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Hyporesponsiveness of SPRET/Ei mice to lethal shock induced by tumor necrosis factor and implications for a TNF-based
Jan Staelens1, Ben Wielockx, Leen Puimège
1Department of Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium.
Abstract:
Tumor necrosis factor (TNF) is a central mediator in lethal shock and an interesting cytokine for anticancer therapy. To inhibit TNF-induced lethal shock, it is important to identify protective genes. Here we demonstrate that the SPRET/Ei mouse strain, derived from Mus spretus, exhibits an extremely dominant resistance to TNF-induced lethal inflammation. An interspecific backcross experiment revealed that the TNF hyporesponse is linked to loci on chromosomes 2, 6, and 11. Treatment of inoculated tumors with TNF and IFN-gamma leads to regression and a highly reduced toxicity in (C57BL/6 x SPRET/Ei)F(1) mice.
Insights
SPRET/Ei mice show strong resistance to lethal inflammation caused by Tumor Necrosis Factor (TNF). This resistance is linked to specific genes, offering potential for reduced toxicity in cancer therapy.
Area of Science:
- Immunology
- Genetics
- Oncology
Background:
- Tumor Necrosis Factor (TNF) is a key mediator in lethal shock and a target for anticancer therapies.
- Identifying genes that confer resistance to TNF-induced inflammation is crucial for therapeutic development.
Purpose of the Study:
- To investigate the genetic basis of resistance to TNF-induced lethal inflammation in the SPRET/Ei mouse strain.
- To evaluate the therapeutic potential of TNF and IFN-gamma in reducing tumor burden and toxicity.
Main Methods:
- An interspecific backcross experiment was conducted using SPRET/Ei mice.
- Genetic linkage analysis was performed to identify loci associated with TNF hyporesponse.
- Mice were treated with TNF and IFN-gamma to assess tumor regression and toxicity.
Main Results:
- The SPRET/Ei mouse strain demonstrated dominant resistance to TNF-induced lethal inflammation.
- TNF hyporesponse was mapped to loci on chromosomes 2, 6, and 11.
- Combined treatment with TNF and IFN-gamma resulted in tumor regression and significantly reduced toxicity in F1 hybrid mice.
Conclusions:
- Genetic factors on chromosomes 2, 6, and 11 contribute to resistance against TNF-induced lethal inflammation.
- Targeted use of TNF and IFN-gamma can lead to effective tumor regression with diminished toxicity, particularly in susceptible genetic backgrounds.
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