JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome

  1. Kathryn D. Tuttle
  2. Katherine A. Waugh
  3. Paula Araya
  4. Ross Minter
  5. David J. Orlicky
  6. Michael Ludwig
  7. Zdenek Andrysik
  8. Matthew A. Burchill
  9. Beth A.J. Tamburini
  10. Colin Sempeck
  11. Keith Smith
  12. Ross Granrath
  13. Dayna Tracy
  14. Jessica Baxter
  15. Joaquin M. Espinosa
  16. Kelly D. Sullivan

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Abstract

No abstract available

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  1. Version published to 10.1016/j.celrep.2020.108407
  2. ScreenIT

    SciScore for 10.1101/2020.04.07.024455: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIACUC: All animal experiments were designed a priori, including proper calculation of numbers of mice based on power analyses, and reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Colorado Anschutz Medical Campus.
    Randomizationnot detected.
    Blindingnot detected.
    Power AnalysisAll animal experiments were designed a priori, including proper calculation of numbers of mice based on power analyses, and reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Colorado Anschutz Medical Campus.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Antibodies against SiglecF, Ly6C, CD115 and CD11b and mouse FC receptors were also included in the stimulation media.
    Antibodies against SiglecF , Ly6C
    suggested: None
    CD115
    suggested: None
    CD11b
    suggested: None
    Following permeabilization cells were stained with the following antibodies conjugated to fluorophores: CD3 (17A2), CD4, CD8 (53.6.7), B220, Ly6C, MHCII, NK1.1 and phospho-STAT1 (Tyr701).
    CD3
    suggested: None
    CD4
    suggested: None
    CD8
    suggested: None
    B220
    suggested: None
    Ly6C
    suggested: None
    phospho-STAT1 ( Tyr701) .
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Mice: The Dp(10Prmt2-Pdxk)1Yey/J (Dp(10)1Yey/ +), Dp(16Lipi-Zbtb21)1Yey/J (Dp(16)1Yey/ +), and Dp(17Abcg1-Rrp1b)1(Yey)/J (Dp(17)1Yey/ +) strains have been previously described (
    Dp(10Prmt2-Pdxk)1Yey/J (Dp(10)1Yey/ +), Dp(16Lipi-Zbtb21)1Yey/J
    suggested: None
    Dp(17Abcg1-Rrp1b)1(Yey)/J
    suggested: None
    Animals were maintained on the C57BL/6J background and housed in specific pathogen-free conditions.
    C57BL/6J
    suggested: RRID:IMSR_JAX:000664)
    Software and Algorithms
    SentencesResources
    Dp16 mice were purchased from Jackson Laboratories or provided by Drs.
    Jackson Laboratories
    suggested: None
    Statistical analysis: All statistical analysis was done with the Prism software and the exact tests employed are described in the legends for each figure.
    Prism
    suggested: (PRISM, RRID:SCR_005375)

    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: We detected the following sentences addressing limitations in the study:
    With regards to its relevance to therapeutic strategies for COVID-19 and other conditions associated with cytokine storms, this study has several limitations. First, our mouse model does not fully reproduce the human conditions associated with cytokine storms. Although intraperitoneal injections of P(I:C) induce a clear cytokine storm in mice, this may be different in quality and magnitude to what is observed in humans. Second, there is no active viral infection or adaptive immune responses in our model. Furthermore, the genomes of SARS-CoV-2 and other lethal viruses that induce cytokine storms encode for proteins that modulate the immune response, including anti-IFN factors (27, 28), and it is unclear how these viral factors may modulate the course of disease and response to JAK inhibitors. Lastly, there may be significant differences in the course of a cytokine storm initiated from the lung tissue, as opposed to the more systemic response elicited in our model. Nevertheless, our results justify a thorough analysis of JAK inhibitors in pre-clinical models and clinical trials in the ongoing efforts to attenuate the impact of the COVID-19 pandemic. Additionally, our results indicate that people with DS, who carry an extra copy of the four IFNRs encoded on chromosome 21, should be considered a high-risk population during the COVID-19 pandemic. Our studies of the Dp16 mice were originally driven by our interest in studying immune dysregulation and IFN hyperactivity in DS. Of not...

    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:
    • No conflict of interest statement was detected. If there are no conflicts, we encourage authors to explicit state so.
    • 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.

  3. Version published to 10.1101/2020.04.07.024455v1 on bioRxiv