Epigenetic regulation of asthma and allergic disease

Epigenetics of asthma and allergic disease is a field that has expanded greatly in the last decade. Previously thought only in terms of cell differentiation, it is now evident the epigenetics regulate many processes. With T cell activation, commitment toward an allergic phenotype is tightly regulated by DNA methylation and histone modifications at the Th2 locus control region. When normal epigenetic control is disturbed, either experimentally or by environmental exposures, Th1/Th2 balance can be affected. Epigenetic marks are not only transferred to daughter cells with cell replication but they can also be inherited through generations. In animal models, with constant environmental pressure, epigenetically determined phenotypes are amplified through generations and can last up to 2 generations after the environment is back to normal. In this review on the epigenetic regulation of asthma and allergic diseases we review basic epigenetic mechanisms and discuss the epigenetic control of Th2 cells. We then cover the transgenerational inheritance model of epigenetic traits and discuss how this could relate the amplification of asthma and allergic disease prevalence and severity through the last decades. Finally, we discuss recent epigenetic association studies for allergic phenotypes and related environmental risk factors as well as potential underlying mechanisms for these associations

L’immunothérapie orale pour le traitement des allergies alimentaires multiples

La prévalence des allergies alimentaires IgE-médiées aurait triplé au cours de la dernière décennie avec des études Nord-Américaines atteignant les 8% chez les enfants. Quoiqu’il n’y ait à ce jour aucun traitement curatif pour les allergies alimentaires, l’immunothérapie oral (OIT) constitue une nouvelle approche expérimentale prometteuse. Cette dernière consiste en l’administration de doses progressive d’allergènes par voie orale sur une période prolongée dans le but d’instaurer un état de désensibilisation et possiblement une tolérance orale soutenue. Cette approche a été démontrée sécuritaire et permettrait la désensibilisation à haute dose de plus de 80% des participants allergiques aux arachides, lait ou œufs. Dans cette thèse, nous présentons 2 études de phase 1 portant sur des protocoles d’OIT, destinés à optimiser l’efficience du traitement chez les sujets avec allergies alimentaires multiples. Près de 30% des enfants avec allergie alimentaire sont allergiques à plus d’un aliment, une proportion qui augmente à 70% lorsqu’on considère les cas les plus sévères. Ces enfants sont à risque augmenté de réactions accidentelles et souffrent d’un impact plus grand sur leur qualité de vie. Dans la première étude, en créant un mélange individualisé avec un ratio stochiométrique 1:1 entre les protéines des aliments allergiques de l’enfant, nous démontrons qu’il est possible de désensibiliser jusqu’à 5 aliments simultanément avec un profil d’innocuité similaire à une monothérapie. Dans la seconde étude, nous utilisons un traitement à l’omalizumab, un anticorps monoclonal anti-IgE, pour permettre une désensibilisation orale multi-allergénique fortement accélérée. Lorsque comparé à l’approche sans omalizumab, ce protocole s’associe à une nette diminution du temps requis pour atteindre les doses d’entretien, passant d’une médiane de 21 à 4 mois, sans affecter le profil d’innocuité. Alors que ces études fournissent des approches cliniques raisonnables pour désensibiliser la population multi-allergique, plusieurs questions persistent, notamment en ce qui a trait à l’induction de tolérance permanente. Une barrière majeure à cet égard réside dans notre piètre compréhension des mécanismes sous-jacents à l’immunothérapie. Prenant avantage d’échantillons cliniques bien caractérisés provenant des essais cliniques ci-haut mentionnés, nous utilisons les nouvelles technologies de séquençage TCR pour suivre la distribution clonale des lymphocytes T spécifiques aux arachides durant une immunothérapie orale. Nous démontrons que l’OIT s’associe à des changements significatifs dans les fréquences des clones spécifiques, suggérant un processus d’épuisement clonal et de remplacement. Nous démontrons par ailleurs que le test de prolifération lymphocytaire, traditionnellement utilisé pour évaluer la réponse cellulaire allergique, est dominé par une distribution polyclonale hautement non-spécifique. Cette observation a des implications majeures considérant que la plupart de la littérature actuelle sur la réponse T se base sur cette technique. En somme, cette thèse jette les bases pour des programmes de recherche translationnelle pour optimiser et personnaliser les protocoles cliniques actuels et développer de nouvelles avenues d’investigation et de traitement pour améliorer la prise en charge des sujets avec allergies alimentaires.The prevalence of IgE-mediated food allergies has tripled over the last decade with prospective studies indicating that up to 8% of children may be affected in North America. There is currently no cure for food allergy but oral immunotherapy (OIT) is an experimental approach to treat food allergies. It consists in the progressive administration from minute to large amounts of the allergenic food by the mouth over a prolonged period of time to induce a state of desensitization and possibly sustained tolerance. This approach has been shown to be safe and to allow desensitization to high doses in over 80% of participants allergic to peanuts, milk or egg. In this thesis, we present two phase 1 trials on OIT protocols designed to efficiently treat multiple foods allergies. About 30% of children with food allergy are allergic to more than one food. This proportion increases to 70% when considering the most severe cases. Children with multiple food allergies are at higher risk of accidental reactions and suffer from greater impact on quality of life than those with single food allergies. By creating a customized treatment mix with a 1:1 stoichiometric ratio for the child’s relevant food proteins, we were first able to safely desensitize up to 5 foods simultaneously with a safety profile similar to single allergen therapy and a minimal increase in time to maintenance. Then, taking advantage of recent evidence showing that omalizumab, an anti-IgE receptor monoclonal antibody, can significantly raise reaction thresholds in food allergic subjects, we used short courses of omalizumab to allow very rapid oral desensitization to various foods in a second phase 1 study. When compared to “standard” multi-OIT, the omalizumab-enabled rush protocol resulted in a decreased time to maintenance from a median of 21 to 4 months. While these studies provide reasonable clinical approaches to this population, many questions remain, especially with regards to long term tolerance. A major limit to our progress in improving these protocols stems from our lack of understanding of the underlying immune mechanisms of oral immunotherapy. Taking advantage of well phenotyped samples from the afore-mentioned trials, we used next-generation high-throughput TCR sequencing to follow clonal distribution of peanut specific T cells during oral immunotherapy. We found that OIT is associated with significant changes in food-specific clonal frequencies, suggesting clonal exhaustion and replacement as an underlying mechanism of OIT. In addition, we show that the proliferation assay which is traditionally used to assess the cellular response is dominated by a highly non-specific polyclonal distribution. This observation has important implications considering most of the current literature on T cell response to immunotherapy is based on this assay. This highlights the need for the development of new tools to assess the cellular allergic response. Overall this thesis lays the ground for further comprehensive translational research programs on the treatment of food allergy

L'influence de la mobilisation sur la performance organisationnelle en contexte manufacturier au Québec

Le secteur manufacturier est en constante évolution. Soucieuses de demeurer compétitives face aux marchés émergents tels que l'Asie, les entreprises doivent maintenir un niveau de performance organisationnelle constant malgré les difficultés économiques des dernières années. Les écrits sur la performance organisationnelle datent de plusieurs années. Au fil du temps, différents outils de mesure tels que les tableaux de bords de gestion ont été développés et différentes variables ont été étudiées afin de mieux expliquer ce concept. Depuis quelques années, nombreux sont ceux qui ont tenté d'associer le niveau d'engagement organisationnel de façon multidimensionnelle (affectif, raisonné et moral) avec celui de la performance. Dans l'explication de la performance organisationnelle, les études antérieures ont fait largement état des caractéristiques individuelles et organisationnelles ainsi que l'engagement avec la performance en obtenant des résultats mitigés qui ne permettent pas d'arriver à des conclusions unanimes. Certaines ajoutent également que l'introduction des attentes et la possibilité de réalisation de celles-ci possèdent le pouvoir d'influencer l'engagement organisationnel qui lui, influencera la performance. Une approche qui en est encore au stade exploratoire veut que la présence de personnel-clé influence également le niveau d'engagement organisationnel et ainsi, aiderait à mieux déterminer le niveau de performance. L'objectif principal de notre étude va dans ce sens et vise à vérifier selon une approche multidimensionnelle l'étude de la performance organisationnelle. Cette approche tente de démontrer que les caractéristiques individuelles, organisationnelles, les attentes, les possibilités de réalisation des attentes, ainsi que la présence de personnel-clé influencent les trois niveaux d'engagement organisationnel (affectif, raisonné et moral) qui à leur tour, influencent la performance de l'organisation. L'étude est à la fois descriptive et explicative. Afin de vérifier le cadre conceptuel qui propose l'influence du personnel-clé sur l'engagement, ainsi que l'influence de l'engagement sur la performance, nous avons mené une étude empirique auprès d'une population de cadres et de salariés du secteur manufacturier au Québec. L'étude se situait dans un milieu qui doit lutter pour sa survie face aux pays émergents. À l'aide d'un questionnaire auto-administré et à partir d'une population de 191 salariés et cadres (taux de réponse de 17,3%) répartie dans deux organisations, nous avons mesuré les indicateurs associés aux caractéristiques individuelles et organisationnelles, aux attentes et aux possibilités de réalisation des attentes, à la présence de personnel-clé, aux trois composantes de l'engagement, ainsi qu'aux deux composantes de la performance organisationnelle (objective et subjective). De façon générale, les résultats de notre étude appuient les thèses antérieures qui font des caractéristiques individuelles et organisationnelles, des déterminants de la performance organisationnelle. Cependant, la performance est influencée significativement seulement par la dimension affective de l'engagement organisationnel. Les dimensions morales et raisonnées n'influencent pas significativement le niveau de performance. En ce qui concerne la façon d'expliquer les déterminants de la performance, notre approche faisant de l'engagement organisationnel une variable médiatrice de la relation entre les caractéristiques individuelles, organisationnelles, les attentes et les possibilités de réalisation de celles-ci, la présence de personnel-clé et le niveau de performance organisationnelle n'appuie pas la thèse de la médiation pour expliquer ce phénomène complexe. Des modèles concurrentiels à"effets directs" se montrent plus concluants. Finalement, l'introduction du concept d'employé-clé amène une nouvelle dimension qui s'est avérée une tendance quant aux employés jugés à haut-potentiel et non-significative quant aux employés jugés stratégiques pour l'organisation. Il est cependant à noter que ces deux catégories de salariés sont peu présentes dans les organisations sondées

Benefits of low-dose inhaled fluticasone on airway response and inflammation in mild asthma

SummaryRationaleCurrent guidelines suggest that asthma should be controlled with the lowest dose of maintenance medication required.ObjectivesTo evaluate the effects of a low dose of inhaled corticosteroid compared to a placebo, on airway inflammation and responsiveness in patients with mild symptomatic asthma.MethodsIn this randomized double-blind, placebo-controlled, parallel group study, we looked at the influence of inhaled fluticasone propionate 250μg/day for 3 months followed by 100μg/day for 9 months on airway inflammation and methacholine responsiveness in non-smoking subjects with mild allergic asthma. Subjects were evaluated at baseline and 3, 6, 9 and 12 months after treatments; a 2-week evaluation of respiratory symptoms and peak expiratory flow measurements was done before each visit.ResultsFifty-seven subjects completed the 3-month study period. Airway responsiveness, expressed as the PC20 methacholine, increased by 0.27 and 1.14 doubling concentrations, respectively, in placebo-treated (n=33) and in fluticasone-treated (n=24) asthmatic subjects (p=0.03). An additional improvement in PC20 up to 2.16 doubling concentrations was observed in the fluticasone-treated group during the 9-month lower-dose treatment (p=0.0004, end of low-dose period compared with placebo). Sputum eosinophil counts decreased after 3 months of fluticasone 250μg/day compared with placebo (p<0.0001) and remained in the normal range during the 9-month lower-dose treatment. Respiratory symptoms and peak expiratory flows did not change significantly throughout the study in both groups.ConclusionIn mild asthma, keeping a regular minimal dose of ICS after asthma control has been achieved, may lead to a further reduction in airway responsiveness and keep sputum eosinophil count within the normal range

Automorphisms of the affine SU(3) fusion rules

We classify the automorphisms of the (chiral) level-k affine SU(3) fusion rules, for any value of k, by looking for all permutations that commute with the modular matrices S and T. This can be done by using the arithmetic of the cyclotomic extensions where the problem is naturally posed. When k is divisible by 3, the automorphism group (Z_2) is generated by the charge conjugation C. If k is not divisible by 3, the automorphism group (Z_2 x Z_2) is generated by C and the Altsch\"uler--Lacki--Zaugg automorphism. Although the combinatorial analysis can become more involved, the techniques used here for SU(3) can be applied to other algebras.Comment: 21 pages, plain TeX, DIAS-STP-92-4

Abatacept to induce remission of peanut allergy during oral immunotherapy (ATARI): protocol for a phase 2a randomized controlled trial

ContextWhile oral immunotherapy (OIT) has been shown to promote the remission of mild peanut allergy in young children, there is still an unmet need for a disease-modifying intervention for older patients and those with severe diseases. In mice models, abatacept, a cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) immunoglobulin fusion protein, has been shown to promote immune tolerance to food when used as an adjuvant to allergen immunotherapy. The goal of this study is to explore the potential efficacy of abatacept in promoting immune tolerance to food allergens during OIT in humans.MethodsIn this phase 2a proof-of-concept study (NCT04872218), 14 peanut-allergic participants aged from 14 to 55 years will be randomized at a 1:1 ratio to abatacept vs. placebo for the first 24 weeks of a peanut OIT treatment (target maintenance dose of 300 mg peanut protein). The primary outcome will be the suppression of the OIT-induced surge in peanut-specific IgE/total IgE at 24 weeks, relative to the baseline. Sustained unresponsiveness will be assessed as a secondary outcome starting at 36 weeks by observing incremental periods of peanut avoidance followed by oral food challenges.DiscussionThis is the first study assessing the use of abatacept as an adjuvant to allergen immunotherapy in humans. As observed in preclinical studies, the ability of abatacept to modulate the peanut-specific immune response during OIT will serve as a proxy outcome for the development of clinical tolerance, given the small sample size. The study will also test a new patient-oriented approach to sustained tolerance testing in randomized controlled trials

A nanoparticle ink allowing the high precision visualization of tissue engineered scaffolds by MRI

Hydrogels are widely used as cell scaffolds in several biomedical applications. Once implanted in vivo, cell scaffolds must often be visualized, and monitored overtime. However, cell scaffolds appear poorly contrasted in most biomedical imaging modalities such as magnetic resonance imaging (MRI). MRI is the imaging technique of choice for high-resolution visualization of low-density, water-rich tissues. Attempts to enhance hydrogel contrast in MRI are performed with “negative” contrast agents that produce several image artifacts impeding the delineation of the implant’s contours. In this study, a magnetic ink based on ultra-small iron oxide nanoparticles (USPIONs; <5 nm diameter cores) is developed and integrated into biocompatible alginate hydrogel used in cell scaffolding applications. Relaxometric properties of the magnetic hydrogel are measured, as well as biocompatibility and MR-visibility (T1-weighted mode; in vitro and in vivo). A 2-week MR follow-up study is performed in the mouse model, demonstrating no image artifacts, and the retention of “positive” contrast overtime, which allows very precise delineation of tissue grafts with MRI. Finally, a 3D-contouring procedure developed to facilitate graft delineation and geometrical conformity assessment is applied on an inverted template alginate pore network. This proof-of-concept establishes the possibility to reveal precisely engineered hydrogel structures using this USPIONs ink high-visibility approach

Safety and feasibility of oral immunotherapy to multiple allergens for food allergy

BACKGROUND: Thirty percent of children with food allergy are allergic to more than one food. Previous studies on oral immunotherapy (OIT) for food allergy have focused on the administration of a single allergen at the time. This study aimed at evaluating the safety of a modified OIT protocol using multiple foods at one time. METHODS: Participants underwent double-blind placebo-controlled food challenges (DBPCFC) up to a cumulative dose of 182 mg of food protein to peanut followed by other nuts, sesame, dairy or egg. Those meeting inclusion criteria for peanut only were started on single-allergen OIT while those with additional allergies had up to 5 foods included in their OIT mix. Reactions during dose escalations and home dosing were recorded in a symptom diary. RESULTS: Forty participants met inclusion criteria on peanut DBPCFC. Of these, 15 were mono-allergic to peanut and 25 had additional food allergies. Rates of reaction per dose did not differ significantly between the two groups (median of 3.3% and 3.7% in multi and single OIT group, respectively; p = .31). In both groups, most reactions were mild but two severe reactions requiring epinephrine occurred in each group. Dose escalations progressed similarly in both groups although, per protocol design, those on multiple food took longer to reach equivalent doses per food (median +4 mo.; p < .0001). CONCLUSIONS: Preliminary data show oral immunotherapy using multiple food allergens simultaneously to be feasible and relatively safe when performed in a hospital setting with trained personnel. Additional, larger, randomized studies are required to continue to test safety and efficacy of multi-OIT. TRIAL REGISTRATION: Clinicaltrial.gov NCT0149017