Neutrophil tissue delivery, early immune protection and quality of life in neutropenia

The role of neutrophils in maintaining oral health has been well documented and is best understood when examining the poor oral health-related quality of life of children with neutropenia. Under normal conditions, the bacterial presence in the mouth is kept under control by a constant influx of neutrophils from surrounding periodontal tissues. This chemotactic recruitment of neutrophils to the oral cavity inspired us to develop and validate a non-invasive oral rinse assay to study the delivery of neutrophils to the mouth following chemotherapy and bone marrow transplantation (BMT), and to compare this information to circulating neutrophil levels, oral mucositis scores and infection-related fever episodes following blood neutrophil recovery. Using this oral rinse, we showed that oral neutrophils reappeared and returned to a stable level earlier in the mouth than in the blood following BMT, thus enabling us to successfully predict engraftment much sooner than it was evident in their blood counts as per the conventional definition of engraftment. Furthermore, the timing of neutrophil tissue delivery in the mouth was a good indicator of neutrophil functionality and infection susceptibility in the post-BMT setting. Consequently, we developed a mouse BMT model which uses enhanced green fluorescent protein-expressing donor neutrophils. Besides recapitulating the results from our human study, this mouse BMT model allowed us to better understand neutrophil recovery kinetics following transplantation and how they relate to the restoration of cellular immune function post-BMT. Using the model, we have demonstrated that protection against bacterial infection is conferred at the time of neutrophil tissue delivery which always occurs before neutrophils are detected in the blood. These findings reaffirmed the clinical utility of the oral rinse assay to predict engraftment and susceptibility to infection following transplantation. Moreover, the mouse BMT model served as an in vivo cell migration model to study the effectiveness of specific drug therapies on neutrophil recovery and functionality. This animal model has the potential to help us better understand the molecular mechanisms of neutrophil mobilization, and will allow us to begin to identify the biological determinants that influence the rate of neutrophil tissue penetration, their levels and survival in the tissues.