Peanut oral immunotherapy increases Tregs and epigenetically modifies FOXP3

The mechanisms contributing to clinical immune tolerance are largely unknown. The objective of Syed et al was to study the changes associated with clinical immune tolerance in antigen induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy (J Allergy Clin Immunol 2014; 133(2): 500-510). The induction of regulatory T (Treg) cells has been a potential mechanism of maintaining immune tolerance, with Treg deficiencies implicated in the development of allergies.  Fork head box protein 3 (Foxp3) is a transcription factor that regulates Tregs, including natural regulatory Tregs (nTregs) and induced regulatory Tregs (iTregs). Epigenetic modifications to regions within the Foxp3 locus have been associated with stable Foxp3 expression and Treg cell-suppressive function.  

The authors investigated whether antigen-induced Tregs (aiTregs) and humoral and basophil immune markers are induced by OIT in clinically immune tolerant (IT) versus non-tolerant (NT) patients after OIT.  20 participants (with 20 peanut allergic controls undergoing standard avoidance therapy) successfully completed 24 months of OIT, tolerating up to 4g of peanut protein after maintenance therapy.   After 3 months of peanut avoidance, only 7 of 20 participants were defined as IT participants; these 7 avoided peanut for an additional 3 months and only 3 of 7 remained clinically nonreactive (IT).  The peanut induced basophil response was reduced in the OIT participants with a trend of more reduction in the IT group. The IT participants had higher numbers of ai-Treg cells with greater suppressive function and with higher levels of FOXP3 hypomethalation compared with NT and control participants.  The population of ai-Tregs the authors identified during OIT had a marked increase in Foxp3 expression and associated increases in both chemotaxis toward intestinal epithelial cells and suppressive function toward antigen-induced effector T cells (Teff).  Furthermore, dendritic cells (DCs) isolated after OIT therapy significantly decreased the methylation of Foxp3 in Teff cells.

These data suggest that ai-Treg cells are a key regulatory cell type modulating the immune response during OIT and that epigenetic regulation of these T cells might contribute to the induction of such immune tolerance. Although larger phase 2 clinical trials in OIT are justified and feasible, the results may be predictive of a state of operationally defined clinical immune tolerance during peanut OIT and contribute to providing safe and effective therapy for patients with peanut allergy.

Below are some questions posed to the authors regarding their article and the authors’ responses:

Why do there seem to be mixed results about the presence of Treg in food oral immunotherapy in humans?
The gating and definition of Treg is very important. Some labs report CD4+CD25+Foxp3+ cells as Treg but Treg should best be defined by suppression assays on the functional level if there is enough blood sample. In addition, the presence of Foxp3 can indicate an activated CD4+ T cell, not necessarily a Treg and Treg don't have to have Foxp3 to be a Treg.

Is there potential for Type 2 cytokines to be immune markers in IT vs NT participants?
We have examined some Th2 markers by flow cytometry and intracellular staining with no specific trends showing a difference between IT vs NT but further studies are underway.

What if any data is available about ILC2 activation during food allergy?
We are currently examining ILC2 cells in the periphery of food allergic patients.

What could be a potential outcome if patients did not avoid peanut after OIT therapy and included it in their diets?
There are several trials around the world examining this and we will be conducting mechanistic studies to try to understand differences in desensitization vs sustained unresponsiveness long term.

Comments

Post a Comment

Popular posts from this blog

Features of the bronchial bacterial microbiome associated with atopy, asthma and responsiveness to inhaled corticosteroid treatment

It’s been known that asthmatic lungs are different from healthy lungs in many aspects, including housing different strains of bacteria.  So far, studies haven’t been able to tell whether these differences are due to asthma, associated allergies (atopy), or treatment with different drugs.  They also haven’t been able to determine how these differences affect the way asthma manifests itself and how asthma can be treated.  In this month’s issue of JACI, Durack and colleagues aim to answer these pressing questions ( J Allergy Clin Immunol 2017; 140(1): 63-75 ). Durack and other investigators looked at the bacterial communities in 84 individuals, split into three groups: (1) 42 atopic asthmatic subjects, (2) 21 atopic non-asthmatic subjects, and (3) 21 non-atopic non-asthmatic, otherwise healthy, subjects.  They also looked at inflammatory markers and changes in bronchial hyperresponsiveness after 6 weeks of treatment with fluticasone, an inhaled steroid commonly used for...
Read more

Introducing an environmental assessment and intervention program in inner-city schools

Few studies have comprehensively examined the role the school environment plays in asthma and how effectively changing the environment may reduce morbidity, when adjusting for exposures in the home. In their review, Huffaker and Phipatanakul summarize the importance and common challenges of school-based environmental assessment and intervention studies linked to health effects ( J Allergy Clin Immunol 2014; 134: 1232-1237 ). They discuss the challenges and potential benefits of comprehensive environmental assessment and health outcomes in inner-city schools. The school environment has been shown to be a significant reservoir for allergens and pollutants. Indoor allergens known to be important in urban home environments may also be important in schools, including cockroach, cat, dog, mouse, dust-mite, and molds. Studies have identified children with asthma in inner-cities have markedly higher levels of mouse allergen in their schools compared to levels in their individual bedrooms. Give...
Read more

Role of viral infections in the development and exacerbation of asthma in children

Wheezing is a common complaint among parents of infants.  About 1 in 5 children have acute wheezing illnesses in their first two years of life.  This is important because an overwhelming majority of these wheezing illnesses are related to viruses, and are linked to asthma development.  In this month’s issue of JACI, Jartti and Gern review the role of viral infections in the development of asthma in children ( J Allergy Clin Immunol 2017; 140(4): 895-906 ).  They survey the viruses -rhinoviruses, respiratory syncytial viruses, and others – and how they impact the developing set of lungs.  Genetic variation and low interferon responses are two factors that increase the risk of these types of infections.  In addition, increased eosinophil counts in blood and nasal mucus and atopic eczema all increase the risk of later asthma.  Additionally, viral infections can lead to exacerbations in children who already have asthma.  This may explain why the rates...
Read more