Genetic reconstitution of autoimmune type 1 diabetes with two major susceptibility genes in the rat.
The Komeda diabetes-prone (KDP) rat is an animal model of human autoimmune type 1 diabetes. We have previously shown that two major susceptibility genes, the major histocompatibility complex (MHC) RT1(u) haplotype and Cblb (Casitas B-lineage lymphoma b) mutation, are responsible for the development of diabetes in KDP rats, suggesting a two-gene model for development of the disease. To confirm the two-gene model, we produced a congenic strain carrying mutated Cblb alleles of the KDP rat on a non-KDP genetic background harboring the RT1(u) haplotype on its MHC. Despite the low incidence and delayed onset of diabetes, the congenic strain did develop the disease, indicating that type 1 diabetes can be reconstituted on a non-KDP genetic background with the RT1(u) haplotype and Cblb mutation. Similar to observations in KDP rats, the congenic strain showed insulitis and thyroiditis, symptoms of autoimmunity. The low incidence and delayed onset of the disease strongly suggest involvement of genetic modifiers; the congenic strain established in this study should be useful for the mapping and identification of such modifiers.
Yokoi
Norihide
N
Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan.
Hayashi
Chihiro
C
Fujiwara
Yuuka
Y
Wang
He-Yao
HY
Seino
Susumu
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D020296:Animals, Congenic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006649:Histocompatibility Antigens / Q000235:genetics*; D006720:Homozygote; D007328:Insulin / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013966:Thyroiditis
D048868:Adaptor Proteins, Signal Transducing; C492213:Cblb protein, rat; D006649:Histocompatibility Antigens; D007328:Insulin; C038353:histocompatibility antigens RT, rat; D050721:Proto-Oncogene Proteins c-cbl