2,4-D-specific IgE antibodies were detected in serum of BALB/c mice using the rat passive cutaneous anaphylaxis (PCA) test following the second intraperitoneal immunization with 1, 10, or 100 ug of 2,4-D0keyhole limpet hemocyanin (KLH) conjugate administered with aluminum hydroxide adjuvant. The groups that received 1 ug of 2,4-D conjugate had the highest antibody titers (geometric mean of 60). A paper radioallergosorbent test (PRAST) was developed for determination of 2,4-D-specific IgE. The PRAST was equally as sensitive as and showed a positive correlation with the PCA assay. The anhydride of the diacid metabolite of malathion (MMA) coupled to KLH elicited MMA-specific IgE following secondary immunization with 10 and 100 ug and tertiary immunizations with 1, 10, and 100 ug of conjugate. The highest PCA titers (geometric means of 208 and 195) were found after three immunizations with 10 or 100 ug of conjugate, respectively. A PRAST for MMA-specific IgE was developed and yielded results equivelant to those obtained using the PCA procedure. Concurrently with these studies, dinitrophenyl-specific IgE elicited with 1 ug of dinitrophenyl-KLH conjugate was measured by the PCA test at all intervals examined. 2,4-D and malathion applied epicutaneously on two days or over four weeks failed to elicit delayed-type hypersensitivity (DTH). Cptafol produced DTH responses at both dose levels tested. Following two applications, ear thickness, incorporation of 5-[125I]iodo-2'deoxyuridine-labelled cells, and histology of ears indicated swelling and cellular infiltration. Multiple sensitizations over the period of a month also produced DTH as indicated by increases in ear thicknesses. Mice pretreated with cyclophosphamide produced larger responses 24 hours post-challenge but equivalent responses at 48 hours as compared to mice pretreated with saline. Sensitization with a known sensitizer, dinitrofluorobenzene, also elicited DTH. Neither 2,4-D- nor MMA-specific IgE antibodies were detected in serum during the four week epicutaneous sensitization period. Low titers of dinitrophenyl-specific IgE were elicited in mic treated with dinitrofluorobenzene.

Yes / Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. To inform the development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost-effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis. Methods: We searched nine international biomedical databases for published, in-progress, and unpublished evidence. Studies were independently screened by two reviewers against predefined eligibility criteria and critically appraised using established instruments. Our primary outcomes of interest were symptom, medication,and combined symptom and medication scores. Secondary outcomes of interest included cost-effectiveness and safety. Data were descriptively summarized and then quantitatively synthesized using random-effects meta-analyses. Results: We identified 5960 studies of which 160 studies satisfied our eligibility criteria. There was a substantial body of evidence demonstrating significant reductions in standardized mean differences (SMD) of symptom (SMD -0.53, 95% CI -0.63,-0.42), medication (SMD -0.37, 95% CI -0.49, -0.26), and combined symptom and medication (SMD -0.49, 95% CI -0.69, -0.30) scores while on treatment that were robust to prespecified sensitivity analyses. There was in comparison a more modest body of evidence on effectiveness post-discontinuation of AIT, suggesting a benefit in relation to symptom scores.Conclusions: AIT is effective in improving symptom, medication, and combined symptom and medication scores in patients with allergic rhinoconjunctivitis while on treatment, and there is some evidence suggesting that these benefits are maintained in relation to symptom scores after discontinuation of therapy. / EAACI and BM4SIT project (grant number601763) in the European Union’s Seventh Framework Programme FP7.

Allergic asthma is a chronic inflammatory disease of the airways. Importantly, the chronic nature of this disease imparts specific additional consequences that would not otherwise be observed in a strictly acute setting. The development ofvarious structural alterations to the airway wall, collectively tem1ed airway remodeling, represents one such example. Decades of research have provided a great deal of insight into the acute allergic asthmatic response and the processes that govern it. However, less is known about the impact of protracted allergen exposure and chronic immune-inflammatory responses. To this end, the research presented in this thesis explores the consequences of chronic allergen exposure and persistent airway inflammation on asthma pathogenesis, using a mouse model of allergic airway disease induced by respiratory exposure to house dust mite (HDM) allergens. Specifically examined are: i) the impact of continuous allergen exposure and the resulting immune-inflammatory response on the development of de nova sensitization to newly encountered allergens (Chapter 2) and, ii) the roles oftransforming growth factor (TGF)-~ and eosinophils, two putatively critical components of the allergic inflammatory response, in the generation of airway remodeling (Chapters 3 and 4). Our data show that chronic exposure to HDM facilitates the development of the full 'asthmatic phenotype' towards an innocuous antigen. Moreover, they demonstrate that, unlike what has been previously observed in ovalbumin-based models, neither TGF-~ nor eosinophils are critically required for remodeling to develop in the context of HDM exposure. These findings highlight the importance of the lung microenvironment in influencing the type of immune response that develops upon initial antigen encounter and, furthermore, underscore the notion that the role of a particular cell type or molecule in the asthmatic response is contextual and not necessarily broadly applicable. / Thesis / Doctor of Philosophy (PhD)

Background: Allergic sensitization is the most important risk factor for asthma and rhinitis among children, adolescents and young adults. Less is known about the incidence and remission of allergic sensitization, particularly in older adults. Furthermore, it is not clear if the earlier documented increase in prevalence of allergic sensitization continues. This thesis is focused on prevalence, incidence and remission of allergic sensitization to airborne allergens among adolescents and adults as well as on time trends in prevalence among adults. Furthermore, associated risk factors and the relation of allergic sensitization to asthma and rhinitis were assessed. Methods: In the study of children and adolescents, incidence, remission and prevalence of allergic sensitization were assessed in a cohort study of schoolchildren, aged 7-8 years (y) at baseline. In the studies of adults, incidence and remission of allergic sensitization were assessed in a randomly selected adult population sample in 1994 (n=664) aged 20-69 y, which was followed up in 2004 (n=555). Trends in prevalence of allergic sensitization were assessed by comparing two cross-sectional studies; the cohort from 1994 and another randomly selsected population sample examined in 2009 (n=737). The relation of allergic sensitization to asthma and rhinitis was determined in the adult cohort in 2009. Allergic sensitization was assessed by skin prick test (SPT) with ten common airborne allergens at ages 7-8, 11-12 and 19 y in the cohort of children and in the participants ≤ 60 y in the adult cohorts. Specific IgE to nine airborne allergens was analyzed in the adult cohorts in 2004 and 2009. Risk factors for allergic sensitization and variables defining respiratory disease and symptoms were assessed by questionnaires in the cohort of children and by structured interviews in the adult cohorts. Results: The 10-year cumulative incidence of allergic sensitization among the adults from 1994 to 2004 was 5%, while remission was 32%. In both adult cohorts, the prevalence of allergic sensitization was highest among young adults, aged 20-29 y, 55% and 61% and decreased significantly with increasing age. Among children and adolescents, both incidence and persistence of allergic sensitization were high, and the prevalence of allergic sensitization increased by age from 21% at age 7-8 y to 42% at age 19 y. Multisensitization at age 19 y was strongly associated with early onset of sensitization. The prevalence of sensitization to the major specific allergens birch, timothy, cat and dog as well as multisensitization (from 40% in 1994 to 56% in 2009, p=0.002) increased significantly from 1994 to 2009 among the adults. Sensitization to any allergen increased from 35% to 39%, however not significantly (p=0.13). A family history of allergic rhinitis was strongly and consistently associated with allergic sensitization in all ages. Male sex and urban living were significantly positively and birth order and furry animals at home in childhood were negatively associated with onset of sensitization before the age of 7-8 y, but not with onset of sensitization from 11-12y to 19 y. Young adult age and urban living were significant factors associated with allergic sensitization in adult age. Sensitization to any animal was significantly positively associated with current asthma (OR4.80 (95% CI 2.68-8.60)), whereas both sensitization to any pollen (OR 4.25 (2.55-7.06)) and any animal (OR 3.90 (95% CI 2.31-6.58)) were associated with current allergic rhinitis. The association between allergic sensitization and allergic rhinitis was strongest in young adult age and decreased with increasing age, while asthma was similarly associated with sensitization to any animal across all adult ages. Among asthmatics, the prevalence of allergic sensitization decreased with increasing age of asthma onset. Conclusion: Both incidence and persistence of allergic sensitization were high among children and adolescents explaining the increase in prevalence by increasing age. An inverse pattern with low incidence and high remission of allergic sensitization was seen among adults. The decrease in prevalence of allergic sensitization by increasing adult age might at least partly be explained by normal ageing and not only by an effect of year of birth (cohort effect). The significant increase in prevalence of sensitization to the specific allergens explained the significant increase in multisensitization over 15 years. A family history of allergy was the strongest and the only consistent risk factor for allergic sensitization in all ages. The prevalence of allergic sensitization decreased with increasing age of asthma onset among adult asthmatics.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

No description available.

Parental reports are often used in studies of asthma and allergic diseases in children. A change in respondent from parent to index subject usually occurs during adolescence. Little is known about the effects this change in method might have on the outcomes of a longitudinal study. Smoking is a major cause of respiratory symptoms among adults and environmental tobacco smoke (ETS) is a risk factor for asthma among children. Less is known about these associations among teenagers. In order to improve prevention of smoking, it is important to identify populations at risk of becoming smokers.       The aim of this thesis were to 1) evaluate the methodological change from parental to self-completion of a questionnaire about asthma and allergic diseases, and 2) to study determinants for, and respiratory health effects of ETS and personal smoking in teenagers. In 1996, a longitudinal study of asthma and allergic diseases among schoolchildren started within the Obstructive Lung Disease in Northern Sweden (OLIN) studies. All children in first and second grades (aged 7-8 years) in three municipalities, Luleå, Kiruna and Piteå (n=3,525) were invited and 97% participated by parental completion of a questionnaire. The cohort has been followed with annual questionnaires until age 16-17 years and with high participation rates (>91%). From age 12-13 years, the teenagers were the respondents and questions about their tobacco use were included. In addition to the questionnaire completed by the teenagers at age 13-14 years, a questionnaire was also distributed to a random sample of 10% of the parents and 294 participated (84%).   The parents and the teenagers reported a similar prevalence of asthma, respiratory symptoms, rhinitis, eczema and environmental factors. Two statistically significant differences were found: the teenagers reported a higher prevalence of wheezing during or after exercise (14% vs 8%, p<0.05), and having a dog in the home in the last 12 months (42% vs 29%, p<0.001). Answer agreement between parents and teenagers on questions about asthma was almost perfect with kappa values of 0.8-0.9. Corresponding kappa values for questions about respiratory symptoms and rhinitis were 0.3-0.6 and for eczema 0.5-0.6. Agreement about environmental factors varied from 0.2-0.9. Kappa values for parental smoking were 0.8-0.9. The risk factor pattern for allergic diseases was similar regardless of respondent, ie parent or teenager. The prevalence of smoking increased from 3% at 12-13 years to 6% at 14-15 years. Smoking was more common among girls, while the use of snus was more common among boys. Significant risk factors related to smoking among teenagers were smoking family members, female sex and living in an apartment. Having physician-diagnosed asthma did not prevent the teenagers from becoming smokers. Factors related to using snus were a smoking mother and male sex.  Daily smokers aged 16-17 years (9%) reported a significantly higher prevalence of wheezing and physician-diagnosed asthma compared to non-smokers. There was a significant dose-response association with higher prevalence of wheeze among those who smoked ≥11 cigarettes per day compared to those who smoked ≤10 per day. In multivariate analyses, maternal environmental tobacco smoke exposure was a significant risk factor for ever wheeze and physician-diagnosed asthma at age 16-17 years, while daily smoking was a risk factor for current wheeze. In conclusion, the methodological change of questionnaire respondent from parent to index subject did not substantially alter the findings of this longitudinal study. There were significant sex differences in the tobacco use: smoking was more common among girls and snus was more common among boys. The most important factor related to tobacco use was presence of family members who smoke. Both maternal ETS exposure and personal smoking was associated with asthma and wheeze in adolescence. ETS was associated with lifetime symptoms but daily smoking was more strongly associated with current symptoms.

The purpose of this investigation has been to determine the characteristics of the immune response to 1-fluoro-2,4-dinitrobenzene when this hapten is conjugated with various types of proteins.

Regulatory T cells (Treg) are critical to the maintenance of immune tolerance, partly by controlling the unwanted activation of effector T cells (Teff) and thereby enhancing the resolution of autoimmune and allergic inflammation. Recent data suggest that Treg can specialize to better control different types of inflammation by using transcriptional machinery which controls differentiation and function of Teff. This thesis addresses questions related to the efficacious use of Treg, notably their ability to adopt distinct phenotypic profiles under different inflammatory contexts and their need to recognize antigen in the inflamed organ. Two differentially mediated mouse disease models were used in this project, namely Th1/Th17-mediated experimental autoimmune encephalomyelitis (EAE) as a model of multiple sclerosis and Th2-mediated allergic airways inflammation (AAI) as a model of asthma. A new model of rMOG-induced AAI was developed to specifically answer the questions on the importance of cell phenotype versus antigen-reactivity for the effective Treg-mediated suppression. It was demonstrated that Treg from the inflamed CNS in EAE had an upregulated expression of Th1 master regulator T-bet and Th1-associated chemokine receptor CXCR3, whereas Treg derived from the inflamed lung in AAI had an increased expression of Th2 master regulator GATA-3, lacked expression of T-bet and displayed decreased levels of CXCR3. This specialized and activated phenotype was restricted to tissue-derived Treg. The importance of appropriate Treg phenotype for effective suppression was suggested by the observed inability of CNS-derived Treg to inhibit AAI. A different Treg subset, TGF-β-induced Treg (iTreg), was shown to express high levels of T-bet and CXCR3, but not GATA-3 upon induction in vitro. iTreg effectively suppressed both Th1 and Th2 types of inflammation and the antigenreactivity was key to this. This thesis demonstrates that Treg are capable of acquiring a distinct phenotype corresponding with a CD4+ T cell response driving inflammatory disease and identifies antigen-reactivity as key to the efficacious suppression of inflammation. It also highlights substantial phenotypic differences between iTreg and naturally-occurring Treg which could be associated with different modes of suppression.