title: Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model.
abstract: The clinical outcome of granulocyte transfusion therapy is often hampered by short ex vivo shelf life, inefficiency of recruitment to sites of inflammation, and poor pathogen-killing capability of transplanted neutrophils. Here, using a recently developed mouse granulocyte transfusion model, we revealed that the efficacy of granulocyte transfusion can be significantly increased by elevating intracellular phosphatidylinositol (3,4,5)-trisphosphate signaling with a specific phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670. Neutrophils treated with SF1670 were much sensitive to chemoattractant stimulation. Neutrophil functions, such as phagocytosis, oxidative burst, polarization, and chemotaxis, were augmented after SF1670 treatment. The recruitment of SF1670-pretreated transfused neutrophils to the inflamed peritoneal cavity and lungs was significantly elevated. In addition, transfusion with SF1670-treated neutrophils led to augmented bacteria-killing capability (decreased bacterial burden) in neutropenic recipient mice in both peritonitis and bacterial pneumonia. Consequently, this alleviated the severity of and decreased the mortality of neutropenia-related pneumonia. Together, these observations demonstrate that the innate immune responses can be enhanced and the severity of neutropenia-related infection can be alleviated by augmenting phosphatidylinositol (3,4,5)-trisphosphate in transfused neutrophils with PTEN inhibitor SF1670, providing a therapeutic strategy for improving the efficacy of granulocyte transfusion.
authors.affiliation: Joint Program in Transfusion Medicine and Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Division of Blood Bank, Department of Lab Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Yitang
authors.initials: Y
authors.lastname: Li
authors.forename: Amit
authors.initials: A
authors.lastname: Prasad
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jia
authors.forename: Saurabh Ghosh
authors.initials: SG
authors.lastname: Roy
authors.forename: Fabien
authors.initials: F
authors.lastname: Loison
authors.forename: Subhanjan
authors.initials: S
authors.lastname: Mondal
authors.forename: Paulina
authors.initials: P
authors.lastname: Kocjan
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Silberstein
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects / Q000637:transplantation*; D017708:Leukocyte Transfusion / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009503:Neutropenia / Q000473:pathology / Q000628:therapy; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D010538:Peritonitis / Q000473:pathology / Q000628:therapy*; D018410:Pneumonia, Bacterial / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D051059:PTEN Phosphohydrolase