Scientific Programme

Background:

Nasal microbiota composition of patients with diffuse type 2 chronic rhinosinusitis with nasal polyps (CRSwNP) is altered compared to healthy individuals. Dupilumab, an anti-IL-4Rα-mab, modulates type 2 inflammation but the effect on microbiota composition in CRSwNP is unknown. The aim of this study was to investigate longitudinal effects dupilumab on the nasal passage and gastrointestinal microbiota.

Methods:

Twenty-seven patients with diffuse type 2 CRSwNP treated with dupilumab 300mg subcutaneously every two weeks, 10 untreated patients with CRSwNP and 11 healthy controls were included. Nasal and stool samples were collected at day 0, 28, 90, and 180 post-treatment of the treated CRSwNP group and at day 0 and 28 of untreated CRSwNP and healthy controls. The samples were analysed using 16S rRNA gene amplicon sequencing (V3/V4).

Results:

In CRSwNP patients, the most abundant genera in nasal passage microbiota were Corynebacterium and Staphylococcus. Cutibacterium and Lawsonella were less abundant in CRSwNP at baseline compared to healthy controls. Dupilumab treatment was associated with increased abundances in nasal passage of genera such as Lawsonella, Corynebacterium and Dolosigranulum. Microbial diversity of the gastrointestinal microbiota in CRSwNP at baseline was significantly higher than in healthy controls.

Conclusion:

Dupilumab treatment was associated with a shift in the nasal passage bacterial microbiota towards that of healthy controls. These findings suggest that nasal passage microbiota composition is influenced by the underlying inflammatory endotype.

Current influenza vaccines target the highly variable surface proteins hemagglutinin (HA) and neuraminidase (NA) of Influenza A virus (IAV), resulting in inconsistent efficacy due to antigenic drift and shift. Frequent changes necessitate annual vaccine updates, creating logistical and financial burdens. In contrast, internal proteins like matrix protein 1 (M1), viral polymerase (PA), and nucleoprotein (NP) are highly conserved. We developed a T-cell vaccine targeting epitopes of these conserved proteins to achieve heterosubtypic protection. Peptides from M1, PA, and NP, as well as full-length NP, were encapsulated with the TLR3/RIG-I ligand Riboxxim into Poly(lactic-co-glycolic acid) (PLGA) microspheres (MS). PLGA-MS offer high bioavailability, biodegradability, and an antigen depot effect. Vaccination with PLGA-MS induced a cytotoxic T-cell response that reduced lung IAV titers and mortality in mice after lethal infection. Cross-protection against distinct IAV strains was observed for both peptide and protein vaccines. However, differences in the magnitude and durability of the immune response highlighted the broader protection achieved with full-length protein vaccines. Our findings underscore the potential of PLGA-MS as a platform for T-cell–mediated influenza vaccines and reveal important distinctions between peptide- and protein-based formulations.

Aim: Patients with CRSwNP often experience disease recurrence despite conventional therapies. Biologics like Dupilumab have shown significant efficacy, but the underlying mechanisms of response and residual disease are not fully understood. This study explores changes in the type 2 immune microenvironment of nasal polyps before and after 12 months of Dupilumab treatment.

Methods: FFPE nasal polyps sections collected from 9 male and 4 female CRSwNP patients (mean age: 54±10 years), before and after 12 months of Dupilumab therapy, were stained with H&E and immunohistochemistry for eosinophils, mast cells (MCs), and M2-like macrophages (M2 Mφ). Immunoreactivity was quantified via computer-assisted image analysis and expressed as a percentage of the total tissue area.

Results: 12 out of 13 subjects fulfilled ≥2 EPOS/EUFOREA response criteria to biologic treatment. Eosinophil immunoreactivity significantly declined from 2.94±2.69% to 0.62±1.21% at 12 months post-treatment (p=0.009). In contrast, MCs increased (3.12±2.77% to 4.16±2.94%; p=ns), and M2 Mφ showed a slight decrease (3.92±2.51% to 2.84±2.38%; p=ns), with no significant correlations observed among the three cell types.

Conclusions: The nasal polyp microenvironment involves diverse interacting immune and non-immune cells. While eosinophils decreased, MCs and M2 Mφ persisted 12 months after Dupilumab treatment. These results suggest further investigation is needed to clarify their roles in CRSwNP pathogenesis and to understand why some patients respond poorly, possibly due to incomplete inflammatory blockade.

Background: Effective management of primary immunodeficiency disorders (PID) requires experienced centers, which are limited in number and funding. We present a Swiss collaborative care model synergizing specialized private practices and university centers to enhance patient care by facilitating earlier access to specialized diagnostics, comprehensive laboratory and genetic analyses, including participation in a prospective research cohort.

Methods: We report on a prospective cohort of 18 patients (median age 52 years, 8 females, mean diagnostic delay 5 years) managed through this collaborative model. All patients underwent detailed clinical phenotyping and comprehensive immunological workup. For the majority of patients (10/18), research-based whole exome sequencing (WES) was performed.

Results: Specific results of rare immune gene variants and their predicted relevance for clinic, prognosis and treatment adaptations will be presented at the meeting.

Conclusion: Rare predicted functionally relevant immune-gene variants were found in all assessed patients, informing on therapeutic adaptations in some. The integration of WES into routine care provided novel insights into underlying molecular mechanisms and supported tailored patient management. The combined expertise of peripheral clinical immunologists and university centers contributed to improved patient outcomes and a deeper molecular understanding of immunodeficiency. Patients benefit from both immediate clinical care with individualized treatment plans and inclusion in a prospective cohort for ongoing research.

Aim
CD8⁺ T cell exhaustion limits the efficacy of immunotherapies such as PD-1 blockade, ACT, and CAR-T. This dysfunction is associated with stable epigenetic changes, including locus-specific DNA methylation. We hypothesize that targeted demethylation of exhaustion-related loci could durably restore T cell functionality. Our aim is to (1) develop a mouse model enabling locus-specific DNA demethylation, and (2) adapt this strategy to human T cells for therapeutic purposes.

Methods
We engineered a transgenic mouse expressing a demethylation machinery recruited by gRNAs to specific genomic regions. We first validated the system on induced regulatory T cells (iTregs), which are inherently unstable due to methylation-driven loss of Foxp3. We then applied it to candidate loci involved in T cell exhaustion.

Results
Targeted demethylation of the Foxp3 locus in iTregs restored stable expression and suppressive function, notably improving disease control in a colitis model. The system also allowed us to identify and functionally interrogate exhaustion-associated genes in CD8⁺ T cells, by actively reversing methylation at several selected loci in vivo.

Conclusions
This approach offers a flexible platform to reshape T cell fate through precise epigenetic editing. It opens new possibilities to enhance the durability and depth of anti-tumor responses by directly targeting the epigenetic roots of exhaustion.

Asthma is a chronic type 2 inflammatory condition in which both innate and adaptive immune cells drive its onset and exacerbation. However, the mechanisms and functions of allergen-induced metabolic and epigenetic reprogramming of these cells remain poorly understood. In a severe eosinophilic asthma model, we found expansion and epigenetic reprogramming of eosinophil progenitors (EoP) using single cell ATAC-Seq of hematopoietic stem and progenitor cells (HSPC).

Mice with chronic asthma induced by house dust mite and curdlan were treated intraperitoneally with anti-IL-4Ra antibody (mimicking dupilumab treatment in patients). Eosinophilic lung inflammation was analyzed by histology, differential cell count, flow cytometry, and immunofluorescence staining, while bone marrow EoP were assessed via flow cytometry. To further study EoP reprogramming, we have established long-term ex vivo HSPC (exHSPC) cultures that preferentially differentiate into either EoP or monocyte progenitors (MoP).

Asthmatic mice showed elevated eosinophils in bronchoalveolar lavage fluid, lung tissue, and increased EoP in the bone marrow. Anti-IL-4Ra treatment significantly reduced both airway eosinophilia and EoP expansion. However, this effect was independent of IL-4Ra expression on eosinophils, as IL-4Ra^fl/flxEpx^Cre mice showed normal airway inflammation, eosinophil development, and activation. Thus, epigenetically “trained” EoP may sustain chronic type 2 inflammation, and dupilumab indirectly targets EoP potentially by targeting IL-4Ra-expressing lymphocytes during chronic asthma.

Aims:The increase of allergic diseases in industrialized countries highlights the need for interventions restoring microbial diversity to support immune balance. Microbial-based therapies, like the bacterial lysate OM-85, show potential for immune modulation in allergic asthma. We hypothesize that intranasal OM-85 reduces HDM-induced airway inflammation by modulating alveolar epithelial cell–macrophage interactions.

Methods: Eight-week-old female BalbC/J mice received intranasal (i.n.) OM-85 (1 mg/kg in 40μl) or vehicle every 48-72 hours, starting 5 days before and continuing through HDM sensitization and challenge (25 μg HDM every 48-72 hours for 2 weeks). Bronchoalveolar lavage (BAL) fluid was collected 96 hours post-challenge for cell counts. Lung immune cell composition and kinetics were analysed by flow cytometry, respiratory function assessed with FlexiVent™, and bulk RNA-sequencing on CD45+ and CD45- lung cells.

Results: I.n. OM-85 reduced HDM-induced AAI, decreasing BAL eosinophilia, airway mucus hypersecretion, and improving respiratory function. Type II alveolar epithelial cells (ATII) and distinct macrophage subsets, including alveolar macrophages, increased following OM-85 treatment in both control and HDM-exposed groups. GM-CSF-mediated ATII-macrophage interactions were observed. RNA-sequencing revealed OM-85-driven modulation of immune pathways, particularly those resolving inflammation.

Conclusions: Intranasal OM-85 reduces HDM-induced AAI by modulating immune and epithelial cells, promoting inflammation resolution, and enhancing lung function.

Trained immunity in innate immune cells provides protection against pathogens; however, its role in type 2 immune responses, such as allergy or helminth infections, remains relatively underexplored. Our previous work has identified an inflammatory macrophage memory in human asthmatics and demonstrated that intranasal exposure to house dust mite (HDM) reprograms myeloid progenitors in the bone marrow of mice, highlighting the involvement of central trained immunity in asthma. In this study, we identify type I interferons (IFNs) as key drivers of macrophage reprogramming in asthma. RNA sequencing of macrophages derived from the bone marrow or airways of HDM-exposed mice revealed the persistent, type I IFN-dependent upregulation of genes involved in extracellular matrix (ECM) remodeling—defining a hallmark of trained immunity in asthma. Supporting this finding, mice lacking hematopoietic type I IFN signaling failed to upregulate cysteinyl leukotrienes (cysLTs), which are critical mediators of type 2 inflammation. Our findings uncover a previously unrecognized role for type I IFNs in trained immunity in asthma and identify a pathway through which these mediators drive an alternative “type 2 training” program in airway macrophages.

Background and aims: The prevalence of food allergy (FA) is raising. It is therefore important to better understand FAs and their course to improve prevention and treatment. This study describes characteristics of FA patients in Northwestern Switzerland.

Methods: This study is part of an ongoing prospective cohort study, including children <2y with newly diagnosed IgE-mediated FA. We analyzed clinical data from 64 patients enrolled between 06/2020 and 02/2022.

Results: Mean age at enrollment was 12.4 months (SD=5.18), with positive family history for atopy in 53/64 patients. Atopic dermatitis was found in most patients (N=62/64, mean SCORAD 9.37), 24/64 patient presented allergic rhinoconjunctivitis/wheezing in the follow up. 36/64 patients were allergic to a single food allergen, milk allergy (MA) being the most common FA (N=30/64), followed by egg (EA) (N=25/64), tree nut (TN) (N=24/64) and peanut allergy (PN) (N=10/64). Patients with MA/EA started a stepwise introduction using food ladders (N=30). Patients who completed food ladders showed resolution after 15.64 months (SD 2.75) for MA (N=26/30) and 13.5 months (SD 8.93) for EA (N=20/23). TN/PN allergy resolved in 10/34 patients. Oral immunotherapy was started in 14/25 patients with persisting food allergy.

Conclusion: Our cohort represents distribution of FA as previously described among children in Europe and is therefore valuable cohort for further investigations. With TN allergy as the second frequent FA, this study supports the need to focus on prevention and treatment strategies for TN allergy.

Aim

Oral food challenges (OFCs) are the gold standard for diagnosing food allergy, yet predicting outcomes remain difficult. We aimed to identify predictors of hazelnut OFC outcomes in a real-world setting.

Methods

We analyzed 166 hazelnut OFCs conducted between 07/2022 and 04/2025. Clinical and diagnostic parameters—including specific IgE (sIgE), skin prick tests, and clinician-assigned risk categories—were assessed. Predictive performance for OFC outcomes was evaluated statistically including positive predictive value (PPV) and negative predictive value (NPV). EAACI cut-offs were included.

Results

OFCs were performed for allergy exclusion (48%), threshold evaluation before oral immunotherapy (OIT; 37%), and family-requested clarification (15%). Overall, 53% tolerated the OFC, while 45% were intolerant. Notably, 11% of OIT candidates tolerated the OFC, while 10% of low-risk patients reacted. Intolerant children were older, with a median reactive dose of 300 mg protein and median oFASS-5 score of 3. The strongest predictor of intolerance was high-risk classification by experienced clinicians (PPV 90%), followed by Cor a 14-specific IgE ≥0.64 kU/L (PPV 86%). Tolerance predictors included sIgE hazelnut <0.35 kU/L (PPV 96%), Cor a 14 <0.64 kU/L (PPV 93%), and low-risk classification (PPV 90%).

Conclusion

Low hazelnut and Cor a 14 sIgE, and a low-risk profile, strongly predicted tolerance. Clinical risk assessment and Cor a 14 ≥0.64 kU/L were the best predictors of intolerance. Outliers in both directions confirm that OFCs remain indispensable.

Aim. Obesity is a growing global health threat and a comorbidity that worsens asthma outcomes. Small Airway Dysfunction (SAD) is a significant but often overlooked contributor to asthma pathophysiology. SAD is common in obese asthmatic patients, but its relationship with BMI and role as a clinical predictor remain unclear.
 

Methods. A 3-year study was conducted on 660 asthmatic patients undergoing spirometry, impulse oscillometry (IOS), and FeNO tests. Patients were divided into non-obese (n=556, BMI 20–29.99 kg/m²) and obese (n=102, BMI ≥30 kg/m²) groups. Obese patients were further classified into mild (n=87, BMI 30–39.99 kg/m²) and morbid (n=15, BMI ≥40 kg/m²) obesity. SAD was defined as R5–R20 > 0.07 kPa/L/s.
 

Results. Obese patients had lower atopy (42.2% vs 65.3%), more nocturnal awakenings (70.6% vs 38.1%), and higher exercise-induced asthma (78.4% vs 48.2%) (Chi-square p<0.005). Exacerbations (0.64±0.701 vs 0.44±0.70) and ER visits (0.24±0.470 vs 0.08±0.273) were higher (p<0.005). IOS showed superior sensitivity compared to spirometry: SAD prevalence was higher in obese patients (90.2% vs 57.7%, p<0.05), with no correlation observed between BMI and FEF 25–75%.
 

Conclusions. SAD is multifactorial and strongly linked to obesity. IOS showed superior sensitivity compared to spirometry, emphasizing limitations of standard lung function tests. Early identification of SAD in obese asthmatic patients allows for better phenotyping and personalized treatments, such as extra-fine inhalers, improving asthma control, reducing exacerbation, and enhancing quality of life.

Background and aim: As the prevalence of food allergy (FA) increases, new treatments such as oral immunotherapy (OIT) are being used more often, especially in young children. OIT is usually well tolerated but can lead to serious side effects like anaphylaxis or eosinophilic esophagitis. Tree/peanut allergies are less likely to outgrow than egg/milk allergies. To date, there are no objective markers to predict FA persistence or outgrowth. We investigated immune-related protein profiles in children with FA, some of whom have outgrown FA, to identify potential diagnostic markers.

Methods: We used Olink® to measure 162 proteins involved in inflammation and immune response in dried blood spots from 64 children aged under 2 years at the time of FA diagnosis. Hierarchical clustering and sparse partial least squares discriminant analysis (sPLS-DA) were used for the analysis.

Results: Clustering of the measured proteins revealed 3 distinct clusters with differences in age and total IgE, but not in FA persistence or outgrowth. Younger children had lower IgE and higher normalized protein expression (NPX) levels, while older children showed the opposite. Interestingly, children who had outgrown their FA showed higher levels of certain cytokines, including IL12b, CCL20 and IL10RB.

Conclusion: This is the first study of protein profiles in children with FA. Certain proteins, including IL12b, CCL20 and IL10RB, may help to identify patients at an early stage who are at higher risk of developing persistent FA and who may therefore benefit from an early OIT.