In vivo Monitoring of Neutrophil Function in Patients after Stem Cell Transplant

Hematopoietic stem cell transplant (HSCT), an essential procedure in the treatment of patients with hematological malignancies, also temporarily increases the risk for infections with invasive fungi. The recovery in the neutrophil number after HSCT is commonly regarded as a key metric for the restoration of antifungal defenses. However, the metric is imprecise, and there is an urgent need for new biomarkers to help identify the patients at risk. In the absence of new tools, the management of invasive fungal infections remains remarkably challenging. The long-term goal of this research is to engineer new tools and validate new metrics estimating the risk for invasive fungal infections in HSCT patients. Achieving this goal requires a focus on neutrophil swarming function, which is critical in effective antifungal immune responses. Swarming is distinct from phagocytosis in that it involves neutrophil-neutrophil communication that helps coordinate the activities of multiple cells toward blocking the growth of invasive fungi. The focus on neutrophil swarming is justified by preliminary results showing that in HSCT patients, even when the neutrophil count recovered at 4 weeks after transplant, a neutrophil swarming deficiency is still present and is substantial. Knowledge about how neutrophil swarming deficiency is resolved over time after HSCT is currently lacking. To address this knowledge gap and evaluate the utility of new biomarkers we will pursue the following specific aims: 1) Determine neutrophil swarming parameters that are distinct in healthy and HSCT patients. 2) Determine what cytokines help restore the swarming activity of neutrophils from HSCT patients and 3) Design new imaging techniques for label-free tracking of human neutrophils responding to microscopic tissue injuries in vivo. If successful, the proposed research could have a major impact on the lives of HSCT patients by improving the monitoring of their recovery and by identifying potential strategies for accelerating the recovery of their neutrophil functions and improving their protection against fungal infections.