Gastrointestinal γδ T cells reveal differentially expressed transcripts and enriched pathways during peanut oral immunotherapy.
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ABSTRACT:
SUBMITTER: Zhang W
PROVIDER: S-EPMC9581524 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Gastrointestinal γδ T cells reveal differentially expressed transcripts and enriched pathways during peanut oral immunotherapy.
Zhang Wenming W Dhondalay Gopal Krishna GK Liu Taryn Audrey TA Kaushik Abhinav A Hoh Ramona R Kwok Shirley S Kambham Neeraja N Fernandez-Becker Nielsen Q NQ Andorf Sandra S Desai Manisha M Galli Stephen J SJ Boyd Scott D SD Nadeau Kari C KC Manohar Monali M DeKruyff Rosemarie H RH Chinthrajah R Sharon RS
Allergy 20220218 5
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Project description:Food allergy affects an estimated 8% of children in the United States. Oral immunotherapy (OIT) is a recently approved treatment, with outcomes ranging from sustained tolerance to food allergens to no apparent benefit. The immunological underpinnings that influence clinical outcomes of OIT remain largely unresolved. Using single-cell RNA-Seq and paired T cell receptor α/β (TCRα/β) sequencing, we assessed the transcriptomes of CD154+ and CD137+ peanut-reactive T helper (Th) cells from 12 patients with peanut allergy longitudinally throughout OIT. We observed expanded populations of cells expressing Th1, Th2, and Th17 signatures that further separated into 6 clonally distinct subsets. Four of these subsets demonstrated a convergence of TCR sequences, suggesting antigen-driven T cell fates. Over the course of OIT, we observed suppression of Th2 and Th1 gene signatures in effector clonotypes but not T follicular helper-like (Tfh-like) clonotypes. Positive outcomes were associated with stronger suppression of Th2 signatures in Th2A-like cells, while treatment failure was associated with the expression of baseline inflammatory gene signatures that were present in Th1 and Th17 cell populations and unmodulated by OIT. These results demonstrate that differential clinical responses to OIT are associated with both preexisting characteristics of peanut-reactive CD4+ T cells and suppression of a subset of Th2 cells.
| S-EPMC8759778 | biostudies-literature
Project description:Background & aimsGastrointestinal side effects are common during oral immunotherapy (OIT) and eosinophilic esophagitis (EoE) is a potential complication. We aimed to characterize eosinophilic gastrointestinal responses to peanut OIT, in which peanut protein is given orally, with incremental increases in dose over time.MethodsTwenty adults with IgE-mediated peanut allergy were randomly assigned to groups given peanut OIT (n = 15) or placebo (n = 5); 1 additional subject withdrew before randomization. Serial gastrointestinal biopsies were collected at baseline (n = 21, 0 weeks), following dose escalation (n = 10, 52 weeks), and during the maintenance phase (n = 11, 104 weeks). Endoscopic findings were characterized using the EoE endoscopic reference score. Biopsies were assessed for eosinophils per high-power field (eos/hpf) and other pathology features using EoE histologic scoring system scores. We performed immunohistochemical analyses of eosinophil peroxidase deposition, quantified using automated image analysis.ResultsAt baseline, no subjects reported current gastrointestinal symptoms. However, 3 of the 21 subjects (14%) had esophageal peak eosinophil counts ≥15 eos/hpf and all subjects had dilated intercellular spaces (DIS). OIT induced or exacerbated esophageal eosinophilia (EE) at 52 weeks in most subjects (peak eosinophil counts >5 eos/hpf in 6 of 7 patients [86%]; peak eosinophil counts ≥15 eos/hpf in 4 of 7 patients [57%]). One subject met clinicopathologic criteria for EoE and withdrew; no significant changes in esophageal peak eosinophil counts were observed in the placebo group. EE in the OIT group corresponded with significant increases in EoE histologic scoring system scores and deposition of eosinophil peroxidase. In 4 of 6 participants (67%), OIT-induced EE and gastrointestinal eosinophilia resolved by the end of the maintenance phase. Gastrointestinal symptoms were not clearly associated with EE or gastrointestinal eosinophilia.ConclusionsIn this pilot study, we found that peanut OIT-induced EE and gastrointestinal eosinophilia are usually transient and are not always associated with gastrointestinal symptoms. Clinicaltrials.gov no: NCT02103270.
| S-EPMC8445108 | biostudies-literature
Project description:Rationale: Oral immunotherapy (OIT) is an emerging treatment for food allergy. While desensitization is achieved in most subjects, many experience gastrointestinal symptoms and few develop eosinophilic gastrointestinal disease. It is unclear whether these subjects have subclinical gastrointestinal eosinophilia (GE) at baseline. We aimed to evaluate the presence of GE in subjects with food allergy before peanut OIT. Methods: We performed baseline esophagogastroduodenoscopies on 21 adults before undergoing peanut OIT. Subjects completed a detailed gastrointestinal symptom questionnaire. Endoscopic findings were assessed using the Eosinophilic Esophagitis (EoE) Endoscopic Reference Score (EREFS) and biopsies were obtained from the esophagus, gastric antrum, and duodenum. Esophageal biopsies were evaluated using the EoE Histologic Scoring System. Immunohistochemical staining for eosinophil peroxidase (EPX) was also performed. Hematoxylin and eosin and EPX stains of each biopsy were assessed for eosinophil density and EPX/mm2 was quantified using automated image analysis. Results: All subjects were asymptomatic. Pre-existing esophageal eosinophilia (>5 eosinophils per high-power field [eos/hpf]) was present in five participants (24%), three (14%) of whom had >15 eos/hpf associated with mild endoscopic findings (edema, linear furrowing, or rings; median EREFS = 0, IQR 0-0.25). Some subjects also demonstrated basal cell hyperplasia, dilated intercellular spaces, and lamina propria fibrosis. Increased eosinophils were noted in the gastric antrum (>12 eos/hpf) or duodenum (>26 eos/hpf) in 9 subjects (43%). EPX/mm2 correlated strongly with eosinophil counts (r = 0.71, p < 0.0001). Conclusions: Pre-existing GE is common in adults with IgE-mediated peanut allergy. Eosinophilic inflammation (EI) in these subjects may be accompanied by mild endoscopic and histologic findings. Longitudinal data collection during OIT is ongoing.
| S-EPMC6261984 | biostudies-literature
Project description:BackgroundThe maximum tolerated dose of peanut protein following peanut oral immunotherapy (POIT) is unknown because most research studies have not examined very high thresholds.ObjectiveTo define the maximum dose tolerated by patients on POIT and severity of allergic reactions after a 1-month period of treatment discontinuation.MethodsIn a phase 2 3-year POIT open-label study, we enrolled participants age 5 to 13 years with a 1-year build-up period followed by a 2-year daily maintenance dose of 3900 mg with assessment of the maximum tolerated dose using double-blind placebo-controlled food challenges (DBPCFCs) of 26,225 mg cumulative dose of peanut protein. The DBPCFC was performed at baseline, after 12-month build-up, at 2 year of maintenance, and after a 1-month period of treatment discontinuation. Biomarkers were assessed every 6 weeks for the first 6 months of therapy. A general linear mixed model was used for analysis.ResultsThe mean maximum cumulative tolerated dose after 12 months increased by 12,063 mg (P < .001) (n = 12), slightly decreased during maintenance (n = 11), and significantly decreased by 7593 mg after avoidance for 1 month (P = .03) (n = 6). Biomarker analysis revealed decreases in cytokine expression within the first 6 weeks of initiation of POIT and decreased peanut-IgG4 and increased cytokine expression after 1 month of discontinuation. The DBPCFC reaction severity, examined through a symptom score with 1 point for each defined symptom, decreased after 12 months, but did not significantly change after 1 month of POIT discontinuation.ConclusionsThe evaluation of POIT and sustained unresponsiveness by maximum tolerated dose by DBPCFCs in this small phase 2 trial showed that desensitization is diminished, with 100% loss of tolerated dose after 1 month of avoidance following 3 years of treatment.
| S-EPMC10404846 | biostudies-literature
Project description:Over the past decade; the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed that they play a major role in the development of various diseases; including cancer. Intronic transcripts are one of the most fascinating lncRNAs that are located within intron regions of protein-coding genes, which have the advantage of encoding micropeptides. There have been several studies looking at intronic transcript expression profiles in cancer; but almost none in osteosarcoma. To overcome this problem; we have investigated differentially expressed intronic transcripts between osteosarcoma and normal bone tissues. The results highlighted that NRG1-IT1; FGF14-IT1; and HAO2-IT1 were downregulated; whereas ER3-IT1; SND1-IT1; ANKRD44-IT1; AGAP1-IT1; DIP2A-IT1; LMO7DN-IT1; SLIT2-IT1; RNF216-IT1; and TCF7L1-IT1 were upregulated in osteosarcoma tissues compared to normal bone tissues. Furthermore, we identified if the transcripts encode micropeptides and the transcripts' locations in a cell.
| S-EPMC9680297 | biostudies-literature
Project description:Differential gene expression is the major mechanism underlying the development of specific body regions. Here we assessed the role of genes differentially expressed in the Drosophila wing imaginal disc, which gives rise to two distinct adult structures: the body wall and the wing. Reverse genetics was used to test the function of uncharacterized genes first identified in a microarray screen as having high levels of expression in the presumptive wing. Such genes could participate in elaborating the specific morphological characteristics of the wing. The activity of the genes was modulated using misexpression and RNAi-mediated silencing. Misexpression of eight of nine genes tested caused phenotypes. Of 12 genes tested, 10 showed effective silencing with RNAi transgenes, but only 3 of these had resulting phenotypes. The wing phenotypes resulting from RNAi suggest that CG8780 is involved in patterning the veins in the proximal region of the wing blade and that CG17278 and CG30069 are required for adhesion of wing surfaces. Venation and apposition of the wing surfaces are processes specific to wing development providing a correlation between the expression and function of these genes. The results show that a combination of expression profiling and tissue-specific gene silencing has the potential to identify new genes involved in wing development and hence to contribute to our understanding of this process. However, there are both technical and biological limitations to this approach, including the efficacy of RNAi and the role that gene redundancy may play in masking phenotypes.
| S-EPMC1698657 | 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