Anti-IL-6 versus Anti-IL-6R Blocking Antibodies to Treat Acute Ebola Infection in BALB/c Mice: Potential Implications for Treating Cytokine Release Syndrome

  1. Reid Rubsamen
  2. Scott Burkholz
  3. Christopher Massey
  4. Trevor Brasel
  5. Tom Hodge
  6. Lu Wang
  7. Charles Herst
  8. Richard Carback
  9. Paul Harris

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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 hours of challenge and repeated every 72 hours. A similar effect was seen in mice treated with the same dose of α-IL-6R mAb when the treatment was delayed 48 hrs 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.

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  1. ScreenIT

    SciScore for 10.1101/2020.06.20.162826: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Experimental groups of 10 mice each were administered rat anti-mouse-IL-6 IgG1 monoclonal antibody (BioXCell, BE0046, Lebanon, NH, RRID AB1107709) or rat anti-mouse-IL-6R IgG2 monoclonal antibody (BioXCell, BE0047, RRID AB1107588) at a dose of 100 µg in sterile saline via intravenous (i.v.) administration via an indwelling central venous catheter, or 400 µg via i.p. injection at 24, 48, or 72 hours post-challenge.
    anti-mouse-IL-6 IgG1
    suggested: None
    Lebanon
    detected: (Bio X Cell Cat# BE0046, RRID:AB_1107709)
    anti-mouse-IL-6R IgG2
    detected: (Bio X Cell Cat# BE0047, RRID:AB_1107588)
    Experimental Models: Organisms/Strains
    SentencesResources
    BALB/c mice (Envigo; n = 146) were challenged with 100 plaque forming units (PFU) of maEBOV via intraperitoneal (i.p.) injection as described previously (Comer et al., 2019; Hodge et al., 2016).
    BALB/c
    suggested: None
    Software and Algorithms
    SentencesResources
    2.4 Statistical Methods: Descriptive and comparative statistics including arithmetic means, standard errors of the mean (SEM), Survival Kaplan-Meier plots and Log-rank (Mantel-Cox) testing, D’Agostino & Pearson test for normality, Area-Under-The-Curve and Z Statistics were calculated using R with data from GraphPad Prism files.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.06.20.162826 on bioRxiv