Saskia Gruber

A Th17- and Th2-skewed Cytokine Profile in Cystic Fibrosis Lungs Represents a Potential Risk Factor for Pseudomonas aeruginosa Infection

RATIONALE Cystic fibrosis (CF) is characterized by progressive pulmonary inflammation that is infection-triggered. Pseudomonas aeruginosa represents a risk factor for deterioration of lung function and reduced life expectancy. OBJECTIVES To assess T-cell cytokine/chemokine production in clinically stable children with CF and evaluate the association between T-cell subtypes and susceptibility for infection with P. aeruginosa. METHODS T-cell cytokine/chemokine profiles were measured in bronchoalveolar lavage fluid (BALF) from children with CF (n = 57; 6.1 ± 5.9 yr) and non-CF control subjects (n = 18; 5.9 ± 4.3 yr). Memory responses to Aspergillus fumigatus and P. aeruginosa were monitored. High-resolution computed tomography-based Helbich score was assessed. In a prospective observational trial the association between BALF cytokine/chemokine profiles and subsequent infection with P. aeruginosa was studied. MEASUREMENTS AND MAIN RESULTS Th1- (INF-γ), Th2- (IL-5, IL-13), Th17- (IL-17A), and Th17-related cytokines (IL-1β, IL-6) were significantly up-regulated in airways of patients with CF. IL-17A, IL-13, and IL-5 were significantly higher in BALF of symptomatic as compared with clinically asymptomatic patients with CF. IL-17A and IL-5 correlated with the percentage of neutrophils in BALF (r = 0.41, P < 0.05 and r = 0.46, P < 0.05, respectively). Th17- (IL-17A, IL-6, IL-1β, IL-8) and Th2-associated cytokines and chemokines (IL-5, IL-13, TARC/CCL17), but not IFN-γ levels, significantly correlated with high-resolution computed tomography changes (Helbich score; P < 0.05). P. aeruginosa- and A. fumigatus-specific T cells from patients with CF displayed significantly higher IL-5 and IL-17A mRNA expression. IL-17A and TARC/CCL17 were significantly augmented in patients that developed P. aeruginosa infection within 24 months. CONCLUSIONS We propose a role for Th17 and Th2 T cells in chronic inflammation in lungs of patients with CF. High concentrations of these cytokines/chemokines in CF airways precede infection with P. aeruginosa.

Preventive sublingual immunotherapy in preschool children: first evidence for safety and pro-tolerogenic effects.

Prevention of new IgE sensitizations has been described during allergen‐specific immunotherapy. However, prospective data using a preventive approach in very young children who would benefit most are missing. We initiated a prospective pilot study investigating the safety, immunomodulatory, and sensitization‐preventive effect of sublingual immunotherapy (SLIT) in mono/oligoclonally sensitized, clinically asymptomatic children 2–5 yr of age.

Impact of systemic immuno-suppression after solid organ transplantation on allergen-specific responses

To cite this article: Eiwegger T, Gruber S, Geiger C, Mayer E, Dehlink E, Bannert C, Frischer T, Kasper D, Jaksch P, Klepetko W, Akdis C, Szépfalusi Z. Impact of systemic immuno‐suppression after solid organ transplantation on allergen‐specific responses. Allergy 2011; 66: 271–278.

Cord Blood Derived CD4+CD25high T Cells Become Functional Regulatory T Cells upon Antigen Encounter

Background: Upon antigen exposure, cord blood derived T cells respond to ubiquitous environmental antigens by high proliferation. To date it remains unclear whether these “excessive” responses relate to different regulatory properties of the putative T regulatory cell (Treg) compartment or even expansion of the Treg compartment itself. Methods: Cord blood (>37 week of gestation) and peripheral blood (healthy controls) were obtained and different Treg cell subsets were isolated. The suppressive potential of Treg populations after antigen exposure was evaluated via functional inhibition assays ([3H]thymidine incorporation assay and CFSE staining) with or without allergen stimulation. The frequency and markers of CD4+CD25highFoxP3+ T cells were characterized by mRNA analysis and flow cytometry. Results: Cord blood derived CD4+CD25high cells did not show substantial suppressor capacity upon TCR activation, in contrast to CD4+CD25high cells freshly purified from adult blood. This could not be explained by a lower frequency of FoxP3+CD4+CD25highcells or FOXP3 mRNA expression. However, after antigen-specific stimulation in vitro, these cells showed strong proliferation and expansion and gained potent suppressive properties. The efficiency of their suppressive capacity can be enhanced in the presence of endotoxins. If T-cells were sorted according to their CD127 expression, a tiny subset of Treg cells (CD4+CD25+CD127low) is highly suppressive even without prior antigen exposure. Conclusion: Cord blood harbors a very small subset of CD4+CD25high Treg cells that requires antigen-stimulation to show expansion and become functional suppressive Tregs.

Immunosuppressive therapy does not prevent the occurrence of immunoglobulin E-mediated allergies in children and adolescents with organ transplants.

BACKGROUND. Allogeneic organ transplantation has become a common procedure in acute and chronic organ failure. The major limitation, rejection of the allograft by the hosts immune system, can be limited by various immunosuppressive drugs that target the adaptive T-cell response. Most of these drugs are used in the treatment of allergic diseases as well, suggesting that transplant recipients under long-term immunosuppressive therapy should not develop any sensitizations or at least not show any clinical signs of allergy. Surprisingly, organ-transplanted children and adults do report symptoms of type 1 allergies, such as allergic rhinoconjunctivitis, bronchial asthma, and food allergies. Thus far, mainly case reports and series on the occurrence of allergy after orthotopic liver transplantation exist. OBJECTIVE. Our purpose with this study was to evaluate in a cross-sectional design the prevalence of immunoglobulin E-mediated sensitizations and type 1 allergies in solid organ–transplanted children and adolescents and to identify risk factors. METHODS. Seventy-eight organ-transplanted subjects (50 kidney, 9 lung, 19 liver; mean age: 14.06 ± 5.94 years; range 1.42 to 24.25 years) were studied by standardized interviews (modified International Study of Asthma and Allergies in Childhood [ISAAC] criteria), skin-prick tests, and measurement of specific and total serum immunoglobulin E. RESULTS. Nineteen patients (24.4%) were found to be sensitized to ≥1 common inhalant or food allergens, as reflected by elevated specific immunoglobulin E levels and/or positive skin-prick test results, and 8 subjects (10.3%) additionally reported a corresponding present history of atopic diseases. No severe anaphylactic reactions were reported. No statistically significant associations with gender, kind of transplanted organ, distinct immunosuppressive therapies, and age at time of transplantation or age at investigation were found (χ2 test, Fishers exact test, and Wilcoxon rank-sum test, respectively). Multiple logistic-regression analysis did not identify any independent risk factor either. CONCLUSION. This study demonstrates that therapeutic immunosuppression does not control sensitizations and clinical manifestation of type 1 allergies in organ-transplanted children and adolescents.

Lung transplantation in children and young adults: a 20-year single-centre experience

Lung transplantation in adults is an accepted therapeutic option, whereas there is ongoing debate on its positive impact on survival in children. We report our experience of the first 20 yrs of paediatric lung transplantation at a single centre in Austria. Patient survival, organ survival and freedom from bronchiolitis obliterans were estimated by Kaplan–Meier curves. Pre- and post-transplant parameters were assessed and their influence on patient and organ survival evaluated by univariate tests and stepwise multivariate analyses. A total of 55 transplantations were performed in 43 patients. 1- and 5-yr patient survival rates were 72.1% and 60.6%, respectively, and 52.6% of patients were found to be free from bronchiolitis obliterans syndrome at 5 yrs post-transplant. Analysing different eras of transplantation suggests an improvement over the years with a 5-yr survival rate of 70.6% in the second decade. A positive effect of pre-transplant diabetes mellitus and immunosuppression was found with the newer drug tacrolimus, and a negative effect of pre-transplant in-hospital admission was reported. A high rate of successful re-transplantation prolonged total patient survival.

Immunoglobulin e-mediated allergies in lung-transplanted adults.

Background. Immunoglobulin E (IgE)-mediated allergy has repeatedly been reported after solid organ transplantation, apparently affecting approximately 10% of pediatric organ transplant recipients. Interestingly, type 1 allergy has not been described in transplanted adults, suggesting a particular propensity in childhood. Methods. The present cross-sectional study assessed the prevalence of type 1 allergy in 42 adult lung transplant recipients aged 25 to 50 years. Instruments included standardized interviews, skin prick tests, and serum IgE measurements. Results. Ten of 42 patients (23.8%) displayed elevated specific IgE levels or positive skin prick test results against one or more allergens. Five individuals (11.9%) additionally reported corresponding clinical symptoms of type 1 allergy. No statistically significant association of sensitization or allergy prevalence with patient age, kind of immunosuppressive therapy, and time since transplantation was found. Conclusions. The phenomenon of transplantation-associated allergy is not age-restricted and thus should be assessed more thoroughly in all age groups.

The influence of retransplantation on survival for pediatric lung transplant recipients

Objectives We reviewed our 25‐year experience in pediatric lung transplantation with the aim to identify trends and influencing factors over time. Methods We reviewed our prospectively maintained database and analyzed all patients younger than age 18 years who underwent primary lung transplantation at Medical University of Vienna between 1990 and 2015. Results Eighty‐six consecutive patients were enrolled with a mean age of 12.9 ± 4.1 years at primary transplantation. The most frequent indication for primary transplantation was cystic fibrosis (64.0). Bilateral double‐lung transplantation was performed in 84 patients (97.7%), including lobar transplantation in 35 patients (40.7%). sixty‐eight patients (79.1%) underwent transplant on venoarterial extracorporeal membrane oxygenation and 7 patients (8.1%) utilized cardiopulmonary bypass. The 30‐day and in‐hospital mortality was 8.1% and 17.4%, respectively, and 1‐, 5‐, and 10‐year overall survival (OS) was 79.0%, 67.5%, and 57.1%, respectively. A significant improvement of OS was observed during the second treatment period after 2003 with a 1‐, 5‐, and 10‐year OS of 86.0%, 73.9%, and 73.9%, respectively (P < .01). Seventeen retransplantations were performed in 14 patients. Twelve patients (85.7%) underwent 15 late elective retransplantations for chronic lung allograft dysfunction resulting in a 1‐ and 5‐year OS of 91.7% and 80.2%, respectively. In contrast, 2 patients (14.3%) who underwent acute retransplantation for primary graft failure died during the postoperative period. Conclusions Our outcomes for pediatric lung transplantation have improved over the past 25 years and have become comparable to those for adult transplantation. Elective re‐transplantations for pediatric patients were performed successfully, and strongly influenced improved long‐term OS.

Aspergillus fumigatus-specific immunoglobulin levels in BALF of CF patients

A lack of correlation between systemic and local IgE production at mucosal sites has been reported for allergic asthma [1–5], allergic rhinitis [6, 7] and chronic rhinosinusitis with nasal polyps [8–10]. In allergic asthmatics, local IgE production is higher than in nonallergic asthmatics [3] and high local IgE levels have been linked to the clinical phenotype. Interestingly, in cases of nasal polyps, local IgE targets mainly superantigens [8]. IgE responses to Aspergillus fumigatus in cystic fibrosis lungs http://ow.ly/XXwv30furqs

Clinical practice: Allergen-specific immunotherapy in children: facts and FAQs.

Allergen-specific immunotherapy (SIT) in its various application forms represents the main treatment approach of IgE-mediated allergic diseases in adults and children. Despite this clear recommendation, many particularities of products, patient characteristics, and product availability in different countries hamper the use of allergen-specific immunotherapy in particular in children. The frequently asked questions by parents, patients, and physicians are the backbone of this review. Thus, the potentials and limitations of allergen-specific immunotherapy in children and adolescents will be highlighted. IgE-mediated allergic diseases are affecting about 20% of the population. They manifest commonly early in life, and hence, the use of SIT should be considered also early in the course of the disease.