Description and Mapping of the Resistance of DBA/2 Mice to TNF-Induced Lethal Shock

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 otherwi...

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Bibliographic Details
Published in:Journal of Immunology 2007-04, Vol.178 (8), p.5069-5075
Main Authors: Wielockx, Ben, Staelens, Jan, Puimege, Leen, Vanlaere, Ineke, Van Roy, Maarten, van Lint, Philippe, Van Roy, Frans, Libert, Claude
Format: Article
Language:English
Subjects:
Animals
Chromosome Mapping
Female
Interferon-gamma - administration & dosage
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Quantitative Trait Loci
Shock - chemically induced
Species Specificity
Tumor Necrosis Factor-alpha - administration & dosage
Tumor Necrosis Factor-alpha - toxicity
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Summary: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.
ISSN:0022-1767
1550-6606
1365-2567
DOI:10.4049/jimmunol.178.8.5069