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Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza.

ABSTRACT: The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha, which directly combat the infectious agent and recruit additional immune responses. This exuberant cytokine release paradoxically injures the host by triggering leakage from capillaries, tissue edema, organ failure, and shock. Current medical therapies target individual pathogens with antimicrobial agents or directly either blunt or boost the host's immune system. We explored a third approach: activating with the soluble ligand Slit an endothelium-specific, Robo4-dependent signaling pathway that strengthens the vascular barrier, diminishing deleterious aspects of the host's response to the pathogen-induced cytokine storm. This approach reduced vascular permeability in the lung and other organs and increased survival in animal models of bacterial endotoxin exposure, polymicrobial sepsis, and H5N1 influenza. Thus, enhancing the resilience of the host vascular system to the host's innate immune response may provide a therapeutic strategy for treating multiple infectious agents.

SUBMITTER: London NR

PROVIDER: S-EPMC2875996 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza.

London Nyall R NR Zhu Weiquan W Bozza Fernando A FA Smith Matthew C P MC Greif Daniel M DM Sorensen Lise K LK Chen Luming L Kaminoh Yuuki Y Chan Aubrey C AC Passi Samuel F SF Day Craig W CW Barnard Dale L DL Zimmerman Guy A GA Krasnow Mark A MA Li Dean Y DY

Science translational medicine 20100301 23

The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha, which directly combat the infectious agent and recruit additional immune responses. This exuberant cytokine release paradoxically injures the host by triggering leakage from capillaries, tissue edema, organ failure, and shock. Current medical therapies target individual pathogens with antimicrobial agents or ...[more]

PMID: 20375003

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Project description:Background Sepsis has no proven specific pharmacologic treatment and reported mortality ranges from 30%–45%. The primary aim of this phase IB study was to determine the safety profile of Allocetra™-OTS (early apoptotic cell) infusion in subjects presenting to the emergency room with sepsis. The secondary aims were to measure organ dysfunction, intensive care unit (ICU) and hospital stays, and mortality. Exploratory endpoints included measuring immune modulator agents to elucidate the mechanism of action. Methods Ten patients presenting to the emergency room at the Hadassah Medical Center with sepsis were enrolled in this phase Ib clinical study. Enrolled patients were males and females aged 51–83 years, who had a Sequential Organ Failure Assessment (SOFA) score ≥2 above baseline and were septic due to presumed infection. Allocetra™-OTS was administered as a single dose (day +1) or in two doses of 140×106 cells/kg on (day +1 and +3), following initiation of standard-of-care (SOC) treatment for septic patients. Safety was evaluated by serious adverse events (SAEs) and adverse events (AEs). Organ dysfunction, ICU and hospital stays, and mortality, were compared to historical controls. Immune modulator agents were measured using Luminex® multiplex analysis. Results All 10 patients had mild-to-moderate sepsis with SOFA scores ranging from 2–6 upon entering the study. No SAEs and no related AEs were reported. All 10 study subjects survived, while matched historical controls had a mortality rate of 27%. The study subjects exhibited rapid resolution of organ dysfunction and had significantly shorter ICU stays compared to matched historical controls (p<0.0001). All patients had both elevated pro- and anti-inflammatory cytokines, chemokines, and additional immune modulators that gradually decreased following treatment. Conclusion Administration of apoptotic cells to patients with mild-to-moderate sepsis was safe and had a significant immuno-modulating effect, leading to early resolution of the cytokine storm. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT03925857. (https://clinicaltrials.gov/ct2/show/study/NCT03925857).

Dataset Information

Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza.

Publications

Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza.

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