Résumé Dendritic cells (DCs) are professional APCs that have a unique capacity to initiate primary immune responses, including tolerogenic responses. We have genetically engineered bone marrow-derived DCs to express the immunosuppressive cytokine IL-10 and tested the ability of these cells to control experimental asthma. A single intratracheal injection of OVA-pulsed IL-10-transduced DCs (OVA-IL-10-DCs) to naive mice prior to OVA sensitization and challenge prevented all the cardinal features of airway allergy, namely eosinophilic airway inflammation, airway hyperreactivity, and production of mucus, Ag-specific Igs and IL-4. OVA-IL-10-DCs also reversed established experimental asthma and had long-lasting and Ag-specific effects. We furthermore showed, by using IL-10-deficient mice, that host IL-10 is required for mediating the immunomodulatory effects of OVA-IL-10-DCs and demonstrated a significant increase in the percentage of OVA-specific CD4+CD25+Foxp3+IL-10+ regulatory T cells in the mediastinal lymph nodes (MLNs) of OVA-IL-10-DC-injected mice. Finally, adoptive transfer of CD4+ MLN T cells from mice injected with OVA-IL-10-DCs protected OVA-sensitized recipients from airway eosinophilia upon OVA provocation. Our study describes a promising strategy to induce long-lasting Ag-specific tolerance in airway allergy./L’asthme atteint des proportions épidémiques dans les pays développés et a un impact négatif sur la qualité de vie. De plus les coûts des soins de santé relatifs à cette maladie ne cessent d’augmenter. La nette augmentation de l’incidence durant ces dernières décennies reste une énigme, les facteurs environnementaux ayant probablement contribués pour une large part dans ce processus. Bien que le traitement actuel de l’asthme avec des corticostéroïdes inhalés et des agonistes β2 à longue durée d’action est satisfaisant et sans danger, des inquiétudes restent sur les effets à long terme des corticostéroïdes, en particulier lorsqu’on voit que les traitements commencent parfois très tôt dans l’enfance. De plus, la thérapie actuelle ne semble pas inhiber le TGF-β ni les dépôts de collagène, importants dans le remodelage des voies aériennes qui, au final, contribue à augmenter l’HRB des voies respiratoires. La prévalence et la sévérité de l’asthme atopique augmentent de façon alarmante partout dans le monde depuis ces vingt dernières années {Eder, 2006 #2}. Les traits pathophysiologiques de l’asthme allergique, à savoir l’éosinophilie pulmonaire chronique, l’hyperréactivité bronchique des voies aériennes (HRB) à une variété de stimuli non spécifiques, la production excessive de mucus dans les voies aériennes et les niveaux élevés d’IgE dans le sérum, sont tous étroitement liés à une réponse immune de type Th2 aberrante envers des antigènes habituellement inhalés (Ag) {Busse, 2001 #466; Larche, 2003 #467; Ray, 1999 #465; Wills-Karp, 1999 #464}. Les lymphocytes Th2 spécifiques de l’antigène exercent des fonctions effectrices cruciales en produisant un répertoire propre de cytokines, les plus importantes d’entre-elles étant l’IL-4, l’IL-5 et l’IL-13 {Busse, 2001 #466; Larche, 2003 #467; Ray, 1999 #465; Wills-Karp, 1999 #464}. Essentiellement, l’asthme atopique est la manifestation d’une réponse immune Th2 aberrante envers un aéroallergène inoffensif. La condition requise pour développer une réponse immune Th2 est la participation de cellules présentatrices d’antigènes pour les réponses primaires et secondaires à un allergène. Les CDs sont les principales cellules pour activer et différencier les lymphocytes T CD4+ naïfs en sous-groupes distincts. De plus, la délétion des CDs durant la réponse immune primaire et secondaire de l’inflammation allergique des voies respiratoires dans les modèles animaux ont montré que ces cellules devaient absolument être présente au cours de ces deux phases. Les cellules dendritiques (CDs) sont des cellules présentatrices d’antigène professionnelles qui ont la capacité unique d’initier les réponses immunes primaires, incluant les réponses tolérogéniques. Nous avons génétiquement généré des CDs dérivés de cellules de la moëlle osseuse capables d’exprimer une cytokine immunosuppressive, l’IL-10. Nous avons testé leur capacité à contrôler un asthme expéritalement induit. Une simple injection par voie intra-trachéale de CDs transduites avec des lentivirus porteurs du gène codant l’IL-10 et chargées avec la protéine OVA (OVA-IL-10-DCs) à des souris naïves avant de les sensibiliser à l’OVA et de les provoquer à l’OVA prévient tous les traits caractéristiques de l’alargie des voies respiratoires, à savoir l’inflammation éosinophiliques des voies aériennes, l’hyperréactivité bronchique et la production de mucus, d’immunoglobulines spécifiques de l’antigène et d’IL-4. Les cellules OVA-IL-10-DCs réversent ausi l’asthme exprimental établi et ont des effets spécifiques de l’antigène, et ce, à long terme. Nous avons ensuite montré, en utilisant des souris déficientes pour l’IL-10, que l’IL-10 produit par l’hôte est nécessaire pour contrôler les effets immunomodulateurs des cellules OVA-IL-10-DCs. De plus, nous avons enfin une augmentation significative du pourcentage des lymphocytes T régulateurs CD4+CD25+Foxp3+IL-10+ spécifiques de l’OVA dans les ganglions médiastinaux (MLNs) des souris injectées avec les cellules OVA-IL-10-DC. Enfin, le transfert adoptif des lymphocytes CD4+ isolés des cellules de ganglions médiastinaux de souris injectées avec les cellules OVA-IL-10-DCs protège les souris receveuses, préalablement sensibilisées à l’OVA, d’une éosinophilie des voies aériennes suite à une provocation à l’OVA. Notre étude décrit une stratégie prometteuse pour induire une tolérance spécifique de l’antigène à long terme dans le cadre d’une allergie des voies aériennes.

SUMMARY Respiratory mucosal surfaces are constantly exposed to a broad range of non-pathogenic environmental antigens. In the absence of proinflammatory signals, inhalation of harmless antigens results in immunological tolerance. Indeed, lung dendritic cells stimulate the development of antigen-specific regulatory T cells. Nevertheless, epidemiological studies have shown that ambient air contains not only inert antigens but also immunostimulatory molecules of microbial origin. Of particular interest are endotoxins, a cell wall component of gram-negative bacteria that is ubiquitous in the environment. In spite of the fact that high levels of endotoxin exposure in early life protect against allergic sensitization, most evidence indicates that exposure to house-dust endotoxin is a significant risk factor for increased asthma prevalence and severity. When the respiratory tract is stimulated with airborne endotoxins, lung dendritic cells lose their tolerogenic properties and rather promote the development of an allergic response directed against concomitant aeroantigens. Although endotoxins are omnipresent in the environment and favour airway allergy, only a minority of people develops asthma. A unifying model reconciling these conflicting observations is still lacking. We report here that LPS-triggered airway allergy is tightly controlled by lung interstitial macrophages, a cell population that remains largely uncharacterized. Interstitial macrophages could be distinguished from alveolar macrophages by their unique capacity to inhibit lung dendritic cell maturation and migration upon LPS stimulation, thereby preventing sensitization to concomitant inhaled antigens. We furthermore demonstrated that functional paralysis of LPS-stimulated dendritic cells involves interleukin-10 production by interstitial macrophages. Finally, we demonstrate that specific in vivo elimination of interstitial macrophages leads to overt asthmatic reactions to innocuous airborne antigens inhaled along with low LPS doses. Our study thus reveals a crucial role for interstitial macrophages in maintaining immune homeostasis in the respiratory tract and provides an explanation for the paradox that airborne LPS has the ability to promote the induction of Th2 responses by lung dendritic cells but does not provoke airway allergy under normal conditions. In the presence of LPS, interstitial macrophages, but not alveolar macrophages, break the link between innate and adaptive immunity, allowing harmless inhaled antigens to escape from T cell-dependent responses. RÉSUMÉ Le système respiratoire est continuellement exposé à de nombreux antigènes environnementaux non pathogéniques. En labsence de signal proinflammatoire, linhalation dantigènes inoffensifs aboutit au développement dune tolérance immunologique. Dans ces conditions, les cellules dendritiques pulmonaires tolérogènes stimulent le développement de lymphocytes T régulateurs. Cependant, les études épidémiologiques montrent que lair ambiant ne contient pas que des antigènes inertes mais également des molécules immunostimulatrices dorigine microbienne dont les endotoxines (LPS, lipopolysaccharide). La présence dans lenvironnement de ce composant de la paroi des bactéries Gram négatives est ubiquiste. Malgré le fait que lexposition à de hauts niveaux de LPS durant lenfance semble protéger contre la sensibilisation allergique, la plupart des études montrent que les endotoxines contenues dans la poussière domestique constituent un facteur de risque significatif pour la prévalence et la sévérité de lasthme. Quand le système respiratoire est stimulé par le LPS aérogène, les cellules dendritiques perdent leurs propriétés tolérogènes et deviennent capables dinduire le développement dune réponse allergique. Bien que les endotoxines soient omniprésentes dans lenvironnement et favorisent lallergie des voies respiratoires, seulement une minorité de personnes est asthmatique. Ces observations contradictoires impliquent lexistence de mécanismes protecteurs non encore décrits capables de prévenir les réponses allergiques induites par les endotoxines. Nous montrons dans ce travail que lallergie des voies respiratoires induite par le LPS est étroitement contrôlée par les macrophages interstitiels, une sous-population de macrophages pulmonaires dont la fonction in vivo navait jamais été caractérisée. Les macrophages interstitiels peuvent être distingués des macrophages alvéolaires par leur capacité unique à inhiber la maturation et la migration des cellules dendritiques induites par lexposition du système respiratoire au LPS, prévenant ainsi la sensibilisation aux aéroantigènes inhalés concomitamment. De plus, nous démontrons que linhibition fonctionnelle des cellules dendritiques implique la sécrétion dIL-10 par les macrophages interstitiels. Finalement, nous montrons que lélimination spécifique des macrophages interstitiels in vivo aboutit au développement dune réponse asthmatique dirigée contre les aéroantigènes inoffensifs inhalés avec de faibles doses de LPS. Notre travail révèle un rôle crucial des macrophages interstitiels dans le maintien de lhoméostasie immunitaire du tractus respiratoire et fournit une explication au paradoxe que le LPS aérogène a la capacité de favoriser linduction de réponses Th2 par les cellules dendritiques mais ne provoque pas dallergie des voies respiratoires dans les conditions normales. En présence de LPS, les macrophages interstitiels, mais pas les macrophages alvéolaires, brisent le lien entre limmunité innée et limmunité adaptative, permettant aux antigènes inhalés déchapper aux réponses dépendantes des lymphocytes T.

Zur Detektion neuer IgE- reaktiver Proteine wurde in dieser Arbeit ein zweidimensionales Proteintrennverfahren verwendet. Resultierende Proteinfraktionen wurden mithilfe von 18 tomatensensibiliesierten Patientenseren im Immunoblot getestet. Detektierte Proteine in der SDS-PAGE wurden mittels LC-MS/MS identifiziert. Dadurch konnten 2 Tomatensamenproteine, die im Immunoblot ein IgE- reaktives Signal zeigten eindeutig mittels Massenspektrometrie identifiziert werden. Diese Proteine sind Legumin und Vicilin. Durch Sequenzabgleich und Proteinstrukturmodellierung im Vergleich zu bereits bekannten Allergenen (Erdnuss und Cashewnuss), konnte eine hohe Homologie gezeigt werden. / For the detection of tomato allergens a multidimensional protein fractionation strategy and LC-MS/MS was used. Putative allergens were detected by IgE immunoblotting using sera from 18 adult tomato sensitised patients selected based on a positive history skin prick test and specific Immunglobulin (Ig) E levels. Two legumin- and vicilin- proteins were purified and showed strong IgE-reactivity in immunoblots. Individual patient sera exhibited varying IgE-sensitivity against the purified proteins. In silico structural modelling indicates high homology between epitopes of known peanut and cashewnut allergens and the detected IgE-crossreactive tomato proteins.

Antibodies are a central part of the immune defense system, and a large variability in their specificity is needed in order to be able to react against all possible foreign substances we may encounter during our lives. In this thesis, results are presented from investigations into how an egg-laying mammal, the Australian duck-billed platypus (Ornithorhynchus anatinus) creates antibody variability. Our results show that despite the lack of many V gene families the antibody repertoire in the platypus seems to be well developed. A long and highly variable complementarity-determining region (CDR) 3 compensates for the limited germline diversity. Interestingly, the presence of additional cysteine residues in the CDRs may form stabilizing disulfide bridges in the antigen binding loops and thereby increasing the affinity of the antibody-antigen interaction. Although the immune system is necessary for survival, it must be strictly controlled since it may otherwise over-react and cause more harm than benefits. Allergies and autoimmune diseases are examples of such over-reactions by the immune system. Allergies are increasing in the western world and have become one of the main medical issues of the 21st century. IgE is the central mediator in atopic allergies such as hay fever, eczema and asthma; it is therefore a prime target in the development of allergen-independent preventative treatments. Here we present results from several studies of a novel vaccine strategy aimed at reducing the levels of IgE antibodies. The vaccine results in the induction of anti-IgE antibodies, and the skin reactivity upon allergen challenge was significantly reduced in vaccinated animals. Our results suggest that active immunization against IgE has the potential to become a therapeutic method for humans. In addition, an evaluation of possible adjuvants that could be used as immune stimulators and thus help break self-tolerance at the time of vaccination is presented.

Immunoglobulin E (IgE) occurs exclusively in mammals and is one of five immunoglobulin (Ig) classes found in man. Unlike other isotypes, IgE is best known for its pathological effects, whereas its physiological role remains somewhat elusive. To trace the emergence of IgE and other post-switch isotypes we have studied Ig expression in two monotreme species, the duck-billed platypus (Ornithorhynchus anatinus) and the short-beaked echidna (Tachyglossus aculeatus), leading to the cloning of IgE, two IgG isotypes in platypus and echidna IgE. The presence of IgE and the conservation of the overall structure in all extant mammalian lineages indicates an early appearance in mammalian evolution and a selective advantage of structural maintenance. Furthermore, both of the two highly divergent platypus γ-chains have three constant domains. Hence, the major evolutionary changes that gave rise to the IgE and IgG isotypes of present day mammals occurred before the separation of monotremes from the marsupial and placental lineages, estimated to have occurred 150-170 million years ago. As the central mediator in atopic allergy, IgE is a prime target in the development of preventive treatments. This thesis describes an active immunization strategy that has the potential to reduce IgE to a clinically significant extent. The active vaccine component is a chimeric IgE molecule, Cε2-Cε3-Cε4. The receptor-binding target domain, Cε3, is derived from the recipient species, whereas the flanking domains, acting both as structural support and to break T-cell tolerance, are derived from an evolutionarily distant mammal. Vaccination of ovalbumin-sensitized rats resulted in a substantial reduction in total IgE in three out of four strains, accompanied by a significant reduction in skin-reactivity upon allergen challenge. No cross-linking activity was observed and the response to vaccination was reversible with time. The apparent safety and efficacy of the vaccine suggest that active immunization against IgE has the potential to become a therapeutic method for humans. Furthermore, the cloning and expression of the pig (Sus scrufa) ε-chain will facilitate the development of sensitive and specific assays for pig IgE, thus increasing the possibilities of using the pig model in future studies of IgE-mediated reactions.

Transition metals such as nickel (Ni), cobalt (Co), palladium (Pd), chromium (Cr) and gold (Au) are widely used as alloys in jewelry and biomaterials such as orthodontic and orthopaedic appliances. These metals also cause cell-mediated allergic contact dermatitis (ACD) reactions in a significant proportion of the population upon prolonged direct exposure. The immune mechanisms underlying the response to these metals are not yet well defined. In the studies described in this thesis we therefore investigated the profile of cytokine responses to various metal ions in vitro and the relationship with the ACD reaction in vivo. In the first study, we investigated the relationship between the profile and magnitude of Ni2+-induced cytokine responses in vitro and the degree of in vivo reactivity to Ni2+. PBMC from Ni2+-reactive (ACD) and non-reactive control subjects were cultured with or without NiCl2. The numbers of IL-4-, IL-5- and IL-13-producing cells and the concentrations of IFN-γ, IL-10 and IL-13 produced were analysed by ELISpot and ELISA respectively. Ni2+ elicited a mixed Th1- and Th2-type cytokine profile in PBMC from ACD subjects with a positive correlation observed between the levels of the elicited cytokines and the degree of patch test reactivity. Hence, suggesting an involvement of both Th1- and Th2-type cytokines in ACD to Ni2+ and a direct association between the magnitude of the Ni2+-induced cytokine response overall and the in vivo reactivity to Ni2+. The impact of the regulatory cytokine IL-10 on Ni2+-induced Th1- and Th2-type cytokine responses in human PBMC was investigated in the next study. PBMC from blood donors with a history of Ni2+ reactivity and non-reactive control donors were stimulated with Ni2+ ex vivo with or without addition of human recombinant IL-10 (rIL-10) or neutralising mAb to IL-10. Depletion/enrichment experiments were performed to phenotype the Ni2+-specific cytokine producing cells. Exogenous rIL-10 significantly down-regulated the production of all cytokines but with a more pronounced effect on IFN-γ. IL-10 neutralisation, on the other hand, enhanced the levels of Ni2+-induced IFN-γ only. Ni2+-specific cytokine-producing cells in PBMC were found to be predominantly CD4+ T cells. Thus, IL-10 may play a regulatory role in vivo by counteracting the ACD reactions mediated by CD4+ T cells producing Th1-type cytokines. In the third study, we investigated the relationship between in vivo patch test reactivity to a number of metals (Ni, Co, Pd, Cr and Au) included in the standard and/or dental patch test series and in vitro responses to the metals in question. PBMC from metal patch test positive and negative control subjects were stimulated with a panel of eight metal salts and cytokine responses analysed by ELISpot and/or ELISA. A mixed Th1- (IL-2 and/or IFN-γ) and Th2-type (IL-4 and/or IL-13) cytokine profile was observed in PBMC from most metal allergic subjects upon in vitro stimulation with the metal(s) to which the subject was patch test positive. Our data suggest that other metals included in the standard and dental patch test series, just like Ni2+, induce a mixed Th1- and Th2-type cytokine profile in PBMC from ACD subjects in vitro. We further developed a simplified ELISpot protocol utilising plates precoated with capture monoclonal antibodies (mAb) and subsequent detection in one step using enzyme-labelled mAb, for enumerating the frequency of allergen (Ni2+)-specific cytokine producing cells. This was compared with a regular ELISpot protocol, with an overnight incubation for capture mAb adsorbtion and detection with biotinylated mAb followed by enzyme-labelled streptavidin. PBMC from Ni2+-reactive and non-reactive subjects were incubated with or without NiCl2 and the enumeration of cells producing IFN-γ, IL-4 or IL-13 by the two protocols were compared. PBMC from Ni2+-reactive subjects showed significantly higher Ni2+-induced IL-4 and IL-13 responses and the number of antigen-specific cytokine-producing cells determined by the two ELISpot protocols correlated well. In a nutshell, our data point to the potential use of in vitro cytokine assays as diagnostic tools in distinguishing ACD subjects sensitised to different metals and non-sensitised subjects.

Background: Atopic disease is an increasing problem. Eczema affects 10-20% of young children, and 33-37% of children with eczema are food allergic. Among other factors, nitric oxide (NO) is thought to play a role in eczema and food allergy. Following the atopic march, pproximately 80% of children with atopic eczema will become sensitized to aeroallergens and develop asthma and/or allergic rhinitis. Skin prick test is used for investigating sensitization and is considered a safe method. However, systemic allergic reactions may appear when the test is performed. In diagnosing food allergy and for evaluating achievement of tolerance, the oral food challenge is the method of choice, and the double-blind placebocontrolled fashion is 'the gold standard'. Skin prick test: We examined six cases of generalized allergic reactions in connection with skin prick testing in order to identify risk factors, and thereby increase safety, and we investigated the necessity of performing skin prick tests in duplicate. We found that all six children with generalized reactions were <6 months of age. When analyzing skin prick tests in duplicate, we found only 1.3% that showed diverging results, and in infants <6 months even fewer, 0.9%. Food challenge: We developed recipes and a protocol for low-dose oral food challenge to milk and egg to be used in young children outgrowing their food allergy so as to facilitate early re-/introduction of small amounts of milk and egg. We performed 52 challenges, both open and double-blind placebo controlled. The recipes were validated for blinding. The lowdose challenge was tolerated well by the children and was easy to perform. Four children had a positive challenge outcome, all reacting to very small amounts of milk. All but two of the non-reacting children were able to introduce milk and egg into their diet. Nitric oxide and eczema: We investigated the effect of eczema treatment on the NO levels in urine. The sum of nitrite and nitrate was measured in urinary samples from 94 infants at two visits, with an interval of 6 weeks, and the results were compared with clinical data. The levels of NO products increased significantly when the eczema improved. The atopic march: The aim was to evaluate the atopic march in children with eczema, from referral at <2 years until 4½ years of age. We followed 123 children with eczema, 78 sensitized and 45 not sensitized to milk and/or egg, with respect to eczema severity, other allergic manifestations, development of airway sensitization, and achievement of food tolerance. The difference in severity of eczema at referral was significant when comparing food-sensitized with non-sensitized children. At follow-up, 62% were still affected by eczema, although 56% only mildly so. Tolerance was achieved in 81% of the children allergic to milk and 68% of those allergic to egg. Fifty-eight percent of the food-sensitized children and 26% of the non-sensitized children had become sensitized to aeroallergens, a significant difference. The difference in airway symptoms was not significant. Very few children were exposed to tobacco smoke in their homes. Conclusions: Increased precautions should be considered when performing skin prick tests in infants <6 months of age. The use of a single prick, to avoid the risk of summation of reactions, is justified when performing skin prick tests. We report recipes and a protocol for standardized open and double-blind placebo-controlled low-dose food challenge in young children, enabling the introduction of small amounts of egg and milk into the diet during tolerance development. NO products in urine increases when eczema improves. This might be due to a Th2/Th1 shift induced by the eczema treatment and skin healing, and the variation in NO response may be due to individual variations in NO-induced feedback downregulation of Th1 and Th2 proliferation. The prognosis for achieving clinical tolerance is very good in children early sensitized and allergic to milk and egg, but they will become significantly more often sensitized to aeroallergens.

The increasing prevalence of allergic diseases in affluent societies has been associated with changes in microbial exposure early in life and a less diverse gut flora. The objective of this thesis was to assess the development of allergic sensitisation and symptoms during the first four years of life in a non-selected birth cohort in relation to environmental factors, family history, gut microbiota and salivary IgA antibodies. The cohort comprised all 1,228 infants living in a Swedish county who were born over a one-year period. The parents replied to questionnaires, and 817 children (67 %) were skin prick tested both at 1 and 4 years of age. Saliva (n=279), faecal (n=139) and blood (n=253) samples were collected at 1 year of age from children with a positive skin prick test at 1 year and from a sample of children with a negative skin prick test. Faecal samples were also obtained from 53 children at 4 years of age. Dog keeping during infancy was associated with a decreased risk of sensitisation to pollen and late-onset wheezing at age 4, and the reduced odds ratios persisted after adjustment for heredity and avoidance measures, OR 0.3, 95% CI 0.1-0.9 and OR 0.5, 95% CI 0.2-1.0, respectively. In contrast, early dog keeping was associated with an increased risk of earlyonset transient wheezing but only in children with parental asthma (OR 2,8, 95% CI 1.3-6.4). Levels of short chain fatty acids (SCFAs) in faeces were assessed both at 1 and 4 years of age and related to the development of sensitisation and symptoms. The levels of acetic (p<.01) and propionic (p<.01) acids decreased from one to four years of age, whereas valeric acid (p<.001) increased which is in line with a more complex gut microbiota with age. Allergic children, compared with non-allergic children, had lower levels of i-butyric, i-valeric and valeric acid in faeces both at 1 and 4 years of age. Low levels of secretory IgA (SIgA) in saliva were associated with wheezing but only in sensitised children. In children with positive SPT to at least one allergen both at 1 and 4 years of age and in children with circulating IgE antibodies to egg or cat at one year of age, those who developed late-onset wheezing had lower levels of SIgA than those who did not, p=.04 and p=.02 respectively. Of 9 children with levels of SIgA in the upper quartile and persistent sensitisation, none developed wheezing, compared with 10/20 children with lower levels, (p=. 01). Having older siblings, more than three infections during infancy, at least one smoking parent and male gender were all associated with high levels (in the upper quartile) of total IgA and SIgA. The findings in this thesis indicate that the microbial load early in life could affect the development of allergy. A functional assessment of the gut flora demonstrated differences between allergic and non-allergic children both at 1 and 4 years of age. Salivary IgA was associated with infections during infancy, and high levels of secretory IgA protected from symptoms in sensitised children. Finally, dog keeping in infancy may offer protection from allergy, but the mechanism is uncertain.

Aim: The aim of this project was to study the age and sex specific occurrence of atopic and non-atopic asthma and other atopic manifestations in a nationwide sample of Swedish pre-school children. Methods: All 70 allergen avoidance day-care centres (AADC) with 84 sections and 140 matched ordinary day-care centres with 440 sections in 62 municipalities across Sweden were sampled. In 2000 the staff at each section responded to a questionnaire on indoor and outdoor environment at the section. In 2002 parents of 5,886 children attending the AADCs and ODCs responded to a postal questionnaire regarding symptoms indicating prevalent asthma, allergic rhinitis, eczema, and food, furred pet and pollen allergy and other data in their children. In 2007, parents of 4255 children responded to an almost identical follow-up questionnaire. Results: The AADCs had far more strict rules than ODCs on furred pets and smoking at home and on perfume use, and the indoor environment was better, owing to better cleaning. The age specific asthma prevalence was curvilinear with a peak at age 3 of 11.4% among boys and 9.8% among girls. In addition the prevalence increased by municipality population density, a proxy for degree of urbanisation. There was a highly significant co-occurrence between all asthma-atopic manifestations, but there was no evidence of ordered sequence of manifestation onset. The asthma incidence was highly dependent on presence or absence of co-occurrence variables. Given the variable mix in the present study population, the annual asthma incidence ranged from 0.6% to 1.2%. Conclusions: AADCs had more strict rules and a better indoor environment than ODCs. The asthma prevalence was affected by age, sex and degree of urbanisation. There was close co-occurrence between all asthma and atopic manifestations but no evidence of ordered sequence of onsets. The annual asthma incidence was strongly dependent of co-occurrence conditions.

Syftet med studien var att undersöka vårdpersonalens inställning till djur samt upplevelsen hos vårdpersonal av delaktighet och inflytande när djur introduceras på särskilda äldreboenden. Metoden var deskriptiv och komparativ studie med kvantitativ ansats med kvalitativa inslag. Enkätstudie besvarades av 102 vårdpersonal på elva särskilda äldreboenden. Resultat visade att 74 %vårdpersonalen ansåg att djur på särskilt äldreboende är mycket bra och om upplevelsen av sin hälsa i relation till djur på avdelningen beskrevs av ett fåtal som att hälsan har försämrats, majoriteten svarade att hälsan inte hade försämrats. Studien visar att förekomsten och frekvensen av besök av djur och längden på besöken är hög.  Nästan hälften (47 %) av vårdpersonalen har varit med om att djur introducerats under deras anställningstid och djuret / djuren sköts främst av vårdpersonalen. Upplevelsen av skötsel av djur är att det är trevligt och stimulerande. Om avdelningsbyte svarade 9 % av vårdpersonalen att de hade haft en kollega som bytt avdelning p g a djur och deras beskrivning av upplevelsen var att det var tråkigt, någon svarade att det var självvalt av den som bytte. Vid beslut om att införa djur i verksamheten upplevde de flesta att det var positivt. / The purpose of this study was to examine nursing staff´s attitudes towards pets and the experience of involvement and influence when animals are introduced at the homes for older people. It was a survey studie which was answered by 102 nursing assistents and nurses. The method was descriptive and comparative study with quantitative approach with qualitative elements. Results showed that 74% of the nursing staff felt that pets at homes for older people are very good and the experience of their health in relation to animals in the ward were described by a few as to health has deteriorated, the majority responded that health had not deteriorated. The study shows that the occurrence and frequency of visits by pets and length of visits is high. Almost half (47%) of nursing staff has experienced pets introduced during their employment period and the pet /pets are primarily looked after by the nursing staff. The experience of care of pets is that it's fun and stimulating. 9 % of the nursing staff that they had had a colleague who changed ward because of pets and their description of the experience was that it was boring, someone replied that it was the choice of the one who changed ward. In deciding whether to include pets in the home for older people experienced most of the staff that it was positive.