Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3)

Abstract

Background The mechanisms contributing to clinical immune tolerance remain incompletely understood. This study provides evidence for specific immune mechanisms that are associated with a model of operationally defined clinical tolerance. Objective Our overall objective was to study laboratory changes associated with clinical immune tolerance in antigen-induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy. Methods In a phase 1, single site study, we studied participants (n=23) undergoing peanut OIT and compared them to age-matched allergic controls (n=20) undergoing standard of care (abstaining from peanut) for 24 months. Participants were operationally defined as clinically immune tolerant (IT) if they had no detectable allergic reactions to a peanut oral food challenge after 3 months of therapy withdrawal (IT, n=7) while those that had an allergic reaction were categorized as non-tolerant (NT, n=13). Results Antibody and basophil activation measurements did not statistically differentiate between NT vs. IT. However, T-cell function and demethylation of FOXP3 CpG sites in antigen-induced Treg were significantly different between IT vs. NT participants. When IT participants were withdrawn from peanut therapy for an additional 3 months (total of 6 months); only 3 participants remained "immune tolerant" and 4 participants regained sensitivity along with increased methylation of FOXP3 CpG sites in antigen-induced Treg. Conclusion In summary, modifications at the DNA level of antigen-induced T-cell subsets may be predictive of a state of operationally-defined clinical "immune tolerance" during peanut OIT.

Low-Dose IL-2 Induces Regulatory T Cell–Mediated Control of Experimental Food Allergy

“…tolerance (28,29) and in the mechanism of AIT efficacy (12,30,31). However, specific Treg-based immunotherapies have not been evaluated in the context of food allergy.…”

Oral Immunotherapy for Food Allergy

“…After 6-12 months of OIT, there appears to be a shift away from T H 2 cytokine production towards a proinflammatory profile characterized by increased production of IL-1β and TNF-α [18]. Syed et al demonstrated increased function of antigen-specific CD4 + CD25 + FoxP3 + regulatory T cells following OIT, thus supporting the theory of active suppression of immune responses [56,58]. Gorelik et al [59] studied the mechanisms and duration of suppression of immune responses during peanut immunotherapy reported in the study by Narisety et al [60] and found that spontaneous and allergen-induced basophil reactivity, including IL-4 production, were suppressed during dose escalation and after 6 months of maintenance dosing.…”

Toward precision medicine and health: Opportunities and challenges in allergic diseases

“…[77][78][79][80] Can we devise tests to identify those subjects who are responding favorably to such OIT? In one small phase 1 single-site study, 4 of the 7 peanut allergic subjects who achieved sustained unresponsiveness to peanut (based on passing a DBPCFC at 3 months after discontinuation of OIT) had regained reactivity to peanut 3 months later, whereas the 3 other patients continued to exhibit a more persistent pattern of non-reactivity.…”

“…In one small phase 1 single-site study, 4 of the 7 peanut allergic subjects who achieved sustained unresponsiveness to peanut (based on passing a DBPCFC at 3 months after discontinuation of OIT) had regained reactivity to peanut 3 months later, whereas the 3 other patients continued to exhibit a more persistent pattern of non-reactivity. 78 That study suggested that persistent demethylation of the FOXP3 gene in T regulatory cells (Tregs) may help to identify this "subtype" of patients who can maintain longer-term clinical non-reactivity to peanut even in the absence of regularly consuming maintenance doses of peanut. 78 Another study of a small number of subjects suggests that successful OIT in peanut allergic patients may be associated with the expansion of a population of allergen-specific CD4+ T cells that develop an 'anergic' T H 2 T cell phenotype, cells that were largely absent in both pretreatment participants and healthy controls.…”

“…78 That study suggested that persistent demethylation of the FOXP3 gene in T regulatory cells (Tregs) may help to identify this "subtype" of patients who can maintain longer-term clinical non-reactivity to peanut even in the absence of regularly consuming maintenance doses of peanut. 78 Another study of a small number of subjects suggests that successful OIT in peanut allergic patients may be associated with the expansion of a population of allergen-specific CD4+ T cells that develop an 'anergic' T H 2 T cell phenotype, cells that were largely absent in both pretreatment participants and healthy controls. 81 While these studies are encouraging, they need extension to larger numbers of subjects and confirmation in multiple test sites.…”