Abstract
Cytokine release syndrome (CRS) is known to be a factor in morbidity and mortality associated with acute viral infections including those caused by filoviruses and coronaviruses. IL-6 has been implicated as a cytokine negatively associated with survival after filovirus and coronavirus infection. However, IL-6 has also been shown to be an important mediator of innate immunity and important for the host response to an acute viral infection. Clinical studies are now being conducted by various researchers to evaluate the possible role of IL-6 blockers to improve outcomes in critically ill patients with CRS. Most of these studies involve the use of anti-IL-6R monoclonal antibodies (α-IL-6R mAbs). We present data showing that direct neutralization of IL-6 with an α-IL-6 mAb in a BALB/c Ebolavirus (EBOV) challenge model produced a statistically significant improvement in outcome compared with controls when administered within the first 24 h of challenge and repeated every 72 h. A similar effect was seen in mice treated with the same dose of α-IL-6R mAb when the treatment was delayed 48 h post-challenge. These data suggest that direct neutralization of IL-6, early during the course of infection, may provide additional clinical benefits to IL-6 receptor blockade alone during treatment of patients with virus-induced CRS.
Highlights
Under normal circumstances, interleukin-6 (IL-6) is secreted transiently by myeloid cells as part of the innate immune response to injury or infections
Mixed results of cytokine release syndrome (CRS) treatment with IL-6 blockers (Herper, 2020; ClinicalTrialsGenetech, 2020; ClinicalTrialsEUSA, 2020; Taylor, 2020; Saha et al, 2020), and our own observations of the role of IL-6 in morbidity and mortality associated with Ebola virus infection (Herst et al, 2020), led us to evaluate the clinical effects of treatment with antibody directed against the IL-6 receptor, and with mAb directed to IL-6 itself
We report here on the observed differences between treatments with a-IL-6R mAbs and a-IL-6 mAbs in a mouse model of EBOV infection and comment on how IL-6 blockade may be relevant to the management and therapy for patients with Ebola infection as well as patients infected with SARS-CoV-2
Summary
Interleukin-6 (IL-6) is secreted transiently by myeloid cells as part of the innate immune response to injury or infections. Disrupting CRS antigen activation and inhibits TGF-beta differentiation, providing a crucial link between innate and acquired immune responses (Korn et al, 2008; Dienz and Rincon, 2009) These actions place IL-6 in a central role in mediating and amplifying cytokine release syndrome (CRS), commonly associated with Ebola virus disease (EVD) infections. It is thought that prolonged exposure to elevated inflammatory cytokine levels is toxic to T cells and results in their apoptotic and necrotic cell death (Younan et al, 2018) Both lymphopenia and elevated serum Il-6 levels are found in Ebola virus infection and are known to be inversely correlated with survival in patients post-infection (Wauquier et al, 2010)and in mouse models of Ebola infection (Herst et al, 2020). We report here on the observed differences between treatments with a-IL-6R mAbs and a-IL-6 mAbs in a mouse model of EBOV infection and comment on how IL-6 blockade may be relevant to the management and therapy for patients with Ebola infection as well as patients infected with SARS-CoV-2
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