Research of the group of Ronald van Ree focuses on a number of inter-related basic and translational questions around IgE-mediated allergies, also referred to as type I allergies. The four major pairs of basic (B1-B4) and translational (T1-T4) questions addressed are: Basic research: B1 - What makes a protein an allergen? This topic focuses on the role of intrinsic physico-chemical properties (such as protease resistance and type of post-translational modifications) and functional properties of proteins (enzymatic activity, ligand binding, PRR-binding) in shaping the process of sensitization and the induction of symptoms. B2 - How is the process of sensitization regulated? Obviously this question has overlap with the question “what makes a protein an allergen”, but it has a broader scope. The intrinsic properties of a protein are just part of the equation. On top of that, timing and level of exposure as well as the context in which the exposure takes place (environmental co-exposures such as pollutants, infections, exposure to non-pathogenic micro-organisms, diet, lifestyle, affluence) have impact on the process of skewing towards tolerance or sensitization and clinical disease. B3 - Which biomarkers can discriminate different clinical phenotypes? This topic centers on finding biomarkers for tolerance and clinical allergy, and within the latter, for symptom severity? Accurate phenotyping is of great importance to understand disease mechanisms and develop strategies for personalized treatments. B4 - What is the mechanism of immunotherapy? Allergen-specific immunotherapy is the only causal treatment of IgE-mediated allergies. Despite the fact that it has been used for over a century now, its mechanism still is not completely clear. Certainly the topic has overlap with the question what makes healthy subjects tolerant to allergens. Better insight in the mechanism of tolerance induction may help improve strategies for immunotherapy, but also for primary prevention. Translational questions: T1 - Can we predict the allergenic risk of proteins? This topic deals with the question whether it is possible to predict if exposure to novel proteins will pose an increased risk of sensitization and symptom elicitation in an atopic population having established allergies or being prone to develop them. Can we establish a risk profile of a novel protein based on its intrinsic physico-chemical and functional properties and the context of exposure? A reliable evidence –based prediction algorithm would be of great importance for protocols to evaluate the allergenic risk transgene candidates for genetically-modified food crops. T2 - Can we develop strategies to prevent sensitization? The longstanding paradigm of prevention by avoidance of exposure to allergens is under serious scrutiny. This development has initially been based on epidemiological observations. High allergen exposure in the first year of life is now slowly gaining support as a better way forward for prevention. This hypothesis needs confirmation in randomized placebo-controlled intervention studies. Also factors linked to the context of exposure to allergens have provided new leads for primary prevention. These factors include the intensity, frequency and chronicity of early childhood infections, gut microbiota composition, dietary composition (vitamins, fatty acids, etc.), environmental co-exposures (non-pathogenic micro-organisms) and (sedentary indoor) life-style. Mechanistic studies (human in vitro and animal models) have to pave the way towards intervention studies. T3 - How can we improve performance of diagnostic tests? In vitro diagnostic tests for specific IgE antibodies are used to support the diagnosis of IgE-mediated allergies. These tests have for more than four decades been based on extracts of allergen sources. These tests have always had problems with sensitivity (important allergens under-represented in extracts) and specificity (detection of IgE without clinical relevance). Molecular allergology has now provided the tools to improve this situation. Important allergens can now be produced as recombinant reagents and evaluated for diagnostic purposes. Epidemiological surveys and diagnostic clinical trials are needed to establish which allergens are responsible for which clinical phenotypes. Based on this knowledge, molecular diagnostic tests can be developed to replace extract-based tests. T4 - How can we improve safety and efficacy of immunotherapy? As is true for allergy diagnostics, allergen-specific immunotherapy is performed with allergen extracts. This therapy is effective but has a serious risk of (allergic) side-effects. In addition, the current therapy requires 3 to 5 years of monthly injections to achieve its long-lasting effect. The challenge is to make immunotherapy safer and more effective, in particular in the sense of shortening the therapy significantly. Molecular allergology has provided the opportunity to design hypo-allergenic recombinant versions of the most important disease-related proteins, the so-called major allergens. In addition, these molecules can be selected for increased immunogenicity and combined with novel adjuvants that effectively induce protective anti-inflammatory immune skewing. These approaches need to be evaluated in first-in-man clinical trials, and subsequently evaluated for superiority to current treatment, both with respect to safety and efficacy. The research group of Ronald van Ree works on all of the above described research topics. It does so using four major research disciplines: epidemiological surveys, mouse models, clinical trials and human in vitro immunology.

Molecular and Translational Allergology