NOD Transgenic Mouse: Prevention of Insulitis by Introducing Major Histocompatibility Complex Class II Gene

Abstract

The NOD mice spontaneously develop insulin-dependent diabetes mellitus characterized by autoimmune insulitis. They have unusual class II MHC: the expression of I-E molecules are clearly absent and I-A molecules have unique characteristics. To determine whether the unusual expression of the class II MHC may be responsible for the development of insulitis in this strain, two series of experiments have been attempted utilizing transgenic mice carrying MHC class II genes.
1) By mating NOD mice with I-E expressing C57BL/6 (Eα^d) transgenic mice, backcross progenies which expressed I-E molecules without having other MHC genes on chromosome 17 derived from C57BL/6 were obtained. No insulitis was observed at 25 weeks of age in these backcross progenies.
2) NOD transgenic mice carrying Eα^d or Aβ^k gene were directly produced by microinjecting these genes into fertilized NOD eggs. I-E or I-A^d/k antigens were detected on the surface of their lymphocytes. In NOD (Eα^d) transgenic mice, no insulitis was observed at 19 weeks of age. On the other hand, in 4 among 5 NOD (Aβ^k) transgenic founders expressing I-A^d/k antigens developed insulitis until 19 weeks of age. These experiments clearly demonstrate that one of the diabetogenic recessive gene linked to the MHC locus on chromosome 17 is Eα gene itself deleted in NOD mouse.