Programmbereich Asthma und Allergie
Allergic diseases result from an aberrant and exacerbated immune response to otherwise harmless airborne environmental agents such as pollen and house dust mites. Although the IgE-mediated response directed against purified allergens (proteins) has been extensively investigated, allergens alone fail to explain the dynamics of allergic airway inflammation; this includes the process of sensitization, followed by the transition towards chronification and the occurrence of exacerbations. Allergens do not reach mucosal surfaces as purified molecules but rather as part of complex particles together with bioactive lipids and complex carbohydrates, which have remained chemically and functionally poorly characterized. Therefore, it is essential to understand how lipids direct the immune response as adjuvants towards the recognition of proteins as allergens and how lipids interact with lipophilic allergens. And finally, how lipids influence the dynamics of allergic inflammation leading to asthma.
Our projects focus on bioactive lipids from the two major airborne indoor and outdoor sources of allergens: house dust mites and pollen grains.
- CARE (Innovative therapy strategies): Development of immunomodulators for allergen immunotherapy. Use of Glycolipids from allergen sources as natural adjuvants for allergen immunotherapy.
Glycolipid antigens presented on CD1d are recognized by invariant Natural Killer (iNKT) T cells, an innate-like lymphocyte population. Upon activation, iNKT cells are an early source of cytokines for the polarization of conventional T cells. The chemical structure of the glycolipid determines the profile of the cytokines produced, thus working as adjuvants. We isolated diverse glycolipids from house dust mite and grass pollen with the capability of driving T cell polarization towards a pro-allergic Th2 phenotype. We aim to understand the structure-activity relationship to design glycolipids as adjuvants able to either neutralize pathologic Th2 polarization or to induce a protective Th1 responses. These glycolipids would be used as adjuvants for allergens to improve the efficacy of current immunotherapy
- CONTROL (Prevention) Identification of lipid-mediated pathomechanisms in allergic inflammation
Lipid mediators are small molecular compounds known for their pro-inflammatory and chemotactic activity. These mediators are known to be rapidly released from the source of allergen upon contact with aqueous media, such as at mucosal surfaces. We isolated diverse lipid mediators from pollen and house dust mite and analyze how they shape the early activation of dendritic cell and how they influence mast cell degranulation. The inhibition of the pathways activated by lipid mediators provide an objective target for therapy.
* Lipid mediators and glycolipids can either activate immune responses on their own, or by interacting with lipophilic allergens.
- CARE (Diagnose & phenotype): Identification of lipid-related cellular biomarkers in allergic Asthma: Innate-like glycolipid-reactive lymphocytes.
A major gap in asthma is the lack of biomarkers allowing to confirm diagnosis, define specific phenotypes, predict outcomes and follow up response to therapy enabling the design of patient-tailored treatment in the long-term.Invariant Natural Killer T (iNKT) cells are a pre-expanded population of innate-like lymphocytes readily detectable in whole peripheral blood by flow cytometry. Several studies have shown that the frequency of iNKT cells and their activation status changes when the immune response is compromised, such as during infection or autoimmunity. This suggests their usefulness as biomarkers during asthma development. We developed a workflow suitable for high-throughput-screening analyses consisting on the improved cryopreservation of whole peripheral blood and flow cytometry. Our method requires as little as 100µl of blood and the cells are responsive to glycolipid stimulation upon thawing. This approach may provide a least invasive and fast method to monitor the immune status of allergic patients.
Figure - Concept of the Group of Allergobiochemistry. Our group isolates glycolipids and lipid mediators from allergen sources and/or allergy-related microorganisms and characterize them chemically. Depending on the structure, lipids are tested in suitable cell type system. This allows the identification of the structure-function relationship directing the dynamics of allergic inflammation. This chemically and functionally defined lipids are prerequisite for targeted development of adjuvants to improve patient-tailored treatment of allergy in the long term.