A targeted mutation in the IL-4Ralpha gene protects mice against autoimmune diabetes

Autoimmune insulin-dependent diabetes mellitus (IDDM) occurs spontaneously in mice-bearing transgenes encoding the influenza hemagglutinin under the control of the rat insulin promoter and a T cell receptor specific for an hemagglutinin peptide associated with I-E(d). Such "double transgenic&qu...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2000-11, Vol.97 (23), p.12700-12704
Main Authors: Radu, D L, Noben-Trauth, N, Hu-Li, J, Paul, W E, Bona, C A
Format: Article
Language:English
Subjects:
Animals
Diabetes
Diabetes Mellitus, Type 1 - immunology
Diabetes Mellitus, Type 1 - pathology
Diabetes Mellitus, Type 1 - prevention & control
Gene Targeting
Genes
Hemagglutinin Glycoproteins, Influenza Virus - genetics
Immunology
Insulin - genetics
Islets of Langerhans - pathology
Mice
Mice, Inbred BALB C
Mice, Transgenic
Mutation
Promoter Regions, Genetic
Rats
Receptors, Antigen, T-Cell
Receptors, Interleukin-4 - genetics
Receptors, Interleukin-4 - immunology
Rodents
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Summary:Autoimmune insulin-dependent diabetes mellitus (IDDM) occurs spontaneously in mice-bearing transgenes encoding the influenza hemagglutinin under the control of the rat insulin promoter and a T cell receptor specific for an hemagglutinin peptide associated with I-E(d). Such "double transgenic" mice expressing wild-type or targeted IL-4Ralpha genes were examined for the onset of IDDM. Eight of 11 mice homozygous for wild-type IL-4Ralpha were hyperglycemic by 8 weeks of age, whereas only 1 of 16 mice homozygous for the targeted allele were hyperglycemic at this time. Most 1L-4Ralpha-/- mice remained normoglycemic to 36 weeks of age. Although only 10% of double transgenic mice homozygous for the wild-type IL-4Ralpha allele survived to 30 weeks, 80% of mice homozygous for the targeted allele did so. Heterozygous mice displayed an intermediate frequency of diabetes. Even as late as 270 days of age, mice homozygous for the targeted allele had no insulitis or only peri-insulitis. Thus, the inability to respond to IL-4 and/or IL-13 protects mice against IDDM in this model of autoimmunity.
ISSN:0027-8424
1091-6490