Title Abstract "Keratinocyte/dendritic cell interactions in the skin determines allergic sensitization and the severity of asthma to house dust mite allergen " "Asthma is a chronic inflammatory disease of the airways that is seen increasingly in westernalized countries. Studies have shown that a majority of patients with asthma have suffered from atopic dermatitis (AD) in their childhood. Moreover, patients with AD develop more severe steroid-resistant forms of asthma. The mechanisms involved in the progression from AD to asthma are currently unknown. Several reports argue that this might mainly due to an aberrant cytokine production by keratinocytes. However, how allergen-induced keratinocyte responses promote the development of asthma is unknown. We propose that sensitization via the skin and asthma development later on might require a crosstalk between keratinocytes and professional antigen presenting cells called dendritic cells (DCs), and that this crosstalk might affect the severity of the disease. In this project, we will test the contribution of DC populations to the process of sensitization using different mouse strains allowing the selective depletion of skin DC populations at the time of allergen exposure. The contribution of keratinocyte will be tested using other strains allowing the overexpression of HMGB1, an endogenous danger signal involved in several inflammatory diseases. Understanding how keratinocytes and DCs communicate in the skin could bring clarity on the process of allergic sensitization and eventually unravel new therapeutic and preventive avenues for asthma " "Uncovering a role for B cells in allergy risk and protection in early life." "Bart Lambrecht" "Department of Internal Medicine and Pediatrics" "The incidence of allergic disease has steadily increased over the past decades, affecting one in ten children in Europe today. It is now understood that a lack of neonatal exposure to antigen of harmless microorganisms, which educate the immune system to discriminate between dangerous and harmless insults, is in part responsible for this phenomenon. In the immune system, certain cell subsets are preferentially generated during early life. These include specific B cell subsets, which sustain lifelong. However, surprisingly little is known about the effect of early life antigen exposure on B cell heterogeneity, and the contribution of different B cell subsets in allergic asthma. Given the state of the art, it is fair to say that our understanding of the role of B cells in allergic asthma is limited. This project aims to close the significant gap in our knowledge of the role of B cells in allergic asthma and I will specifically focus on the influence of neonatal exposure to allergens and microbial components on disease development during adult life. This project will combine the use of novel models, state-of-the-art immunology tools and single cell gene expression profiling to address these questions. The knowledge acquired through this project will not only increase our understanding of the roots of allergic asthma in early life, it could also help us to develop targeted preventive measures to alter the natural progression of allergic disease during the course of life." "BASIC: Biomarkers of respiratory Allergy Susceptiblity In Children" "Sabine LANGIE" "Environmental Biology, Theory lab" "Early life exposures can alter DNA methylation patterns, and thereby predispose a child to develop respiratory allergy (RA) later in life. Longitudinal birth cohorts are instrumental to study disease development and the use of saliva, as non-invasive DNA source, has simplified biomarker research. Recently we identified differential methylation gene regions (DMR) in saliva of children with RA vs. controls in 2 independent longitudinal birth cohorts. Illumina Methylation 450K BeadChips revealed 13 DMR in saliva from 11y old allergic children (N=26) vs. controls (N=20). 5 DMR were located in genes involved in IL4 signalling and Th2-response, showing a link with wheezing and other RA phenotypes. The 13 DMR were selected for further biological and technical validation by iPLEX MassArray analysis in the same birth cohort as well as in a second cohort involving 5y old children (N=78). BASIC aims to confirm initial observations and develop added-value for recently identified biomarkers for prediction and/or diagnosis of RA. More specific we aim to: 1) validate these saliva biomarkers in a new birth cohort in the context of preventive screening; and 2) confirm the applicability of the biomarkers in clinically characterized children, including various RA subtypes (e.g. hay fever, house dust allergy). The ultimate goal is to identify objective biomarkers that in the long run could contribute to the development of new prevention strategies, particularly in young people." "Discovery of metabolite biomarkers for early diagnosis and prognosis of cow's milk allergy in children" "Lynn Vanhaecke" "Department of Veterinary Public Health and Food Safety, Department of Translational Physiology, Infectiology and Public Health" "Cow’s milk allergy (CMA) is one of the most prevalent and first food allergies to occur in early childhood. Diagnosis of CMA currently relies on challenge-based tests, which have to be repeated on a yearly basis to assess possible spontaneous resolution. These tests inherently result in allergic reactions in patients. As metabolites represent the total contribution of genomic, transcriptomic and proteomic activities, as well as external factors such as food, they constitute the most promising candidates for early detection of food allergies. Given the emerging evidence for the involvement of the gut microbiota in the onset of food allergy and its spontaneous resolution, this project will embark on state-of-the-art high-resolution mass spectrometry based metabolomics and metagenomics on patients’ bioluid samples, to decipher microbiome/metabolome correlations and provide a framework for identifying diagnostic and prognostic biomarkers for children with CMA. Alterations in the metabolomes of germfree and specific-pathogen free mice following sensitization to cow’s milk will be compared to similar alterations in CMA patients’ human fecal flora associated mice, to map the origin of the proposed biomarkers. Specific bacterial groups involved in the allergy cascade or proposed biomarkers, will be manipulated and/or administered to mice to provide mechanistic information on how the biomarkers are produced or affect allergic responses as a means to achieve biomarker qualification." "Education of lung epithelial cells as an alternative explanation for the protective effect of infectious pressure on development of allergy and asthma." "There is an epidemic of allergy and asthma in the Western industrialized world, with up to 30% of children showing reactivity to common inhaled and food allergens. The reason for the increase in these Th2-associated diseases is currently unclear. The hygiene hypothesis of allergy states that lifestyle changes leading to less ""infectious pressure"" in the first year of life are associated with more allergy. Conversely, growing up on a farm (with high environmental endotoxin exposure) or amongst older siblings strongly protects against allergy. The immunological explanation has been that less infections, normally cleared by Th1 cells, lead to a dysbalance in the immune system so that Th2 responses are stimulated. We have obtained preliminary data that endotoxin exposure prior to allergen exposure strongly protects against allergy because lung epithelial cells upregulate TNFAIP3 (A20), a negative regulator of Toll like receptor and IL-1R family signalling. In this project we will address how A20 controls the epithelial threshold for allergen recognition and how this leads to alterations in dendritic cell and T cell activation. We have developed the necessary tools to measure and eliminate A20 selectively in lung epithelial cells. Our epithelium-centered view on regulation of pulmonary immunity offers an entirely new explanation for the effect of infectious pressure on development of allergy and asthma that may one day lead to development of new preventive strategies." "Stepwise Heat-Denaturated protein introduction for tolerance induction in food allergy and pediatric Eosinophilic Esophagitis (TEHITI)" "Dominique Bullens" "Allergy and Clinical Immunology Research Group" "Children with cow’s milk allergy (CMA) who accidentally have cow’s milk intake, can show symptoms varying from eczema exacerbation, urticaria & angio-oedema, gastro-intestinal and respiratory complaints to (potentially fatal) anaphylaxis. To reduce this risk, children and parents receive personal treatment action plans with medication eg adrenalin auto-injectors. Medical care, buying cow’s milk free food alternatives, as well as those plans come at a high cost and yet Quality of Live (QoL) of these children remains low. Most (85%) children become tolerant before reaching adolescence. One specific type of cow’s milk mediated hypersensitivity is oesinophilic esophagitis in remission withcow’s milk free diet. This relatively rare disease leads to strongly reduced QoL, risk of dysphagia by food blockage and is frequently associated with sensitivity to hen’s egg and/or wheat. Spontanous tolerance induction does not occur, requiring a life-long diet. If the study reaches its purposes, the 12 month protocol can shorten the time to complete tolerance with several years in 85% of children with CMA (not persistently allergic). Those years will increaseQoL, reduce the chance of serious reactions upon cow’s milk intake, emergency visits and hospitalization. The use of the developed Flemish Milk Ladder and/or gradually less boiled cow’s milk comes at low cost. Furthermore, the study in EoE children in remission by diet free of cow’s milk and/or hen’s egg, can demonstrate that at least in some children, extensively heated proteins could be tolerated, which would hugely liberate their diet and increase their QoL, also at a low cost. The defined bio-markers should allow us to select the correct children for these protocols with reduced number of oral food challenges to that aim in the future. The knowledge about the immunological changes that accompany tolerance induction, should be of help to develop similar tolerance induction protocols for other food allergies." "Identifying lymphocyte homing receptors to facilitate canine food allergy diagnosis." "Eric Cox" "Department of Translational Physiology, Infectiology and Public Health" "The diagnosis of canine food allergy is difficult and time-consuming. At first, this project will focus on the identification of homing receptors expressed by allergen-specific lymphocytes. Subsequently, we will evaluate whether purification of cells expressing these receptors can be used to develop a test that can quickly and reliably diagnose canine food allergy." "Assesment of the impact of a non-invasive clinical decision support tool for antibiotic allergy label delabeling and refinement" "Rik Schrijvers" "Allergy and Clinical Immunology Research Group, Clinical Pharmacology and Pharmacotherapy" "Our final goal is to initiate a more proactive antibiotic allergy delabeling strategy in Belgium, instead of the ‘urgency’-driven approach that is mostly performed in clinical practice nowadays (i.e., when patients are in high need of the respective antibiotic (class), or are triggered to investigate their antibiotic allergy label due to, e.g., a perceived reaction or upcoming surgery). Currently, the standard approach is invasive skin and provocation testing, traditionally delivered by allergists, mostly targeting only those patients with the highest benefit-risk, because of time- and resources constraints.However, an optimized non-invasive approach will make delabeling more assessable to non-allergists, and can cover a much broader patient population, i.e., eventually all patients with an antibiotic allergy label, without any consumable cost. Therefore, we suggest implementation of our non-invasive delabeling tool as a standard first step before antibiotic prescription in patients with an antibiotic allergy label, and eventually, retrospective use of the tool in all electronic patient record systems.Hereby we contribute to the safe and more rational use of antibiotics." "Non-invasive antibiotic allergy delabeling and refinement to optimize antimicrobial stewardship" "Rik Schrijvers" "Allergy and Clinical Immunology Research Group, Environment and Health, Clinical Pharmacology and Pharmacotherapy" "Antibiotic allergy labels (AAL) are frequently observed and, although intended to reduce  iatrogenicity, cause harm by restraining patients from first-line treatments. My PhD research in over 1 million patients in a Belgian tertiary care center showed that 7% of inpatients carries an AAL, mainly for beta-lactams (84%). The majority of AAL can be invalidated upon a drug allergy work-up with skin and provocation testing, rendering most secondary effects as avoidable. However, these tests are invasive, time- and resource-consuming. Also, the clinical, microbiological and economical consequences of AAL are mostly unknown in a European or Belgian context. In this project, I propose to delineate the impact of AAL in inpatients. My preliminary data indicates that beta-lactam AAL are associated with an increased length-of-stay and use of second-line or broad spectrum antibiotics, but contrary to US studies, not with an increased mortality. In the second part, I therefore focus on a strictly non-invasive delabeling protocol. In a prospective pilot study in inpatients, we could delabel 38% and refine another 27% of beta-lactam AAL. Here, I will explore the impact of our non-invasive clinical decision support tool for AAL in a multicenter randomized controlled trial in inpatients, and provide the first steps towards improving AAL in primary care as well. I expect to improve antimicrobial stewardship and aim to impact a broader socio-economic scale. " "Food allergy after pediatric liver transplantation: role of the immature immune system and liver in oral tolerance" "Department of Internal medicine" "Food allergy (FA) after pediatric liver transplantation (LT) is a frequent problem occurring in more than 20% of patients. Symptoms are often severe with a major impact on quality of life. In-depth study of patient characteristics and literature revealed that post transplant FA is primarily associated with LT (and not so much with other solid organ transplants), young age at time of transplantation and use of tacrolimus as maintenance immunosuppression (IS). In the first part of this study we aim to perform extensive immunological characterization of pediatric LT recipients with and without FA.In the second part we will explore two hypotheses. The first is that the immature immune system might respond differently to tacrolimus as IS. Therefore we will study the in vitro effect of IS on human cord blood lymphocytes and intestinal explants. Secondly, we hypothesize the neontatal liver plays a crucial role in conferring tolerance to ingested antigens. To address this, we will study the development of the liver immune system in neonatal mice and its role in oral tolerance with emphasis on tolerogenic cell types in the liver.With this study we hope to be able to recognize LT patients at risk for FA, improve our insight in the pathophysiology of LT associated FA and provide a basis for future therapeutic interventions in these patients."