Role of platelets and their interactions in anaphylactic reactions – PlanA

Over the last century allergies have developed from a rare disease to a major health concern that affects 30%-40% of the world population today (WAO 2012). Due to sustained changes in personal lifestyle and environmental conditions this tendency is not ready to decline. Not only do allergies impact on the quality of life of each individual, they also present a significant financial burden for the national health systems. Current allergy treatments are often symptomatic, cost-intensive and do not prevent future allergic episodes. In order to propose novel therapeutic strategies, a deeper understanding of the different mechanisms that underlie allergic reactions is therefore urgently required.
The PlanA project aims at contributing to this challenging task. Exploiting anaphylaxis as a (first) example of a severe allergic reaction, we propose to investigate the mechanisms that lead to these reactions with the long-term goal to identify novel molecular targets for a therapeutic intervention. Anaphylaxis is a life threatening systemic allergic reaction associated with intense vasodilatation, bronchoconstriction, a drop of cardiac pressure and hypothermia. It results from the effects of numerous mediators liberated during an inflammatory reaction. The best-characterized anaphylaxis induction pathway concludes in the liberation of histamine by mast cells in response to an antigen-dependent aggregation of IgE antibodies bound to their high-affinity receptors for IgE. While this IgE-dependent pathway may be involved in most human anaphylactic reactions, no correlative evidence can be found in about 15% of anaphylactic cases (i.e. idiopathic or “non-IgE”-anaphylaxis). This suggests the presence of an alternative pathway. Indeed, it was shown in experimental models that IgG antibodies can trigger anaphylaxis that relies on the aggregation of activating IgG receptors and on the release of platelet-activating factor (PAF). Likewise, the severity of anaphylaxis in humans is correlated with serum PAF levels. Interestingly, human platelets express receptors for IgG and IgE, and in addition to being key regulators of hemostasis, platelet aggregates may block circulation and thus impact on organ functions. These features make platelets prime candidates to become activated during and contribute to anaphylactic reactions.
The PlanA project therefore proposes to investigate the role of platelets in anaphylactic reactions, focusing in particular on their activation processes, their dynamic behavior inside organs and their interactions with other cells. It is an ambitious project that consists of three intricate tasks: 1) Using unique humanized mouse models we will characterize the stimuli and mechanisms that underlie platelet activation in anaphylactic reactions and determine the consequences for the platelets themselves. Results obtained in mice will be complemented by the analysis of platelet activation in human samples from patients undergoing an anaphylactic shock. 2) Development of new visualization approaches to monitor platelet behavior in vivo and in real time in healthy mice and in mice undergoing anaphylaxis. 3) Building on results from the previous tasks we aim to identify and characterize the interactions that platelets maintain with other cells (i.e. neutrophils and endothelial cells) to propose new therapeutic targets in these reactions.
Starting from the investigation of a single cell type (platelets) the PlanA project will develop strategies for the intravital assessment of anaphylactic reactions, to finally widen its focus and take into consideration the complex environment of the organism with its multiple cell types and dynamic interactions. Addressing these three objectives will enable to describe the causal relationships between the different cellular players and thereby provide an unprecedented opportunity for the identification of new therapeutic targets.