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Improving granulocyte transfusion in neutropenia-related infections

改善中性粒细胞减少相关感染的粒细胞输注

基本信息

批准号：
10682602
负责人：
Hongbo R Luo
金额：
$ 66.47万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682602
关键词：
Affect Aging Animal Experiments Animal Model Animals Antibiotics Antifungal Agents Antioxidants Apoptosis Apoptotic Aspergillus fumigatus Bacteria Bacterial Infections Binding Blood Component Removal Blood Transfusion CASP3 gene CSF3 gene Caspase Caspase Inhibitor Cell Death Cell Differentiation process Cell Membrane Permeability Cell physiology Cells Cessation of life Chemotaxis Clinical Clinical Trials Collection Colony-Stimulating Factors Combined Modality Therapy Complement Cytoplasmic Granules Disadvantaged Disease Effectiveness Elastases Escherichia coli FDA approved Fracture Goals Granulocyte Colony-Stimulating Factor Half-Life Heat-Shock Proteins 70 Host Defense Human Impairment Infection Inflammatory Response Invaded Investigation Knowledge Leukocyte Elastase Life Longevity Lytic Mediating Mediator Membrane Mission Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Mycoses Nature Neutropenia Outcome Oxidants Oxidative Stress Pathway interactions Patients Peptide Hydrolases Persons Phagocytosis Pharmaceutical Preparations Play Pneumonia Procedures Process Production Research Resolution Role Serine Serine Protease Signal Transduction Testing Therapeutic Transfusion Translational Research Transplant Recipients Transplantation Treatment Factor United States National Institutes of Health aged bactericide clinically relevant design experimental study granulocyte hematopoietic cell transplantation improved in vivo inhibitor insight mortality mouse model neutrophil novel novel strategies novel therapeutic intervention pathogen pharmacologic phosphatidylinositol 3,4,5-triphosphate pneumonia model preservation programs response screening single-cell RNA sequencing therapeutic target transfusion medicine

项目摘要

Project Summary Granulocyte transfusion (aka. neutrophil transfusion or GTX) has been utilized as a therapeutic approach for the treatment of life-threatening bacterial and fungal infections in severe neutropenic patients, including hematopoietic cell transplantation (HCT) recipients. Clinical outcomes from GTX are disadvantaged by the short shelf life and compromised function of donor neutrophils. Spontaneous neutrophil death is heterogeneous and mediated by multiple pathways. Leveraging mechanistic knowledge and pharmacological screening, we identified a combined treatment, caspases–lysosomal membrane permeabilization–oxidant– necroptosis inhibition plus granulocyte colony-stimulating factor (CLON-G), which alters neutrophil fate by simultaneously targeting multiple cell death pathways. CLON-G treatment significantly prolongs neutrophil ex vivo survival, increasing their half-life from less than 1 day to greater than 5 days. Compared to freshly isolated neutrophils, the stored CLON-G-treated neutrophils display normal functions, including chemotaxis, ROS production, phagocytosis, and bacteria killing. These results led us to hypothesize that CLON-G treatment can significantly increase the ex vivo shelf life of granulocyte transfusion products without impairing the function of the neutrophils in the GTX recipients. Due to the prolonged intracellular retention of the drugs, CLON-G treatment may even improve the survival and increase the half-life of the transfused neutrophils in vivo and therefore further improve the efficacy of GTX. In this study, we will first test this hypothesis in a clinically relevant murine model of granulocyte transfusion in neutropenia-related pneumonia. We will determine whether the stored CLON-G-treated neutrophils can function normally and survive even longer in vivo compared to freshly isolated neutrophils (Aim 1A). Additionally, we will investigate the survival and function of transfused human neutrophils in vivo in neutrophil-depleted NSG mice (Aim 1B). Next, we will examine whether transfusion with stored CLON-G-treated neutrophils can ultimately enhance the inflammatory response and bactericidal capability of the recipients as effectively as, or even more effectively than, transfusion with untreated fresh neutrophils (Aim 2). Last, to identify novel CLON-G-inducible factors and pathways that play critical role in regulating neutrophil death and function, we will perform single-cell RNA sequencing (scRNA-seq) to reveal the molecular signature of CLON-G reprogrammed neutrophils (Aim 3) . Together, experiments proposed in the three aims will assist us to better understand the molecular and cellular mechanism leading to neutrophil death and to design novel clinical procedures for the long-term storage and application of neutrophils in transfusion medicine. This study also provides a new strategy for treatment of neutropenia-related pneumonia. The ability to utilize GTX through better understanding of granulocyte function and survival could have a major impact on patients with no other options. This will be an important and necessary complementation to the current antibiotic and G-CSF therapies.

项目总结