162.7 - HoxB8-conditional Neutrophil Progenitor Transplant Provides a Therapeutic Benefit for S. aureus Pulmonary Infection in a Murine Model of Chronic Granulomatous Disease (CGD)

Kristina Hinman (Brown University), Joshua Cohen (Brown University, Brown University), Miles Mundy (Brown University), Craig Lefort (Brown University)

CGD is a congenital disease marked by neutrophil dysfunction leading to increased infectious susceptibility. Despite prophylactic treatment with antimicrobial agents, outcomes for CGD patients are troubling with a typical lifespan of 30-40 years due to breakthrough infections. As we strive to stay ahead of the impacts of drug-resistant microbes, it is reasonable to consider cellular therapeutics which replace immune cells to treat CGD and other immunodeficiencies. We hypothesize that a conditionally-immortalized neutrophil progenitor cell line has a translational application as a therapy for immune compromised hosts. This cell line was first generated by Wang, et al. through inducing ectopic expression of the transcription factor HoxB8 in murine bone marrow stem cells . Induction of HoxB8 leads to exponential growth of cells, while withdrawal leads to differentiation into neutrophil-like cells. We have found that unconditioned transplant of HoxB8 progenitors lead to robust engraftment in the bone marrow. Engrafted progenitor cells differentiate in vivo into donor-derived neutrophils found circulating in the peripheral blood. Donor neutrophils are also recruited to the lungs of mice infected with Staphylococcus aureus. Using a novel fluorescent killing assay, we demonstrate that donor-derived neutrophils can kill pulmonary S. aureus both in vitro and in vivo with comparable efficiency to wild type host neutrophils. Strikingly, our results find that treatment with HoxB8-conditional progenitors improves survival of CGD animals infected with S. aureus from 0% to gt;50%. This work demonstrates the potential of conditionally-immortalized neutrophil progenitors as a novel cellular therapy in the context of neutrophil dysfunction.

NIH R35GM124911