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

Autoimmune insulin-dependent diabetes mellitus (IDDM) occurs spontaneously in mice-bearing transgenes encoding the influenza hemagglutinin under the c ontrol of the rat insulin promoter and a T cell receptor specific for an he magglutinin peptide associated with I-E-d. Such "double transgenic" mice ex pressing wild-type or targeted IL-4R alpha genes were examined for the onse t of IDDM. Eight of 11 mice homozygous for wild-type IL-4R alpha were hyper glycemic by 8 weeks of age, whereas only 1 of 16 mice homozygous for the ta rgeted allele were hyperglycemic at this time. Most IL-4R alpha-/- mice rem ained normoglycemic to 36 weeks of age. Although only 10% of double transge nic mice homozygous for the wild-type IL-4R alpha allele survived to 30 wee ks, 80% of mice homozygous for the targeted allele did so. Heterozygous mic e 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 p eri-insulitis. Thus, the inability to respond to IL-4 and/or IL-13 protects mice against IDDM in this model of autoimmunity.