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For Peanut and Tree nut Allergic participants.

Inclusion criteria:

• - More than 2 years.

• - Male or Female.

• - Allergic to peanut (assessed by anamnesis, skin reactivity testing, sera testing for specific IgE) - Sign an Informed Consent.

Exclusion criteria:

• - Pregnancy.

• - Less than 2 years of age.

• - Co-existing chronic medical condition such as cardiovascular disorders.

• - Peanut or tree nut-allergic patients/families who are unwilling to undergo oral food challenges.

The eligible participants will be assigned to the oral immunotherapy (OIT) group but if they are not eligible for OIT based on either on the reasons mentioned below, they will be assigned to the avoidance group. Reasons for ineligibility of OIT :

• - risk of poor compliance with immunotherapy.

• - lack of understanding of the OIT protocol.

• - uncontrolled asthma.

• - incompatibility with lifestyle (regular intense physical activities, multiple vacations) - unwilling to undergo OIT.

• - long-term or frequent use of non-steroidal anti-inflammatory drugs.

• - multiple nut allergy with no direct clinical benefit of OIT to one nut.

• - co-existing comorbidities such as active systemic autoimmune diseases, active malignancy, eosinophilic esophagitis.

For Healthy Controls.

Inclusion Criteria:

• - Adults.

• - Male or Female.

• - Sign an Informed Consent.

• - Tolerates any type of nut.

• - No known food allergy.

Exclusion Criteria:

• - Pregnancy.

- Co-existing chronic medical condition such as cardiovascular disorders

Background: The prevalence of peanut together with tree nut allergies have increase over the years and accounts for most of the life-threatening reactions even to minute doses of the allergen. Consequently, peanut and tree-nut allergies cause significant physical and mental burden to patients and their caretakers due to anxiety and fear of anaphylaxis from accidental exposures, stress from following a strict elimination diet, lack of proactive management plan and due to the low probability of natural recovery of such allergies. For decades, the management relied on a strict avoidance of the culprit foods. Oral immune therapy (OIT) is a ground breaking alternative modality to strict avoidance diets. OIT consist of gradual introduction of low doses of the implicated food allergen with the aim to modulate the patient's immune response and help build immunological and clinical tolerance. Though OIT has its strong advantages, the clinical outcome is variable among the patients. Therefore, there is a clear need for reliable ex-vivo biomarkers that are reflective of the clinical progression and therapy outcome that could aid with a more accurate patient stratification for personalized treatment approaches in the future. Aims: This project aims at measuring immune targets, antibodies, immune cells and immune mediators, in patients' blood during oral food challenges (OFCs) and during the course of standard-of-care oral immunotherapy to identify new immune markers correlating to with the clinical outcome of the treatment. The identification of immune modifications during OIT will allow us to endotype patients and possibly aid in unraveling markers of food challenges and therapy progression as well as OIT outcome. Luxembourg partners: The Luxembourg Institute of Health (LIH), Department of Infection and Immunity (DII; head Prof. M. Ollert) has the scientific project lead (Principal Investigator Dr. A. Kuehn). Main clinical partners are Dr. F. Codreanu-Morel and Dr.

• V. Petit-Cordebar from the National Unit of Immunology-Allergology, Centre Hospitalier (CHL), Luxembourg.

Medical Principal Investigator for healthy controls is Dr. Alessia Pochesci, MD, Clinical and Epidemiological Investigation Center (CIEC), Luxembourg Institute of Health (LIH), Luxembourg. The Integrated Biobank of Luxembourg (IBBL) will prepare and store a subset of clinical samples until use. Other biological samples are prepared and stored at DII, LIH. Clinical samples (blood, sera, plasma,stool) will be analyzed at DII, LIH. Project implementation: The clinicians at CHL will perform detailed clinical examinations of participants including skin prick test (SPT), serological analysis for specific IgE and food challenges to the implicated food allergen as per their routine clinical practice at the National Unit of Immunology-Allergology (CHL). Based on the European Academy of Allergy and Clinical Immunology (EAACI) guidelines and procedures established at CHL, all peanut- and tree-nut-allergic participants eligible for the study will undergo a baseline OFC. OFC is adapted from PRACTALL protocol and allergen doses are adjusted according to the clinical reactivity of the patient. For participants eligible for immunotherapy (N= 30 Peanut-OIT and N=30 Tree nut-OIT), the OIT is based on the established protocol at the clinic and adapted from the current literature. Briefly, participant ingest incremental doses of the allergen (peanut/tree nut) at home until they reach a maintenance dose of 300 mg nut-protein in approximately 26 weeks (6 months). This initial phase of OIT is termed as the build-up phase. This is then followed by continued daily intake of this maintenance dose. After a minimum of 12 months of the maintenance phase of OIT, participants undergo another final OFC at the hospital to assess for desensitization to peanut or tree nut. Participants follow up at the hospital every 6 months i.e at end of the build-up phase, after 6 months and after 12 months of daily intake of maintenance dose. Participants who are not eligible for OIT (N=30 peanut and tree-nut allergic) and who are on avoidance diet, are also followed up every 6 months for 18 months. However, final OFC will not be done for these participants. The data collection of the study participants is carried out by the medical lead. In addition, healthy adults (N=20) tolerating any type of nut and without any known food allergies will be recruited as controls. Dr. Alessia Pochesci, CIEC, LIH is responsible for the data collection from these healthy participants. Blood sample collection: i) For OIT group:

• - During the baseline and final OFC , blood samples will be collected at the beginning, during and at the end of the food challenge in three different vials.

• - During OIT follow-up, a one-time blood sample will be collected at the end of the build-up phase and after 6 months of maintenance phase in addition to the routine blood collection during these follow-up visits.

ii) For avoidance group:

• - During the baseline OFC , blood samples will be collected at the beginning, during and at the end of the food challenge.

• - During follow-up visits, one-time blood sampling will be taken six monthly i.e. at 6, 12 and 18 months after the baseline OFC.

iii) Healthy Adult participants: A one-time blood sampling will be done. Stool sample collection: Stool sample will be collected from nut-allergic participants at baseline and after the completion of a minimum of 18 months of the study duration using commercial at-home stool sampling kits. Participants receive a collection kit, containing special sampling tubes, accessories and instructions. Collected clinical samples will be pseudonymized at the clinical centers. A synonym list containing the information on the identify of the participants recruited and their corresponding pseudonym, will be available at the clinical center only (medical investigators). Personal data is protected under the regulation (EU) 2016/679 of 27 April 2016 on the protection of individuals with regard to the processing of personal data (GDPR) and the law of 1 August 2018 on the organization of the National Data Protection Commission and the General Data Protection Act.

Arms

: Oral Immunotherapy

Participants in this group undergo oral immunotherapy as part of their routine management of their nut allergies

: Avoidance diet

Participants in this group are on strict avoidance diet as part of their nut allergy management

Interventions