, and the identification of the mTOR pathway as a potential therapeutic target, collectively indicate the implication of trained immunity in SLE.

In Rheumatoid Arthritis (RA), stemming from immune cell infiltration in the synovial membrane, β-glucan has been found to exacerbate severe chronic arthritis (78). Moreover, in the collagen-induced arthritis (CIA) model, which mimics RA in experimental settings, β-glucan has been shown to worsen autoimmune diseases (79). While BCG therapy for RA remains unexplored, its use in bladder cancer has been linked to arthritis-like symptoms, possibly due to immune cross-reactivity (62). RA patients also exhibit a metabolic shift in innate cells, activating the mTOR/HIF-1α pathway, and prompting the secretion of proinflammatory cytokines (80). The utilization of glycolysis inhibitor 2-deoxy-D-glucose (2-DG) reduces RA pathology (81), and together with study on the efficacy of tylophorine-based compounds in shifting macrophages from aerobic glycolysis to oxidative phosphorylation, suggests the potential involvement of the metabolic remodeling mechanism of trained immunity in the pathogenesis of RA (82).

Allergic diseases, including asthma and food allergies, are characterized by two main immunological phases: sensitization/memory and effector phases. Allergic sensitization is influenced by Western lifestyles and environmental factors, highlighting the crucial role of epigenetic and metabolic rewiring, which is the fundamental notion of trained immunity (83). Asthma, characterized by airway obstruction, bronchial hyperresponsiveness, and inflammation, has shown potential links to trained immunity (84). Bacterial preparations like OM-85 have demonstrated protection against viral respiratory infections and asthma features by targeting DCs, interleukin-33 (IL-33)-activated ILC2s, and enhancing mucosal antibody production (85, 86). This suggests a potential role for trained immunity, though its exact induction in humans remains unclear. Additionally, murid gamma herpes virus (MuHV-4) infection before experimental asthma induction blocks asthma development by reprogramming bone marrow-derived monocytes (87). ILC2s, crucial in type 2 asthma, may acquire memory through IL-33 dependent mechanisms, enhancing cytokine production upon re-stimulation, and potentially exacerbating allergic asthmatic inflammation (12, 88).

Food allergy shows a potential link with trained immunity mechanisms, as evidenced by excessive innate immune responses correlated with a predisposition to allergen-specific type 2 observed in allergic children at birth (89, 90). Additionally, egg- and peanut-allergic infants exhibit increased circulating monocytes and DCs, with a heightened production of cytokines in response to LPS stimulation, compared to non-allergic individuals (91). Allergen Immunotherapy (AIT), the causative treatment for allergic diseases, involves administering high doses of causative allergens to induce desensitization and tolerance (92). Recent research suggests a role of innate immunity in AIT, with restoring the frequencies of innate immune cells to levels seen in non-allergic individuals (93). While studies have explored Sublingual AIT inducing IL-10-producing ILCs in grass-pollen allergic patients (94), there is currently insufficient evidence demonstrating the metabolic and epigenetic reprogramming associated with trained immunity. Thus, further research is required to elucidate the mechanisms through which trained immunity contributes to the effectiveness of AIT.

CONCLUDING REMARKS

The expanding field of trained immunity has unveiled a new dimension of innate immune responses, transcending conventional paradigms. The intricate interplay between metabolic and epigenetic reprogramming has emerged as a basic mechanism for shaping innate immune memory. While this review offers insights into trained immunity across viral infectious diseases, cancer, and autoimmune disorders, it highlights the dynamic and continually evolving nature of the processes of trained immunity. Future research holds the promise of uncovering novel aspects of trained immunity, further elucidating its therapeutic potential, and refining strategies for targeted interventions in diverse pathological contexts.

ACKNOWLEDGEMENTS

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT, MSIT) (NRF-2023R1A2C1005804, and NRF-2022M3A9B6017424 to L.K.K. RS-2023-00245958 to U.Y.C.). Support was also provided by a grant from the MD-PhD/Medical Scientist Training Program, administered by the Korea Health Industry Development Institute (KHIDI) and funded by the Ministry of Health & Welfare of the Republic of Korea (S.M.K.).

CONFLICTS OF INTEREST

The authors have no conflicting interests.

FIGURES
Fig. 1. Epigenetic reprogramming during trained immunity. Innate immune cells, when exposed to stimuli like β-glucan, BCG, undergo epigenetic reprogramming. This leads to the initial activation of genes, marked by the accumulation of specific epigenetic markers such as H3K4me3 at gene promoters, H3K4me1 at enhancer. Some of these markers, like H3K4me1, remain even after the initial stimulus is gone (priming of enhancer/promoter). As a result of this epigenetic reprogramming, if the cells encounter a secondary stimulus, the transcription of immune genes is significantly enhanced. Figure was illustrated by Biorender (https://biorender.com/) accessed on 10th May 2024. BCG, Bacillus Calmette-Guérin; ATAC, Assay for Transposase-Accessible Chromatin.
Fig. 2. Interplay between metabolic and epigenetic rewiring during the trained immunity process. Various pathogens, vaccines, and stimuli can cause long-lasting changes in the functionality, metabolism, and epigenetic profiles of innate immune cells. Trained immunity enables an improved response upon a subsequent encounter with either the same or different pathogens, thereby providing broad-spectrum protection. The signaling pathway involving trained immunity activates mTOR-HIF1α signaling pathway, modifying the activity of various intracellular pathways. This results in the enhanced production of metabolites and co-factors necessary for the functioning of epigenetic enzymes, leading to changes in the chromatin and DNA’s epigenetic landscape. These alterations in gene expression play a pivotal role in the development of trained immunity. This figure was illustrated by Biorender (https://biorender.com/), accessed on 26th Mar 2024. BCG, Bacillus Calmette-Guérin; ILC, Innate lymphoid cell; DC, Dendritic cell; NK cell, Natural killer cell; ATP, Adenosine triphosphate; α-KG, α-Ketoglutarate; PRC, Polycomb repressive complex; Me, Methylation; TF, Transcription factor; RNAPII, RNA polymerase II; PRRs, Pattern recognition receptors; DAMPs, Damage-Associated Molecular Patterns; PAMPs, Pathogen-Associated Molecular Patterns.
TABLE

Roles of trained immunity in diverse pathological contexts

Pathologic contexts Inducer 2nd stimulation Role Mechanism Involved cells Ref.
Viral infection BCG RSV Protective Enhancing humoral immunity ? (41, 42)
Yellow fever virus Protective Enhancing IL-1β production Monocyte (48)
IVA Protective Enhancing efferocytosis Neutrophils, monocyte (46, 53)
Ectromelia virus Protective Enhancing IFN production ? (47)
SARS-CoV-2 Protective Reduction of cytokine production ? (52)
No effect ? ? (53)
β-glucan VSV Protective Enhancing IFN-β and IL-6 production Macrophage (49)
HSV Protective Enhancing IFN-β and IL-6 production Macrophage (49)
Herpesvirus Listeria monocytogenes Protective Enhancing TNF-α and IFN-γ production Macrophage (54)
Yersinia pestis Protective Enhancing TNF-α and IFN-γ production Macrophage (54)
West Nile virus No effect Enhancing TNF-α and IFN-γ production Macrophage (54)
Yellow fever virus Dengue virus Protective ? ? (55)
IVA SARS-CoV-2 Protective Downregulation of systemic inflammation Monocyte (56)
Cancer BCG Bladder cancer Protective Induction of autophayorelated gene transcription Monocyte (60)
Protective Enhancing TNF-α and IL-1β production Monocyte (63)
β-glucan Melanoma Protective Epigenetic rewiring of granulopoiesis Neutrophils (9)
Pancreatic cancer Protective Enhancing cytotoxicity Monocyte, macrophage (61)
Lung cancer Protective Enhancing phagocytiossis and cytotoxicity Monocyte, macrophage (64)
Autoimmune disease BCG MS (EAE) Protective Suppressing the Th17 response ? (72)
β-glucan Detrimental Enhancing Th17 and Th1 responses ? (71)
Helminth Protective Suppressing IL-17 production Macrophage (73)
β-glucan MS (TMEV-IDD) Protective ? ? (71)
SLE Detrimental ? ? (77)
RA Detrimental ? DCs (78)
Herpesvirus Asthma Protective ? Monocyte (87)

REFERENCES
  1. Netea MG, Quintin J and van der Meer JW (2011) Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355-361.
    Pubmed CrossRef
  2. Lemaitre B, Reichhart JM and Hoffmann JA (1997) Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proc Natl Acad Sci U S A 94, 14614-14619.
    Pubmed KoreaMed CrossRef
  3. Quintin J, Saeed S and Martens JHA et al (2012) Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223-232.
    Pubmed KoreaMed CrossRef
  4. de Bree LCJ, Koeken V and Joosten LAB et al (2018) Non-specific effects of vaccines: current evidence and potential implications. Semin Immunol 39, 35-43.
    Pubmed CrossRef
  5. Thysen SM, Jensen AKG and Rodrigues A et al (2019) Can earlier BCG vaccination reduce early infant mortality? Study protocol for a cluster randomised trial in Guinea-Bissau. BMJ Open 9, e025724.
    Pubmed KoreaMed CrossRef
  6. Garly ML, Martins CL and Balé C et al (2003) BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG?. Vaccine 21, 2782-2790.
    Pubmed CrossRef
  7. Saeed S, Quintin J and Kerstens HH et al (2014) Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086.
    Pubmed KoreaMed CrossRef
  8. Cheng SC, Quintin J and Cramer RA et al (2014) mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684.
    Pubmed KoreaMed CrossRef
  9. Kalafati L, Kourtzelis I and Schulte-Schrepping J et al (2020) Innate immune training of granulopoiesis promotes anti-tumor activity. Cell 183, 771-785.
    Pubmed KoreaMed CrossRef
  10. Hole CR, Wager CML and Castro-Lopez N et al (2019) Induction of memory-like dendritic cell responses in vivo. Nat Commun 10, 2955.
    Pubmed KoreaMed CrossRef
  11. Kleinnijenhuis J, Quintin J and Preijers F et al (2014) BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin Immunol 155, 213-219.
    Pubmed KoreaMed CrossRef
  12. Martinez-Gonzalez I, Matha L, Steer CA, Ghaedi M, Poon GF and Takei F (2016) Allergen-experienced group 2 innate lymphoid cells acquire memory-like properties and enhance allergic lung inflammation. Immunity 45, 198-208.
    Pubmed CrossRef
  13. de Laval B, Maurizio J and Kandalla PK et al (2020) C/EBPβ- dependent epigenetic memory induces trained immunity in hematopoietic stem cells. Cell Stem Cell 26, 657-674.
    Pubmed CrossRef
  14. Naik S, Larsen SB and Gomez NC et al (2017) Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475-480.
    Pubmed KoreaMed CrossRef
  15. Al B, Suen TK, Placek K and Netea MG (2023) Innate (learned) memory. J Allergy Clin Immunol 152, 551-566.
    Pubmed CrossRef
  16. Kleinnijenhuis J, Quintin J and Preijers F et al (2012) Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 109, 17537-17542.
    Pubmed KoreaMed CrossRef
  17. Schrum JE, Crabtree JN and Dobbs KR et al (2018) Cutting edge: plasmodium falciparum induces trained innate immunity. J Immunol 200, 1243-1248.
    Pubmed KoreaMed CrossRef
  18. Crișan TO, Cleophas MC and Oosting M et al (2016) Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann Rheum Dis 75, 755-762.
    Pubmed CrossRef
  19. Bekkering S, Quintin J, Joosten LA, van der Meer JW, Netea MG and Riksen NP (2014) Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler Thromb Vasc Biol 34, 1731-1738.
    Pubmed CrossRef
  20. van der Heijden C, Groh L and Keating ST et al (2020) Catecholamines induce trained immunity in monocytes in vitro and in vivo. Circ Res 127, 269-283.
    Pubmed CrossRef
  21. Jentho E, Ruiz-Moreno C and Novakovic B et al (2021) Trained innate immunity, long-lasting epigenetic modulation, and skewed myelopoiesis by heme. Proc Natl Acad Sci U S A 118, e2102698118.
    Pubmed KoreaMed CrossRef
  22. Tsoni SV and Brown GD (2008) Beta-glucans and dectin-1. Ann N Y Acad Sci 1143, 45-60.
    Pubmed CrossRef
  23. Chen J, Gao L and Wu X et al (2023) BCG-induced trained immunity: history, mechanisms and potential applications. J Transl Med 21, 106.
    Pubmed KoreaMed CrossRef
  24. Schnack L, Sohrabi Y and Lagache SMM et al (2019) Mechanisms of trained innate immunity in oxLDL primed human coronary smooth muscle cells. Front Immunol 10, 13.
    Pubmed KoreaMed CrossRef
  25. Bekkering S, Arts RJW and Novakovic B et al (2018) Metabolic induction of trained immunity through the mevalonate pathway. Cell 172, 135-146.
    Pubmed CrossRef
  26. van der Heijden C, Noz MP, Joosten LAB, Netea MG, Riksen NP and Keating ST (2018) Epigenetics and trained immunity. Antioxid Redox Signal 29, 1023-1040.
    Pubmed KoreaMed CrossRef
  27. Zhao S, Zhong Y and Fu X et al (2019) H3K4 methylation regulates lps-induced proinflammatory cytokine expression and release in macrophages. Shock 51, 401-406.
    Pubmed CrossRef
  28. Chen YG, Satpathy AT and Chang HY (2017) Gene regulation in the immune system by long noncoding RNAs. Nat Immunol 18, 962-972.
    Pubmed KoreaMed CrossRef
  29. Pombo A and Dillon N (2015) Three-dimensional genome architecture: players and mechanisms. Nat Rev Mol Cell Biol 16, 245-257.
    Pubmed CrossRef
  30. Fanucchi S, Fok ET and Dalla E et al (2019) Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat Genet 51, 138-150.
    Pubmed CrossRef
  31. Moorlag S, Rodriguez-Rosales YA and Gillard J et al (2020) BCG vaccination induces long-term functional reprogramming of human neutrophils. Cell Rep 33, 108387.
    Pubmed KoreaMed CrossRef
  32. Fanucchi S, Domínguez-Andrés J, Joosten LAB, Netea MG and Mhlanga MM (2021) The intersection of epigenetics and metabolism in trained immunity. Immunity 54, 32-43.
    Pubmed CrossRef
  33. Domínguez-Andrés J, Fanucchi S, Joosten LAB, Mhlanga MM and Netea MG (2020) Advances in understanding molecular regulation of innate immune memory. Curr Opin Cell Biol 63, 68-75.
    Pubmed CrossRef
  34. Mookerjee SA, Gerencser AA, Nicholls DG and Brand MD (2018) Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements. J Biol Chem 293, 12649-12652.
    Pubmed KoreaMed CrossRef
  35. Mitroulis I, Ruppova K and Wang B et al (2018) Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147-161.
    Pubmed KoreaMed CrossRef
  36. Groh LA, Ferreira AV and Helder L et al (2021) oxLDL-induced trained immunity is dependent on mitochondrial metabolic reprogramming. Immunometabolism 3, e210025.
    Pubmed KoreaMed CrossRef
  37. Keating ST, Groh L and van der Heijden C et al (2020) The Set7 lysine methyltransferase regulates plasticity in oxidative phosphorylation necessary for trained immunity induced by β-glucan. Cell Rep 31, 107548.
    Pubmed KoreaMed CrossRef
  38. Arts RJ, Novakovic B and Ter Horst R et al (2016) Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab 24, 807-819.
    Pubmed KoreaMed CrossRef
  39. Domínguez-Andrés J, Novakovic B and Li Y et al (2019) The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab 29, 211-220.
    Pubmed CrossRef
  40. Stensballe LG, Nante E and Jensen IP et al (2005) Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls community based case-control study. Vaccine 23, 1251-1257.
    Pubmed CrossRef
  41. Bueno SM, Gonzalez PA and Cautivo KM et al (2008) Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG. Proc Natl Acad Sci U S A 105, 20822-20827.
    Pubmed KoreaMed CrossRef
  42. Soto JA, Galvez NMS and Rivera CA et al (2018) Recombinant BCG vaccines reduce pneumovirus-caused airway pathology by inducing protective humoral immunity. Front Immunol 9, 2875.
    Pubmed KoreaMed CrossRef
  43. Spencer JC, Ganguly R and Waldman RH (1977) Nonspecific protection of mice against influenza virus infection by local or systemic immunization with Bacille Calmette-Guerin. J Infect Dis 136, 171-175.
    Pubmed CrossRef
  44. Ikeda S, Negishi T and Nishimura C (1985) Enhancement of non-specific resistance to viral infection by muramyldipeptide and its analogs. Antiviral Res 5, 207-215.
    Pubmed CrossRef
  45. Ishihara C, Mizukoshi N, Iida J, Kato K, Yamamoto K and Azuma I (1987) Suppression of Sendai virus growth by treatment with N alpha-acetylmuramyl-L-alanyl-D-isoglutaminyl-N epsilon-stearoyl-L-lysine in mice. Vaccine 5, 295-301.
    Pubmed CrossRef
  46. Mukherjee S, Subramaniam R, Chen H, Smith A, Keshava S and Shams H (2017) Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia. PLoS One 12, e0180143.
    Pubmed KoreaMed CrossRef
  47. Suenaga T, Okuyama T, Yoshida I and Azuma M (1978) Effect of Mycobacterium tuberculosis BCG infection on the resistance of mice to ectromelia virus infection: participation of interferon in enhanced resistance. Infect Immun 20, 312-314.
    Pubmed KoreaMed CrossRef
  48. Arts RJW, Moorlag S and Novakovic B et al (2018) BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe 23, 89-100.
    Pubmed CrossRef
  49. Wang G, Li Z and Tian M et al (2023) Beta-glucan induces training immunity to promote antiviral activity by activating TBK1. Viruses 15, 1204.
    Pubmed CrossRef
  50. Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y and Otazu GH (2020) Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. medRxiv, 2020.2003.2024.20042937.
    CrossRef
  51. Green CM, Fanucchi S and Dominguez-Andres J et al (2020) COVID-19: a model correlating BCG vaccination to protection from mortality implicates trained immunity. medRxiv, 2020.2004.2010.20060905.
    CrossRef
  52. Hilligan KL, Namasivayam S and Clancy CS et al (2022) Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge. J Exp Med 219, e20211862.
    Pubmed CrossRef
  53. Kaufmann E, Khan N and Tran KA et al (2022) BCG vaccination provides protection against IAV but not SARS-CoV-2. Cell Rep 38, 110502.
    Pubmed CrossRef
  54. Barton ES, White DW and Cathelyn JS et al (2007) Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326-329.
    Pubmed CrossRef
  55. Izurieta RO, Macaluso M and Watts DM et al (2009) Anamnestic immune response to dengue and decreased severity of yellow Fever. J Glob Infect Dis 1, 111-116.
    Pubmed KoreaMed CrossRef
  56. Debisarun PA, Gossling KL and Bulut O et al (2021) Induction of trained immunity by influenza vaccination - impact on COVID-19. PLoS Pathog 17, e1009928.
    Pubmed KoreaMed CrossRef
  57. Cheong JG, Ravishankar A and Sharma S et al (2023) Epigenetic memory of coronavirus infection in innate immune cells and their progenitors. Cell 186, 3882-3902.
    Pubmed KoreaMed CrossRef
  58. Pandori WJ, Padgett LE and Alimadadi A et al (2022) Single-cell immune profiling reveals long-term changes in myeloid cells and identifies a novel subset of CD9(+) monocytes associated with COVID-19 hospitalization. J Leukoc Biol 112, 1053-1063.
    Pubmed CrossRef
  59. Chen C, Man N and Liu F et al (2022) Epigenetic and transcriptional regulation of innate immunity in cancer. Cancer Res 82, 2047-2056.
    Pubmed KoreaMed CrossRef
  60. Buffen K, Oosting M and Quintin J et al (2014) Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog 10, e1004485.
    Pubmed KoreaMed CrossRef
  61. Geller AE, Shrestha R and Woeste MR et al (2022) The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression. Nat Commun 13, 759.
    Pubmed KoreaMed CrossRef
  62. Abdelghani KB, Nacef L and Miladi S et al (2021) Reactive arthritis following bacillus calmette-guerin therapy for bladder cancer: a systematic literature review. Curr Rheumatol Rep 23, 39.
    Pubmed CrossRef
  63. van Puffelen JH, Novakovic B and van Emst L et al (2023) Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections. J Immunother Cancer 11, e005518.
    Pubmed KoreaMed CrossRef
  64. Ding C, Shrestha R and Zhu X et al (2023) Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis. Nat Immunol 24, 239-254.
    Pubmed KoreaMed CrossRef
  65. Yi M, Li T and Niu M et al (2023) Exploiting innate immunity for cancer immunotherapy. Mol Cancer 22, 187.
    Pubmed KoreaMed CrossRef
  66. Lerias JR, de Sousa E and Paraschoudi G et al (2019) Trained immunity for personalized cancer immunotherapy: current knowledge and future opportunities. Front Microbiol 10, 2924.
    Pubmed CrossRef
  67. Singh AK, Praharaj M and Lombardo KA et al (2022) Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer. Nat Commun 13, 878.
    Pubmed KoreaMed CrossRef
  68. Chen Z, Yong T and Wei Z et al (2023) Engineered probiotic-based personalized cancer vaccine potentiates antitumor immunity through initiating trained immunity. Adv Sci (Weinh), e2305081.
    Pubmed CrossRef
  69. Priem B, van Leent MMT and Teunissen AJP et al (2020) Trained immunity-promoting nanobiologic therapy suppresses tumor growth and potentiates checkpoint inhibition. Cell 183, 786-801.
    Pubmed KoreaMed CrossRef
  70. Rodríguez Murúa S, Farez MF and Quintana FJ (2022) The immune response in multiple sclerosis. Annu Rev Pathol 17, 121-139.
    Pubmed CrossRef
  71. Sato F, Nakamura Y and Katsuki A et al (2022) Curdlan, a microbial β-glucan, has contrasting effects on autoimmune and viral models of multiple sclerosis. Front Cell Infect Microbiol 12, 805302.
    Pubmed KoreaMed CrossRef
  72. Matsuzaki G, Teruya N and Kiyohara Kohama H et al (2021) Mycobacterium bovis BCG-mediated suppression of Th17 response in mouse experimental autoimmune encephalomyelitis. Immunopharmacol Immunotoxicol 43, 203-211.
    Pubmed CrossRef
  73. Quinn SM, Cunningham K and Raverdeau M et al (2019) Anti-inflammatory trained immunity mediated by helminth products attenuates the induction of T cell-mediated autoimmune disease. Front Immunol 10, 1109.
    Pubmed KoreaMed CrossRef
  74. Kaul A, Gordon C and Crow MK et al (2016) Systemic lupus erythematosus. Nat Rev Dis Primers 2, 16039.
    Pubmed CrossRef
  75. Idborg H and Oke V (2021) Cytokines as biomarkers in systemic lupus erythematosus: value for diagnosis and drug therapy. Int J Mol Sci 22, 11327.
    Pubmed KoreaMed CrossRef
  76. Funes SC, Rios M, Fernández-Fierro A, Di Genaro MS and Kalergis AM (2022) Trained immunity contribution to autoimmune and inflammatory disorders. Front Immunol 13, 868343.
    Pubmed KoreaMed CrossRef
  77. Fagone P, Mangano K and Mammana S et al (2014) Acceleration of SLE-like syndrome development in NZBxNZW F1 mice by beta-glucan. Lupus 23, 407-411.
    Pubmed CrossRef
  78. Yoshitomi H, Sakaguchi N and Kobayashi K et al (2005) A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med 201, 949-960.
    Pubmed KoreaMed CrossRef
  79. Hida S, Miura NN, Adachi Y and Ohno N (2005) Effect of Candida albicans cell wall glucan as adjuvant for induction of autoimmune arthritis in mice. J Autoimmun 25, 93-101.
    Pubmed CrossRef
  80. Bekkering S, Stiekema LCA and Bernelot Moens S et al (2019) Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia. Cell Metab 30, 1-2.
    Pubmed CrossRef
  81. Yin Y, Choi SC and Xu Z et al (2015) Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med 7, 274ra218.
    Pubmed KoreaMed CrossRef
  82. Lee YZ, Guo HC and Zhao GH et al (2020) Tylophorine-based compounds are therapeutic in rheumatoid arthritis by targeting the caprin-1 ribonucleoprotein complex and inhibiting expression of associated c-Myc and HIF-1α. Pharmacol Res 152, 104581.
    Pubmed CrossRef
  83. Agache I, Cojanu C, Laculiceanu A and Rogozea L (2020) Genetics and epigenetics of allergy. Curr Opin Allergy Clin Immunol 20, 223-232.
    Pubmed CrossRef
  84. Holgate ST, Wenzel S, Postma DS, Weiss ST, Renz H and Sly PD (2015) Asthma. Nat Rev Dis Primers 1, 15025.
    Pubmed KoreaMed CrossRef
  85. Lauzon-Joset JF, Mincham KT and Scott NM et al (2021) Protection against neonatal respiratory viral infection via maternal treatment during pregnancy with the benign immune training agent OM-85. Clin Transl Immunology 10, e1303.
    Pubmed KoreaMed CrossRef
  86. Troy NM, Strickland D and Serralha M et al (2022) Protection against severe infant lower respiratory tract infections by immune training: mechanistic studies. J Allergy Clin Immunol 150, 93-103.
    Pubmed CrossRef
  87. Machiels B, Dourcy M and Xiao X et al (2017) A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat Immunol 18, 1310-1320.
    Pubmed CrossRef
  88. Steer CA, Mathä L, Shim H and Takei F (2020) Lung group 2 innate lymphoid cells are trained by endogenous IL-33 in the neonatal period. JCI Insight 5, e135961.
    Pubmed KoreaMed CrossRef
  89. Tulic MK, Hodder M and Forsberg A et al (2011) Differences in innate immune function between allergic and nonallergic children: new insights into immune ontogeny. J Allergy Clin Immunol 127, 470-478.
    Pubmed CrossRef
  90. Zhang Y, Collier F and Naselli G et al (2016) Cord blood monocyte-derived inflammatory cytokines suppress IL-2 and induce nonclassic "T(H)2-type" immunity associated with development of food allergy. Sci Transl Med 8, 321ra328.
    Pubmed CrossRef
  91. Neeland MR, Koplin JJ and Dang TD et al (2018) Early life innate immune signatures of persistent food allergy. J Allergy Clin Immunol 142, 857-864.
    Pubmed CrossRef
  92. Pfaar O, Creticos PS, Kleine-Tebbe J, Canonica GW, Palomares O and Schülke S (2021) One hundred ten years of allergen immunotherapy: a broad look into the future. J Allergy Clin Immunol Pract 9, 1791-1803.
    Pubmed CrossRef
  93. Eljaszewicz A, Ruchti F and Radzikowska U et al (2021) Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy. J Allergy Clin Immunol 147, 1865-1877.
    Pubmed CrossRef
  94. Golebski K, Layhadi JA and Sahiner U et al (2021) Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response. Immunity 54, 291-307.
    Pubmed CrossRef


This Article


Cited By Articles
  • CrossRef (0)

Funding Information

Collections

Services
Social Network Service

e-submission

Archives