Another look at human granulocyte kinetics

Abstract

This thesis mainly focuses on the lifespan of granulocytes in healthy humans and in patients with asthma.

Using a non-toxic label in humans, called deuterated glucose, we discovered that neutrophils, have a longer lifespan than was mentioned before in the literature. We believe that these white blood cells have a lifespan of at least 2 days, regardless of the compartment in which they reside: blood or tissue. This finding could be important in our comprehension of many diseases, in which these cells play a pivotal role. In eosinophilic asthma, these cells are also found in the sputum. We have discovered that the kinetics of neutrophils in the blood and sputum is not altered after treatment with mepolizumab (anti-IL-5). This suggests that tissue damage present in eosinophilic asthma does not lead to a considerable change in neutrophil kinetics. In another chapter we have confirmed that buoyant density of neutrophils is characterized by a spectrum which as a whole shifts to a lower density after activation. In a different study that, we have demonstrated a cross-talk between the GM-CSF and the CXCR4 receptor on human neutrophils. This cross-talk was able to drastically inhibit CXCL12 induced signaling.

Moreover, we have confirmed that IL-5 is important but not essential for the production of eosinophils. We have discovered this by using the same non-toxic label in patients with asthma, who were treated with mepolizumab. Although, this finding was already proven in mice, studies in humans were scarce. We have also provided a novel flow cytometric method to identify eosinophil (middle late) progenitors in the bone marrow. Next, we have proposed a model in which experimental human endotoxemia induces a partial mobilization of mature eosinophils from the BM into the circulation and a large mobilization of circulatory eosinophils into tissues without signs of activation, degranulation or enhanced production of eosinophil precursors. This mechanism is probably regulated through VLA-4 and eotaxin-1. Finally, we have provided a concept that treatment with dupilumab decreases eosinophil trafficking to the skin of atopic dermatitis (AD) patients, by decreasing local production of eotaxins. Furthermore, peripheral blood eosinophils of AD patients show an elevated activation state compared to healthy volunteers. This state is not altered after treatment with dupilumab.