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Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19.
Wigerblad, Gustaf; Warner, Seth A; Ramos-Benitez, Marcos J; Kardava, Lela; Tian, Xin; Miao, Rui; Reger, Robert; Chakraborty, Mala; Wong, Susan; Kanthi, Yogendra; Suffredini, Anthony F; Dell'Orso, Stefania; Brooks, Stephen; King, Christopher; Shlobin, Oksana; Nathan, Steven D; Cohen, Jonathan; Moir, Susan; Childs, Richard W; Kaplan, Mariana J; Chertow, Daniel S; Strich, Jeffrey R.
Affiliation
  • Wigerblad G; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, MD, USA.
  • Warner SA; Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.
  • Ramos-Benitez MJ; Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.
  • Kardava L; Postdoctoral Research Associate Training Program, National Institute of General Medical Sciences, Bethesda, MD, USA.
  • Tian X; Ponce Health Science University and Ponce Research Institute, Department of Basic Sciences, School of Medicine, Ponce, Puerto Rico, USA.
  • Miao R; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.
  • Reger R; Office of Biostatistics Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • Chakraborty M; Office of Biostatistics Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • Wong S; Laboratory of Transplantation Immunotherapy, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • Kanthi Y; Laboratory of Transplantation Immunotherapy, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • Suffredini AF; Laboratory of Transplantation Immunotherapy, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • Dell'Orso S; Laboratory of Vascular Thrombosis and Inflammation, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • Brooks S; Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.
  • King C; Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Shlobin O; Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Nathan SD; Advanced Lung Disease and Lung Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA.
  • Cohen J; Advanced Lung Disease and Lung Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA.
  • Moir S; Advanced Lung Disease and Lung Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA.
  • Childs RW; Adventist Healthcare Shady Grove Medical Center, Rockville, MD, USA.
  • Kaplan MJ; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.
  • Chertow DS; Laboratory of Transplantation Immunotherapy, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
  • Strich JR; United States Public Health Service Commissioned Corps, Rockville, MD, USA.
Sci Adv ; 9(1): eade8272, 2023 01 04.
Article in En | MEDLINE | ID: mdl-36598976
Spleen tyrosine kinase (SYK) is a previously unidentified therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improvements in many secondary end points related to efficacy. Here, we used a multiomic approach to evaluate cellular and soluble immune mediator responses of patients enrolled in this trial. We demonstrated that SYK inhibition was associated with reduced neutrophil activation, increased circulation of mature neutrophils (CD10+CD33-), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DR-CD33+CD11b-). SYK inhibition was also associated with normalization of transcriptional activity in circulating monocytes relative to healthy controls, an increase in frequency of circulating nonclassical and HLA-DRhi classical monocyte populations, and restoration of interferon responses. Together, these data suggest that SYK inhibition may mitigate proinflammatory myeloid cellular and soluble mediator responses thought to contribute to immunopathogenesis of severe COVID-19.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: COVID-19 Type of study: Clinical_trials Limits: Humans Language: En Journal: Sci Adv Year: 2023 Document type: Article Affiliation country: Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: COVID-19 Type of study: Clinical_trials Limits: Humans Language: En Journal: Sci Adv Year: 2023 Document type: Article Affiliation country: Country of publication: