Increased diversity of gut microbiota during active oral immunotherapy in peanut-allergic adults.
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ABSTRACT:
SUBMITTER: He Z
PROVIDER: S-EPMC7858691 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
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Increased diversity of gut microbiota during active oral immunotherapy in peanut-allergic adults.
He Ziyuan Z Vadali Vl Gouri VG Szabady Rose L RL Zhang Wenming W Norman Jason M JM Roberts Bruce B Tibshirani Robert R Desai Manisha M Chinthrajah R Sharon RS Galli Stephen J SJ Andorf Sandra S Nadeau Kari C KC
Allergy 20200825 3
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Project description: Not available
| S-EPMC9899491 | biostudies-literature
Project description:In Westernized countries, over 1% of the population is allergic to peanuts or tree nuts, which carries a risk of severe allergic reactions. Several studies support the efficacy of peanut oral immunotherapy (OIT) for reducing the clinical sensitivity of affected individuals; however, the mechanisms of this effect are still being characterized. One mechanism that may contribute is the suppression of effector cells, such as basophils. Basophil anergy has been characterized in vitro as a pathway-specific hyporesponsiveness; however, this has not been demonstrated to occur in vivo.To evaluate the hypothesis that basophil anergy occurs in vivo due to chronic allergen exposure in the setting of a clinical oral immunotherapy trial.Samples of peripheral blood were obtained from subjects during a placebo-controlled clinical trial of peanut OIT. Basophil reactivity to in vitro stimulation with peanut allergen and controls was assessed by the upregulation of activation markers, CD63 and CD203c, measured by flow cytometry.The upregulation of CD63 following stimulation of the IgE receptor, either specifically with peanut allergen or non-specifically with anti-IgE antibody, was strongly suppressed by active OIT. However, OIT did not significantly suppress this response in basophils stimulated by the distinct fMLP receptor pathway. In the subset of subjects with egg sensitization, active peanut OIT also suppressed CD63 upregulation in response to stimulation with egg allergen. Allergen OIT also suppressed the upregulation of CD203c including in response to stimulation with IL-3 alone.Peanut OIT induces a hyporesponsive state in basophils that is consistent with pathway-specific anergy previously described in vitro. This suggests the hypothesis that effector cell anergy could contribute to clinical desensitization.
| S-EPMC3779434 | biostudies-literature
Project description:BackgroundOral immunotherapy (OIT) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted. Newly diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment.ObjectiveWe sought to test the safety, effectiveness, and feasibility of early OIT (E-OIT) in the treatment of peanut allergy.MethodsWe enrolled 40 children aged 9 to 36 months with suspected or known peanut allergy. Qualifying subjects reacted to peanut during an entry food challenge and were block-randomized 1:1 to receive E-OIT at goal maintenance doses of 300 or 3000 mg/d in a double-blinded fashion. The primary end point, sustained unresponsiveness at 4 weeks after stopping early intervention oral immunotherapy (4-SU), was assessed by double-blinded, placebo-controlled food challenge either upon achieving 4 prespecified criteria, or after 3 maintenance years. Peanut-specific immune responses were serially analyzed. Outcomes were compared with 154 matched standard-care controls.ResultsOf 40 consented subjects, 3 (7.5%) did not qualify. Overall, 29 of 37 (78%) in the intent-to-treat analysis achieved 4-SU (300-mg arm, 17 of 20 [85%]; 3000 mg, 12 of 17 [71%], P = .43) over a median of 29 months. Per-protocol, the overall proportion achieving 4-SU was 29 of 32 (91%). Peanut-specific IgE levels significantly declined in E-OIT-treated children, who were 19 times more likely to successfully consume dietary peanut than matched standard-care controls, in whom peanut-specific IgE levels significantly increased (relative risk, 19.42; 95% CI, 8.7-43.7; P < .001). Allergic side effects during E-OIT were common but all were mild to moderate.ConclusionsAt both doses tested, E-OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary reintroduction.
| S-EPMC5222765 | biostudies-literature
Project description:IntroductionAllergen-specific immunotherapy (AIT) induces long-term immune tolerance to allergens and is effective for treating allergic rhinitis (AR). However, the impact of sublingual immunotherapy (SLIT) on gut microbiota from AR patients and its correlation with treatment efficacy remains unclear.MethodsIn the present study, we enrolled 24 AR patients sensitized to Dermatophagoides farinae (Der-f) and 6 healthy donors (HD). All AR patients received SLIT treatment using standardized Der-f drops. Stool samples were collected from AR patients before treatment, and 1- and 3-months post-treatment, as well as from HD, for metagenomic sequencing analysis.ResultsAR patients had significantly lower richness and diversity in gut microbiota compared to HD, with notable alterations in composition and function. Besides, three months post-SLIT treatment, significant changes in gut microbiota composition at the genus and species levels were observed in AR patients. Streptococcus parasanguinis_B and Streptococcus parasanguinis, which were significantly lower in AR patients compared to HD, increased notably after three months of treatment. LEfSe analysis identified these species as markers distinguishing HD from AR patients and AR patients pre- from post-SLIT treatment. Furthermore, changes in the relative abundance of S. parasanguinis_B were negatively correlated with changes in VAS scores but positively correlated with changes in RCAT scores, suggesting a positive correlation with effective SLIT treatment.DiscussionSLIT treatment significantly alters the gut microbiota of AR patients, with S. parasanguinis_B potentially linked to its effectiveness. This study offers insights into SLIT mechanisms and suggests that specific strains may serve as biomarkers for predicting SLIT efficacy and as modulators for improving SLIT efficacy.
| S-EPMC11626388 | biostudies-literature
Project description:BackgroundOnly limited evidence is available regarding the cytokine repertoire of effector T cells associated with peanut allergy, and how these responses relate to IgE antibodies to peanut components.ObjectiveTo interrogate T cell effector cytokine populations induced by Ara h 1 and Ara h 2 among peanut allergic (PA) children in the context of IgE and to evaluate their modulation during oral immunotherapy (OIT).MethodsPeanut-reactive effector T cells were analysed in conjunction with specific IgE profiles in PA children using intracellular staining and multiplex assay. Cytokine-expressing T cell subpopulations were visualized using SPICE.ResultsAra h 2 dominated the antibody response to peanut as judged by prevalence and quantity among a cohort of children with IgE to peanut. High IgE (> 15 kU(A)/L) was almost exclusively associated with dual sensitization to Ara h 1 and Ara h 2 and was age independent. Among PA children, IL-4-biased responses to both major allergens were induced, regardless of whether IgE antibodies to Ara h 1 were present. Among subjects receiving OIT in whom high IgE was maintained, Th2 reactivity to peanut components persisted despite clinical desensitization and modulation of allergen-specific immune parameters including augmented specific IgG4 antibodies, Th1 skewing and enhanced IL-10. The complexity of cytokine-positive subpopulations within peanut-reactive IL-4(+) and IFN-γ(+) T cells was similar to that observed in those who received no OIT, but was modified with extended therapy. Nonetheless, high Foxp3 expression was a distinguishing feature of peanut-reactive IL-4(+) T cells irrespective of OIT, and a correlate of their ability to secrete type 2 cytokines.ConclusionAlthough total numbers of peanut-reactive IL-4(+) and IFN-γ(+) T cells are modulated by OIT in highly allergic children, complex T cell populations with pathogenic potential persist in the presence of recognized immune markers of successful immunotherapy.
| S-EPMC4472497 | biostudies-literature
Project description:BackgroundFor patients with peanut allergy, there are currently no methods to predict who will develop sustained unresponsiveness (SU) after oral immunotherapy (OIT).ObjectiveAssess IgE binding to peanut (PN), Ara h 2, and specific linear epitopes of Ara h 2 as predictors of the important clinical parameters: eliciting dose threshold and attainment of SU following OIT.MethodsSamples and clinical data were collected from children undergoing OIT. PN- and Ara h 2-sIgE were quantified by ImmunoCAP® . IgE binding to linear peptides of Ara h 2 and Ara h 6 was measured with peptide microarrays.ResultsValues of PN-sIgE correlated with eliciting dose (P = .001) and with a higher likelihood of achieving SU (P < .0001), but these relationships were lost at higher values for PN-sIgE (≥14 kIU for eliciting dose and ≥35 kIU/L for SU). In subjects with PN-sIgE ≥ 14 kIU/L, binding of IgE to epitopes 5 and 6 of Ara h 2 was associated with a lower eliciting dose at baseline challenge (P < .001; Pc < .02). In subjects with PN-sIgE ≥ 35 kIU/L, a combined model of IgE binding to epitopes 1, 5 and 6 with PN-sIgE was highly predictive of attainment of SU (AUC of 0.86; P = .0067).ConclusionIn young patients with peanut allergy, measurement of PN-sIgE and IgE binding to specific linear epitopes of Ara h 2 in baseline samples may allow stratification of patients regarding sensitivity to challenge and outcome of OIT.
| S-EPMC6906227 | biostudies-literature
Project description:Peanut allergy is on the rise in industrialized countries, affecting 1%-4.5% of children and generally persisting into adulthood. It is associated with a risk of severe anaphylaxis and is one of the major causes of food allergy-induced deaths. Health-related quality of life is significantly impaired for patients and affected families due to food restrictions attributable to omnipresent precautionary allergen labeling, constant risk of potentially life-threatening reactions, and limitation of social activities. Oral immunotherapy (OIT) has emerged as a valid treatment option for patients with IgE-mediated peanut allergy, with randomized controlled trials and real-life studies showing a high rate of desensitization and a favorable safety profile, especially in young children. Ultimately, the decision to initiate peanut OIT relies on a multidisciplinary shared decision-making process, involving open, personalized and evidence-based discussions with patients and their caregivers.
| S-EPMC9458956 | biostudies-literature
Project description:BackgroundPatients with peanut allergy have highly stable pathologic antibody repertoires to the immunodominant B-cell epitopes of the major peanut allergens Ara h 1 to 3.ObjectiveWe used a peptide microarray technique to analyze the effect of treatment with peanut oral immunotherapy (OIT) on such repertoires.MethodsMeasurements of total peanut-specific IgE (psIgE) and peanut-specific IgG(4) (psIgG(4)) were made with CAP-FEIA. We analyzed sera from 22 patients with OIT and 6 control subjects and measured serum specific IgE and IgG(4) binding to epitopes of Ara h 1 to 3 using a high-throughput peptide microarray technique. Antibody affinity was measured by using a competitive peptide microarray, as previously described.ResultsAt baseline, psIgE and psIgG(4) diversity was similar between patients and control subjects, and there was broad variation in epitope recognition. After a median of 41 months of OIT, polyclonal psIgG(4) levels increased from a median of 0.3 μg/mL (interquartile range [25% to 75%], 0.1-0.43 μg/mL) at baseline to 10.5 μg/mL (interquartile range [25% to 75%], 3.95-45.48 μg/mL; P < .0001) and included de novo specificities. psIgE levels were reduced from a median baseline of 85.45 kU(A)/L (23.05-101.0 kU(A)/L) to 7.75 kU(A)/L (2.58-30.55 kU(A)/L, P < .0001). Affinity was unaffected. Although the psIgE repertoire contracted in most OIT-treated patients, several subjects generated new IgE specificities, even as the total psIgE level decreased. Global epitope-specific shifts from IgE to IgG(4) binding occurred, including at an informative epitope of Ara h 2.ConclusionOIT differentially alters Ara h 1 to 3 binding patterns. These changes are variable between patients, are not observed in control subjects, and include a progressive polyclonal increase in IgG(4) levels, with concurrent reduction in IgE amount and diversity.
| S-EPMC3529994 | biostudies-literature
Project description:BackgroundAlthough peanut oral immunotherapy (OIT) has been conclusively shown to cause desensitization, it is currently unknown whether clinical protection persists after stopping therapy.ObjectiveOur primary objective was to determine whether peanut OIT can induce sustained unresponsiveness after withdrawal of OIT.MethodsWe conducted a pilot clinical trial of peanut OIT at 2 US centers. Subjects age 1 to 16 years were recruited and treated for up to 5 years with peanut OIT. The protocol was modified over time to permit dose increases to a maximum of 4000 mg/d peanut protein. Blood was collected at multiple time points. Clinical end points were measured with 5000-mg double-blinded, placebo-controlled food challenges once specific criteria were met.ResultsOf the 39 subjects originally enrolled, 24 completed the protocol and had evaluable outcomes. Twelve (50%) of 24 successfully passed a challenge 1 month after stopping OIT and achieved sustained unresponsiveness. Peanut was added to the diet. At baseline and the time of challenge, such subjects had smaller skin test results, as well as lower IgE levels specific for peanut, Ara h 1, and Ara h 2 and lower ratios of peanut-specific IgE/total IgE compared with subjects not passing. There were no differences in peanut IgG₄ levels or functional activity at the end of the study.ConclusionsThis is the first demonstration of sustained unresponsiveness after peanut OIT, occurring in half of subjects treated for up to 5 years. OIT favorably modified the peanut-specific immune response in all subjects completing the protocol. Smaller skin test results and lower allergen-specific IgE levels were predictive of successful outcome.
| S-EPMC3960331 | biostudies-literature
Project description:BackgroundOral immunotherapy (OIT) offers a promising therapeutic option for peanut allergy. Given that during OIT an allergic patient ingests an allergen that could potentially cause a serious reaction, the safety of OIT is of particular concern.ObjectiveThe purpose of this study was to examine safety during the initial escalation day, buildup phase, and home dosing phase in subjects enrolled in a peanut OIT study.MethodsSkin, upper respiratory tract, chest, and abdominal symptoms were recorded with initial escalation day and buildup phase dosings. Subjects also maintained daily diaries detailing symptoms after each home dosing. A statistical analysis of these data was performed.ResultsTwenty of 28 patients completed all phases of the study. During the initial escalation day, upper respiratory tract (79%) and abdominal (68%) symptoms were the most likely symptoms experienced. The risk of mild wheezing during the initial escalation day was 18%. The probability of having any symptoms after a buildup phase dose was 46%, with a risk of 29% for upper respiratory tract symptoms and 24% for skin symptoms. The risk of reaction with any home dose was 3.5%. Upper respiratory tract (1.2%) and skin (1.1%) symptoms were the most likely after home doses. Treatment was given with 0.7% of home doses. Two subjects received epinephrine after 1 home dose each.ConclusionsSubjects were more likely to have significant allergic symptoms during the initial escalation day when they were in a closely monitored setting than during other phases of the study. Allergic reactions with home doses were rare.
| S-EPMC2731305 | biostudies-literature