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Fixed Volume or Fixed Pressure: A Murine Model of Hemorrhagic Shock
Published on: June 6, 2011
Description and mapping of the resistance of DBA/2 mice to TNF-induced lethal shock
Ben Wielockx1, Jan Staelens, Leen Puimège
1Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and University of Ghent, Ghent, Belgium.
Abstract:
In our search for genes that inhibit the inflammatory effects of TNF without diminishing its antitumor capacities we found that, compared with C57BL/6 mice, DBA/2 mice exhibit a dominant resistance to TNF-induced lethality. Tumor-bearing (C57BL/6 x DBA/2)(BXD)F(1) mice completely survived an otherwise lethal TNF/IFN-gamma-antitumor therapy with complete regression of the tumor. This was not the case for C57BL/6 mice. Genetic linkage analysis revealed that TNF resistance is linked to a major locus on distal chromosome 6 and a minor locus on chromosome 17. Compared with littermate controls, chromosome substitution mice carrying a DBA/2 chromosome 6 in a C57BL/6 background were significantly protected against TNF and TNF/IFN-gamma, albeit less so than DBA/2 mice. Definition of a critical region of 13 Mb on chromosome 6 was the highest mapping resolution obtained. Further analysis of candidate genes may provide a powerful tool to control TNF-induced pathologies in humans.
Insights
DBA/2 mice show resistance to tumor necrosis factor (TNF)-induced lethality, a trait linked to chromosome 6. This resistance allows for effective antitumor therapy without diminishing tumor-fighting capabilities.
Area of Science:
- Immunology
- Genetics
- Cancer Research
Background:
- Tumor necrosis factor (TNF) has potent antitumor effects but also causes lethal inflammation.
- Identifying mechanisms to separate these effects is crucial for effective cancer therapy.
Purpose of the Study:
- To find genes that inhibit TNF-induced inflammation while preserving its antitumor activity.
- To investigate the genetic basis of resistance to TNF-induced lethality.
Main Methods:
- Comparative genetic analysis between C57BL/6 and DBA/2 mouse strains.
- Tumor-bearing (BXD)F1 mice were subjected to TNF/IFN-gamma antitumor therapy.
- Genetic linkage analysis and chromosome substitution studies were performed.
Main Results:
- DBA/2 mice exhibited dominant resistance to TNF-induced lethality compared to C57BL/6 mice.
- Tumor-bearing (BXD)F1 mice survived lethal TNF/IFN-gamma therapy with complete tumor regression.
- TNF resistance was mapped to a major locus on chromosome 6 and a minor locus on chromosome 17.
- Chromosome substitution mice with DBA/2 chromosome 6 showed significant protection against TNF and TNF/IFN-gamma.
Conclusions:
- A major genetic locus on chromosome 6 controls resistance to TNF-induced lethality.
- This resistance can be exploited for enhanced efficacy of TNF-based antitumor therapies.
- Further investigation of candidate genes may lead to novel strategies for managing TNF-related pathologies.
