Therapeutic targeting of trained immunity

Mulder, Willem J. M.; Ochando, Jordi; Joosten, Leo A. B.; Fayad, Zahi A.; Netea, Mihai G.

doi:10.1038/s41573-019-0025-4

Cited by 343 publications

(314 citation statements)

References 155 publications

(197 reference statements)

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“…43 It is well-recognized that TLR activation in DCs and macrophages induces a glycolytic burst, 44,45 but data for CLRs are mostly limited to Dectin-1 activated by β-glucan. 29 We demonstrate that mTOR activation is implicated in the induction of IL-10 and PD-L1 in human PM-activated DCs. Schülke et al also described that in mDCs activated by the fusion protein rFlaA:Betv1, mTOR regulates IL-10 production.…”

Section: Discussionmentioning

confidence: 70%

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Benito-Villalvilla

Soria

Pérez‐Diego

et al. 2019

Allergy

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Background Polymerized allergoids conjugated to mannan (PM) are suitable vaccines for allergen‐specific immunotherapy (AIT). Alum remains the most widely used adjuvant in AIT, but its way of action is not completely elucidated. The better understanding of the mechanisms underlying alum adjuvanticity could help to improve AIT vaccine formulations. Objective We sought to investigate the potential influence of alum in the tolerogenic properties imprinted by PM at the molecular level. Methods Flow cytometry, ELISAs, cocultures, intracellular staining and suppression assays were performed to assess alum and PM effects in human dendritic cells (DCs). BALB/c mice were immunized with PM alone or adsorbed to alum. Allergen‐specific antibodies, splenocyte cytokine production and splenic forkhead box P3 (FOXP3)+ regulatory T (Treg) cells were quantified. Metabolic and immune pathways were also studied in human DCs. Results Alum decreases PD‐L1 expression and IL‐10 production induced by PM in human DCs and increases pro‐inflammatory cytokine production. Alum impairs PM‐induced functional FOXP3+ Treg cells and promotes Th1/Th2/Th17 responses. Subcutaneous immunization of mice with PM plus alum inhibits in vivo induction of Treg cells promoted by PM without altering the capacity to induce functional allergen‐specific blocking antibodies. Alum inhibits mTOR activation and alters metabolic reprogramming by shifting glycolytic pathways and inhibiting reactive oxygen species (ROS) production in PM‐activated DCs, impairing their capacity to generate functional Treg cells. Conclusion We uncover novel mechanisms by which alum impairs the tolerogenic properties induced by PM, which might well contribute to improve the formulation of novel vaccines for AIT.

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Section: Discussionmentioning

confidence: 70%

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Benito-Villalvilla

Soria

Pérez‐Diego

et al. 2019

Allergy

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“…Stem cells express receptors for several inflammatory mediators, which enables them to adjust to their specific inflammatory milieu [96][97][98] . Moreover, stem cells Box 1 | Trained immunity as a therapeutic target regulating trained immunity can be a powerful therapeutic paradigm in different disease contexts 176 . Depending on the condition, it could be beneficial to induce trained immunity to aid specific cancer therapies or to treat the immune paralysis associated with sepsis.…”

Section: Trained Immunity In Stromal and Epidermal Stem Cellsmentioning

confidence: 99%

Defining trained immunity and its role in health and disease

et al. 2020

Self Cite

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| Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity. ✉

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“…Interestingly, HK administration of the S. pyogenes antigen, still cured half of the infected hosts. This could possibly happen as a result of trained immunity, a de facto immune memory of the innate immune system, which is believed to empower a stronger immune response upon a subsequent inflammatory stimulus 40 . To clarify this possibility, future work could be to experiment with infected mice deprived of T cells (e.g.…”

Section: Discussionmentioning

confidence: 99%

ChronicStaphylococcus aureusinfection is cured by theory-driven therapy

Zhao

Khailaie

et al. 2020

Preprint

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19Staphylococcus aureus (S. aureus) is a challenging human pathogen due to its ability to evade the 20 immune system and resist multidrug antibiotics. These evasive strategies lead to chronic and re-21 current infections. Many studies have documented that during chronic infections Myeloid Derived 22 Suppressor Cells (MDSCs) exert immunosuppressive mechanisms on T cells. A mathematical 23 model explains how the steady state of chronic infection can be disturbed and suggests therapeutic 24 strategies to clear the infection. Model-driven suggestions were tested experimentally and con-25 firmed complete clearance of S. aureus chronic infection. 26 Keywords 27 Myeloid Derived Suppressor Cells, MDSCs, Staphylococcus aureus, chronic infection, mathematical model, 28 therapy, cure, heat-killed cells 29Staphylococcus aureus (S. aureus) is a bacterial human pathogen colonizing 20%-30% of the world pop-30 ulation and responsible for the genesis of nosocomial-acquired and community-acquired bacterial infections. 31 Colonization by S. aureus is typically asymptomatical, implying an equilibrated state between host and bac-32 terium. However, the bacterium can become opportunistic often post-surgery or after implantation of medical 33 devices and can cause skin and soft tissue infections, such as dermatitis, impetigo, and cellulitis 1 , as well as 34 life-threatening conditions like pneumonia and chronic osteomyelitis 2 . Additionally, individuals with immune 35 deficiencies are more susceptible to S. aureus infections. The pathogen constitutes a serious problem in clin-36 ics worldwide because it uses multiple mechanisms to persist in the host. These include strategies of bacterial 37 1 evasion, multi-drug antibiotic resistance, immunosuppression 3 or manipulation of the host's immune regulatory 38 mechanisms, 4;5 which lead to chronic and difficult-to-treat infections. 39Typically, immunosuppression is achieved via regulatory T cells (Tregs), T cell lysis, regulatory B cells 40 (Bregs) 6 , and Myeloid-Derived Suppressor Cells (MDSCs). In the case of S. aureus chronic infections, immuno-41 suppression is not attributed to Bregs, tolerogenic dendritic cells, nor Tregs 7 . Treg-depletion has only a minor 42 effect, whereas T-cell proliferation remains inhibited despite the absence of B220 + and CD11c + cells 7 . Never-43 theless, T-cell suppression in chronically infected mice has been associated with the expansion of monocytic-like 44 (CD11b + Ly6C + Ly6G low phenotype), neutrophilic-like (CD11b + Ly6C low Ly6G + phenotype) and eosonophilic-45 like (CD11b + Ly6C low Ly6G low phenotype) MDSCs 7;8;9;10;11 , affirming the dominant immunosuppressive role of 46 MDSCs during chronic S. aureus infections. 47MDSCs constitute a heterogeneous population of immature myeloid cells, which exert their suppressive 48 effect on T cells by producing reactive oxygen species, nitric oxide, arginase, and inducible nitric oxide syn-49 thase. Significant MDSC expansion and the consequent immunosuppressive effect were reported in long-lasting 50 p...

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Therapeutic targeting of trained immunity

Cited by 343 publications

References 155 publications

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Defining trained immunity and its role in health and disease

ChronicStaphylococcus aureusinfection is cured by theory-driven therapy

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