Interferon in Human Serum After Injection of Endotoxin

Sauter, Christian; Wolfensberger, C

doi:10.1016/s0140-6736(80)90189-0

Cited by 64 publications

(43 citation statements)

References 6 publications

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“…Relative to the human response, mice are highly resilient to inflammatory challenge (28,29). For example, the lethal dose of endotoxin is 5-25 mg/kg for most strains of mice, whereas a dose that is 1,000,000-fold less (30 ng/kg) has been reported to cause shock in humans (30). The extreme sensitivity of humans relative to mice to massive inflammation may result in genomic responses that reach an upper threshold in each human disease, whereas the resilience of mice may prevent maximum responses and lead to greater heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Genomic responses in mouse models poorly mimic human inflammatory diseases

Seok

Warren²,

Cuenca

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

2,554

1,921

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A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R 2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.human disease | translational medicine | inflammation | immune response | injury M urine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials (1-3). However, few of these human trials have shown success (4-7). The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed (8-11). Despite commentaries that question the merit of an overreliance of animal systems to model human immunology (3,12,13), in the absence of systematic evidence, investigators and public regulators assume that results from animal research reflect human disease. To date, there have been no studies to systematically evaluate, on a molecular basis, how well the murine clinical models mimic human inflammatory diseases in patients.The Inflammation and Host Response to Injury, Large Scale Collaborative Research Program has completed multiple studies on the genomic responses to systemic inflammation in patients and human volunteers as well as murine models (14-18). These datasets include genome-wide expression analysis on white blood cells obtained from serial blood draws in 167 patients up to 28 d after severe blunt trauma (15), 244 patients up to 1 y after burn injury, and 4 healthy humans for 24 h after administration of low-dose bacterial endotoxin (14) and expression analysis on analogous samples from well-established mouse models of trauma, burns, and endotoxemia (16 treated and 16 controls per model) (16-18). In humans, severe inflammatory stress produces a genomic storm affecting all major cellular functions and pathways (15) and therefore, provided sufficient perturbations to allow comparisons between the genes in the human conditions and their orthologs in the murine models.In this article, we report on a systematic comparison of the genomic respo...

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Section: Discussionmentioning

confidence: 99%

Genomic responses in mouse models poorly mimic human inflammatory diseases

Seok

Warren²,

Cuenca

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

2,554

1,921

View full text Add to dashboard Cite

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“…In comparison with humans, rodents are generally highly resistant to most types of induced inflammation. For example, the sensitivity to lipopolysaccharide (LPS) is 1,000 to 10,000 times higher in humans (51,52) than in mice (53). These distinctly different immune responses are most likely due to diverse reactions in humans and mice, such as, e.g., cytokine release.…”

Section: Discussionmentioning

confidence: 99%

Humanized Mice, a New Model To Study the Influence of Drug Treatment on Neonatal Sepsis

et al. 2013

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cBacterial infection with group B Streptococcus (GBS) represents a prominent threat to neonates and fetuses in the Western world, causing severe organ damage and even death. To improve current therapeutic strategies and to investigate new approaches, an appropriate in vivo model to study the immune response of a human immune system is needed. Therefore, we introduced humanized mice as a new model for GBS-induced sepsis. Humanized mice feature deficiencies similar to those found in neonates, such as lower immunoglobulin levels and myeloid cell dysfunction. Due to the husbandry in specific-pathogen-free (SPF) facilities, the human immune cells in these mice also exhibit a naive phenotype which mimics the conditions in fetuses/ neonates. Following infection, cytokine release and leukocyte trafficking from the bone marrow to the lymphoid organ (spleen) and into the peritoneum (site of infection) as well as bacterial spreading and clearance were traceable in the humanized mice. Furthermore, we investigated the effects of betamethasone and indomethacin treatment using this novel sepsis model. Although both drugs are commonly used in perinatal care, little is known about their effects on the neonatal immune system. Treatment of infected humanized mice not only induced the reduction of human leukocytes in the spleen but also increased the bacterial load in all analyzed organs, including the brain, which did not show infiltration of live GBS in untreated controls. These studies demonstrate the utility of the humanized mice as a new model to study an immature human immune response during bacterial infection and allow the investigation of side effects induced by various treatments.

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“…The challenge dose of LPS used in most published in vivo studies in mice is 1-25 mg/kg, which approximates the dose that causes death in half of the mice [4 -7]. This dose is 1000 -10,000 times the dose required to induce severe disease with shock in humans [8,9] and ϳ1,000,000 times the dose used in carefully controlled study environments in which human volunteers are challenged with highly characterized preparations of 2-4 ng/kg LPS to elicit fever and cytokines [10]. A direct comparison between the species for live bacteria is obviously not possible.…”

mentioning

confidence: 99%

Editorial: Mouse models to study sepsis syndrome in humans

Warren

2009

Journal of Leukocyte Biology

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Interferon in Human Serum After Injection of Endotoxin

Cited by 64 publications

References 6 publications

Genomic responses in mouse models poorly mimic human inflammatory diseases

Genomic responses in mouse models poorly mimic human inflammatory diseases

Humanized Mice, a New Model To Study the Influence of Drug Treatment on Neonatal Sepsis

Editorial: Mouse models to study sepsis syndrome in humans

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