MICA: To evaluate the role of the histamine four receptor (H4R) in the clearance of lung pathogens using the H4R antagonist UCB1344778

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A hallmark of cystic fibrosis (CF) is severe and persistent bacterial infections in the lungs despite massive influx of polymorphonuclear leukocytes (neutrophils). Neutrophils are the first line of defence against infecting microbes; however, CF pulmonary neutrophils have a reduced capacity to engulf pathogens. It remains unclear why the function of neutrophils is compromised in CF patients. Our project is aimed at understanding what blocks neutrophils in the lungs and how to overcome this inhibition. We believe that bacteria colonizing the lungs of CF patients produce a substance called histamine and that histamine blocks the killing capacity of neutrophils by binding to a specific receptor, the histamine-4 receptor (H4R), expressed on the membrane surface of these cells. We hypothesize that histamine produced by Gram-negative bacteria colonizing CF lungs impairs phagocytosis by neutrophils by affecting their ability to capture pathogens and killing them after engulfment. We also believe that the inhibitory effect of histamine is due to engagement of the H4R on human neutrophils. We demonstrated that the H4R is expressed in human PMNs and it is a potent inhibitor of PMN degranulation. Further, we showed that the H4R also negatively regulates engulfment of bacteria, while treatment with a H4R antagonist overcomes this histamine-dependent inhibition of engulfment. In this project, we will explore the role of the H4R in neutrophil engulfment by using the H4R antagonist UCB1344778. We will investigate whether UCB1344778 can prevent histamine from blocking capture of pathogens and inhibition of intracellular killing using model CF pathogens both in vitro and in vivo experiments suing a CF mouse model. The pre-clinical data generated in this project will be exploited for future clinical studies in patients with CF and other chronic lung inflammatory diseases (e.g. chronic obstructive pulmonary disease).