Characterization of Non-canonical Way in Inflammasome Monocytes of Patients With Severe Sepsis (CASPASEs)

February 20, 2017 updated by: Groupe Hospitalier Paris Saint Joseph
Activation of caspase-4 and human caspase-5 (orthologs of caspase-11 in mice) in innate immune cells.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Lipopolysaccharide (LPS) of the wall of Gram-negative bacteria is one of pathogen associated molecular patterns (PAMPs), which are recognized by cells of the innate immune system via Toll-like receptor 4 (TLR4) . The LPS / TLR4 interaction induces the secretion of a variety of proinflammatory cytokines. Among them, interleukin-1β (IL-1β) is a major cytokine, and alterations to its secretion has been associated with various diseases, such as periodic syndrome associated cryopyrin (CAPS), gout, rheumatoid arthritis or multiple sclerosis.

The release of IL-1β is controlled by a molecular platform protein, known as the inflammasome name. The canonical protein (that is to say conserved in evolution) of the inflammasome NLRP3 are NLRC4 and that engages the ASC adapter protein to activate caspase-1, which promotes the cleavage of interleukin IL-1β. Gram-negative bacteria such as Escherichia coli cause non-canonical activation of caspase-1, caspase-11In involving more NLRP3 and AUC. In mouse, caspase-11 is essential to the immune response to gram-negative bacteria, but bacterial PAMPs that are responsible for triggering of the non-canonical inflammasome remain to be identified. It has recently been shown that caspase-11 is involved in the death of the mice subjected to septic shock. The mouse model requires caspase-11-dependent mechanism, caspase-independent -1 since the CASP1 - / - mouses are also susceptible to LPS as wild type mice. A key question to be answered is whether LPS triggers similar events in human cells. If this is the case, this knowledge may be useful in drug development for treatment of sepsis.

Study Type

Observational

Enrollment (Actual)

6

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
    • Ile de France
      • Paris, Ile de France, France, 75014
        • Groupe Hospitalier Paris Saint Joseph

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • ADULT
  • OLDER_ADULT
  • CHILD

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Patients with sepsis severe (bacterial infection associated with deterioration of at least one vital function) defined according to the criteria consensus conference

Description

Inclusion Criteria:

  • patients with sepsis severe (bacterial infection associated with deterioration of at least one vital function) defined according to the criteria consensus conference
  • patients whose diagnosis is made within 24 hours of the opening hours of Pasteur Research Laboratory
  • patients with arterial catheter (not to impose an additional puncture to the patient) will be recruited in the intensive care unit of the Hospital St. Joseph. Arterial blood (20 ml) will be charged within 24 hours of the onset of severe sepsis criteria, during working hours of the laboratory of the Pasteur Institute, using vacuum tubes under heparin (Vacutainer), sent by a courier within 2 hours following the removal (to ensure that the cells are sufficiently "fresh" during processing in the laboratory)

Exclusion Criteria:

  • none

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
patients with severe sepsis
blood samples from patients with severe sepsis
Biological: blood samples
Isolation and stimulation of monocytes, preparation of cell lysates, measurement of cytokine production, Western blot

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Characterize the expression of caspase-4 and -5 in by measuring the production of cytokines: IL-1β concentrations and IL-1α will determined by ELISA in the cell supernatant will be collected from monocytes stimulated or not
Time Frame: Two hours after blood collection : isolation and stimulation of monocytes than preparation of cell lysates
Two hours after blood collection : isolation and stimulation of monocytes than preparation of cell lysates

Secondary Outcome Measures

Outcome Measure
Time Frame
Correlate the activation of caspases-4 and -5 with IL-1β production with (canonical inflammasome) and IL-1α (Non-canonical inflammasome) measured by Western blot
Time Frame: Two hours after blood collection : isolation and stimulation of monocytes than preparation of cell lysates
Two hours after blood collection : isolation and stimulation of monocytes than preparation of cell lysates

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Groupe Hospitalier Paris Saint Joseph

Collaborators

Institut Pasteur
Agency for Science, Technology and Research

Investigators

  • Principal Investigator: Benoit Misset, Professor, Groupe Hospitalier Paris Saint Joseph
  • Principal Investigator: Jean Marc Cavaillon, Professor, Unité Cytokines et Inflammation, Institut Pasteur, Paris
  • Principal Investigator: Alessandra Mortellaro, Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, #04-06 Immunos, Singapore

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2014

Primary Completion (Actual)

December 1, 2014

Study Completion (Actual)

December 1, 2014

Study Registration Dates

First Submitted

August 21, 2015

First Submitted That Met QC Criteria

August 31, 2015

First Posted (Estimate)

September 2, 2015

Study Record Updates

Last Update Posted (Actual)

February 23, 2017

Last Update Submitted That Met QC Criteria

February 20, 2017

Last Verified

August 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2013-A01617-38

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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