<i>Gata3</i> hypermethylation and <i>Foxp3</i> hypomethylation are associated with sustained protection and bystander effect following epicutaneous immunotherapy in peanut‐sensitized mice

Mondoulet, Lucie; Dioszeghy, Vincent; Busato, Florence; Plaquet, Camille; Dhelft, Véronique; Bethune, Kévin; Leclere, Laurence; Daviaud, Christian; Ligouis, Mélanie; Sampson, Hugh A.; Dupont, Christophe; Tost, Jörg

doi:10.1111/all.13479

Cited by 64 publications

(61 citation statements)

References 53 publications

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“…In the present study, we demonstrated that AIT differentially modifies the activation and function of several Treg subsets. AIT in vivo increased subsets of allergen‐specific Treg cells with distinct phenotypes, and the mechanisms of action include the CD4 + CD25 + CD127 − FOXP3 + nTreg and the CD4 + IL‐10‐secreting Tr1 cells . In addition to changes in allergen‐specific Treg cells, we observed that in 9 out of 12 patients, overall IL‐10 + Tr1 cells also increased during AIT, which is concordant with the previous data reported by others …”

Section: Discussionsupporting

confidence: 91%

Der p 1‐specific regulatory T‐cell response during house dust mite allergen immunotherapy

Boonpiyathad

Sokołowska

Morita

et al. 2019

Allergy

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Background: Allergen-specific immunotherapy (AIT) is the only available treatment for allergic diseases that can induce specific immune tolerance to allergens. The key mechanisms involved in this process include changes in allergen-specific regulatory T (Treg) cells. Methods:We studied 25 allergic rhinitis patients undergoing subcutaneous house dust mite-specific immunotherapy. Peripheral blood mononuclear cells were studied before and after 10, 30 weeks, and 3 years of AIT. Der p 1-specific T regulatory cell responses were investigated by characterization of Der p 1-MHC class II tetramerpositive cells and correlated with nasal symptom score. Results: Twelve of 25 AIT patients matched with their MHC class II expression to the Der p 1 peptide-MHC class II tetramers. A significant increase in the numbers of Der p 1-specific FOXP3 + Helios + CD25 + CD127 − Treg cells after 30 weeks was observed, which slightly decreased after 3 years of AIT. In contrast, Der p 1-specific immunoglobulin-like transcript 3 (ILT3) + CD25 + Treg cells decreased substantially from baseline after 3 years of AIT. ILT3 + Treg cells displayed compromised suppressive function and low FOXP3 expression. In addition, Der p 1-specific IL-10 and IL-22 responses have increased after 30 weeks, but only IL-10 + Der p 1-specific Treg cells remained present at high frequency after 3 years of AIT. Increased number of FOXP3 + Helios + and IL-10 + and decreased ILT3 + Treg cell responses correlated with improved allergic symptoms. Conclusion: The results indicate that AIT involves upregulation of the activated allergen-specific Treg cells and downregulation of dysfunctional allergen-specific Treg cell subset. Correction of dysregulated Treg cells responses during AIT is associated with improved clinical response. K E Y W O R D Sallergen-specific T cells, antigen-specific immunotherapy, house dust mite allergy, Treg Abbreviations: AIT, antigen-specific immunotherapy; AR, allergic rhinitis; HDM, house dust mite; ILT3, immunoglobulin-like transcript 3; Treg, T regulatory.

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Section: Discussionsupporting

confidence: 91%

Der p 1‐specific regulatory T‐cell response during house dust mite allergen immunotherapy

Boonpiyathad

Sokołowska

Morita

et al. 2019

Allergy

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“…82 In the same context, Foxp3 promoter hypomethylation in CD62L Tregs and GATA3 promoter hypermethylation in Th2 cells were associated with sustained protection in mice. 83 More recently, it was shown that while both Langerhans cells and CD11b+ cDC2s acquire and present topical antigen to T cells, the IRF-4-dependent cDC2s are required for T-cell priming and LAP+ Treg expansion. 84 In contrast to epicutaneous immunotherapy, epicutaneous sensitization resulting in food allergy can occur when the skin barrier is damaged.…”

Section: Mechanistic Insights From Mouse Models On How To Treat Foomentioning

confidence: 99%

Recent developments and highlights in food allergy

Eiwegger

Hung

Diego

et al. 2019

Allergy

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The achievement of long-lasting, safe treatments for food allergy is dependent on the understanding of the immunological basis of food allergy. Accurate diagnosis is essential for management. In recent years, data from oral food challenges have revealed that routine allergy testing is poor at predicting clinical allergy for tree nuts, almonds in particular. More advanced antigen-based tests including component-resolved diagnostics and epitope reactivity may lead to more accurate diagnosis and selection of therapeutic intervention. Additional diagnostic accuracy may come from cellular tests such as the basophil activation test or mast cell approaches. In the context of clinical trials, cellular tests have revealed specific T-cell and B-cell populations that are more abundant in food-allergic individuals with distinct mechanistic features.Awareness of clinical markers, such as the ability to eat baked forms of milk and egg, continues to inform the understanding of natural tolerance development.Mouse models have allowed for investigation into multiple mechanisms of food allergy including modification of epithelial metabolism, and the induction of regulatory cell subsets and the microbiome. Increasing numbers of children who underwent food immunotherapy enlarged the body of evidence on mechanisms and predictors of treatment success. Experimental immunological markers in conjunction with clinical determinants such as lower age and lower initial specific IgE appear to be of benefit.More research on the optimal dose, preparation, and route of application integrating a high-level safety and efficacy is demanded. Alternatively, biologics blocking TSLP, IL-33, IL-4 and IL-13, or IgE may help to achieve that. K E Y W O R D Sallergy treatment, biologics, food allergy, immune tolerance, immunotherapy | 2357 EIWEGGER Et al.

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“…Similarly, recently, we have shown in a mouse model of epicutaneous immunotherapy for peanut allergy that Foxp3 methylation was reduced on successful epicutaneous immunotherapy, whereas methylation of the T H 2 key transcription factor Gata3 was specifically increased in splenic CD4 1 IL-4 1 T cells. 19 In contrast, oral immunotherapy induced only demethylation of Foxp3 but not methylation of Gata3, suggesting that the latter might be important to maintain the level of sustained unresponsiveness and protection against sensitization to a second allergen observed in epicutaneous immunotherapy.…”

Section: Dna Methylation As a Biomarker For Treatment And Immunotherapymentioning

confidence: 95%

“…Although a major criticism of DNA methylation analyses has been that changes will only reflect variations in proportions of the analyzed cell populations, recent results have also shown that not only are cell proportions changed but also the epigenomic landscape is modified in specific cell populations. 10,19 Nonetheless, EWASs have great potential for explaining phenotypic variability, as exemplified by a study on DNA methylation levels associated with serum IgE levels, which showed a 10-fold greater capacity of genome-wide DNA methylation patterns to explain the observed variability in IgE concentrations compared with genetic variation. 20 EWASs might not only deepen our understanding of the underlying disease etiology by pointing to disease-relevant pathways, such as the T H 1/T H 2 pathway 21 and other immunologically relevant pathways in patients with cow's milk allergy 22 but could also provide a multitude of other target genes that need to be further investigated in functional studies, including transcription factors, mitochondrial proteins, and proteins involved in T-cell maturation or oxidative stress.…”

Section: Dna Methylationmentioning

confidence: 99%

A translational perspective on epigenetics in allergic diseases

Tost

2018

Journal of Allergy and Clinical Immunology

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The analysis of epigenetic modifications in allergic diseases has recently attracted substantial interest because epigenetic modifications can mediate the effects of the environment on the development of or protection from allergic diseases. Furthermore, recent research has provided evidence for an altered epigenomic landscape in disease-relevant cell populations. Although still in the early phase, epigenetic modifications, particularly DNA methylation and microRNAs, might have potential for assisting in the stratification of patients for treatment and complement or replace in the future biochemical or clinical tests. The first epigenetic biomarkers correlating with the successful outcome of immunotherapy have been reported, and with personalized treatment options being rolled out, epigenetic modifications might well play a role in monitoring or even predicting the response to tailored therapy. However, further studies in larger cohorts with well-defined phenotypes in specific cell populations need to be performed before their implementation. Furthermore, the epigenome provides an interesting target for therapeutic intervention, with microRNA mimics, inhibitors, and antisense oligonucleotides being evaluated in clinical trials in patients with other diseases. Selection or engineering of populations of extracellular vesicles and epigenetic editing represent novel tools for modulation of the cellular phenotype and responses, although further technological improvements are required. Moreover, interactions between the host epigenome and the microbiome are increasingly recognized, and interventions of the microbiome could contribute to modulation of the epigenome with a potential effect on the overall goal of prevention of allergic diseases.

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Gata3 hypermethylation and Foxp3 hypomethylation are associated with sustained protection and bystander effect following epicutaneous immunotherapy in peanut‐sensitized mice

Abstract: Our study demonstrates that EPIT leads to a unique and stable epigenetic signature in specific T-cell compartments with downregulation of Th2 key regulators and upregulation of Treg transcription factors, likely explaining the sustainability of protection and the observed bystander effect.

Cited by 64 publications

References 53 publications

Der p 1‐specific regulatory T‐cell response during house dust mite allergen immunotherapy

Der p 1‐specific regulatory T‐cell response during house dust mite allergen immunotherapy

Recent developments and highlights in food allergy

A translational perspective on epigenetics in allergic diseases

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