Myelopoiesis of acute inflammation: lessons from TGN1412-induced cytokine storm
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RESEARCH REPORT
Myelopoiesis of acute inflammation: lessons from TGN1412‑induced cytokine storm Nicki Panoskaltsis1,2,3,4 · Neil E. McCarthy2,5 · Stella C. Knight2 Received: 29 May 2020 / Accepted: 15 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract TGN1412, a superagonist monoclonal antibody targeting CD28, caused cytokine storm in six healthy volunteers in a firstin-man study in 2006. Despite clinical improvement and termination of the cytokine release syndrome within days, anemia persisted in all patients with hemoglobin reaching baseline levels as much as 6 months later. Granulocytic dysplasia continued for 20 days in association with increased expression of CD69 and IL-4, but reduced IL-10; with resolution, this profile reversed to higher IL-10 expression and counter-balanced circannual cycling of IL-4 and IL-10 thereafter over 7 months. Along with immune cell subset and cytokine correlates monitored over 2 years, these observations offer unique insights into the expected changes in myelopoiesis and natural resolution in otherwise healthy young individuals in response to acute inflammation and cytokine storm in the absence of concomitant infection or comorbidity. Keywords Cytokine storm · Cytokine release syndrome · TGN1412 · Anemia of inflammation · Dysgranulopoiesis
Introduction
The long-term consequences of marrow inflammation in healthy humans are unclear. Here, we characterize the anemia and dysgranulopoiesis that resulted from affected myelopoiesis following TGN1412-induced cytokine storm. The work was done at Antigen Presentation Research Group and Department of Hematology, Imperial College London, Northwick Park and St. Mark’s Campus, London UK. * Nicki Panoskaltsis [email protected] 1
Department of Haematology, Imperial College London, Northwick Park and St. Mark’s Campus, London, UK
2
Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark’s Campus, London, UK
3
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
4
BioMedical Systems Engineering Laboratory, Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, USA
5
Centre for Immunobiology, The Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Cytokine storm occurs following an immune imbalance favoring excessive pro-inflammatory cytokine release [1, 2]. The result is ongoing inflammation, tissue damage, multiorgan failure, and death if the cytokine release syndrome (CRS) is not contained [1, 2]. Most CRS studies focus on the immune activation and acute response phase; little is known about longer-term effects on responding organs [1–4]. Bone marrow (BM) is the most productive human organ, generating hundreds of billions of cells daily during homeostasis, and is likely the most affected by CRS. Granulocytes become toxic during acute inflammation and can app
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