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Protection from septic shock by neutralization of macrophage migration inhibitory factor
T Calandra1, B Echtenacher, D L Roy
1Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. Thierry.Calandra@chuv.hosp.vd.ch
Nature Medicine
|February 2, 2000
Summary
Macrophage migration inhibitory factor (MIF) is a critical mediator of septic shock. Targeting MIF with antibodies offers a promising new therapeutic strategy for severe sepsis, even when treatment is delayed.
Area of Science:
- Immunology
- Pathophysiology
- Critical Care Medicine
Background:
- Current septic shock therapies targeting cytokines like TNF and IL-1 have failed to reduce mortality.
- New therapeutic targets are urgently needed for severe sepsis management.
Purpose of the Study:
- To investigate the role of macrophage migration inhibitory factor (MIF) in the pathogenesis of septic shock.
- To evaluate MIF as a potential therapeutic target for septic shock.
Main Methods:
- MIF concentrations were measured in mice with bacterial peritonitis and in human septic shock patients.
- Experiments utilized TNFalpha knockout mice to isolate MIF's role.
- Therapeutic efficacy of anti-MIF antibodies was assessed in mouse models of sepsis (CLP and E. coli).
Main Results:
- High MIF concentrations were found in septic mice and human patients.
- Anti-MIF antibody protected mice from lethal sepsis, independent of TNFalpha.
- Treatment with anti-MIF antibody was effective even when initiated 8 hours post-sepsis induction.
- Recombinant MIF exacerbated sepsis lethality.
Conclusions:
- Macrophage migration inhibitory factor (MIF) plays a critical role in the pathogenesis of septic shock.
- Anti-MIF antibody therapy represents a novel and effective treatment strategy for septic shock.
- MIF is identified as a key therapeutic target for severe sepsis and septic shock.