Genetic Reconstitution of Autoimmune Type 1 Diabetes With Two Major Susceptibility Genes in the Rat

Abstract

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. Diabetes 56:506 -512, 2007

Visualizing the Role of Cbl-b in Control of Islet-Reactive CD4 T Cells and Susceptibility to Type 1 Diabetes

“…The findings above extend previous evidence from the KDP rat strain that Cbl-b is important for regulating islet-specific autoimmunity (20)(21)(22) by showing that Cblb deficiency predisposes to diabetes and formation of islet autoantibodies in mice (Fig. 1).…”

“…The effects of Cblb deficiency are only manifest as autoimmunity when peripheral tolerance is stressed by increasing the frequency of autoreactive T cells through elevated thymic production in the TCR insHEL transgenic mice studied in this study. Similarly, the autoimmune effects of Cblb mutation in rats are only manifest as insulitis, diabetes, and thyroiditis when combined with a diabetessusceptible MHC haplotype (20)(21)(22) that, speculatively, may diminish thymic negative selection of islet-specific CD4 cells (47). Even with these combined defects, diabetes only develops after a variable latent phase.…”

“…Analyses of polygenic susceptibility to autoimmunity also implicates defects in specific T cell tolerance checkpoints, notably subtle genetic variants of IL2RA and IL-2 associated with type 1 diabetes in humans and NOD mice, respectively, and polygenic defects in TCR signaling for thymic deletion in NOD mice (3,(15)(16)(17)(18)(19). Spontaneous type 1 diabetes in the Komeda diabetes-prone (KDP) rat results from cooperation between a specific MHC haplotype-probably MHC class II-and a truncating mutation in the gene encoding Cbl-b (20)(21)(22). However, it is not known whether Cbl-b deficiency disrupts thymic deletion of MHC class II-restricted diabetogenic CD4 + cells, formation of islet-specific Foxp3 T cells, or other peripheral self-tolerance checkpoints.…”

Ubiquitin ligase Cbl-b and obesity-induced insulin resistance [Review]

“…These results indicate that Cbl-b deficiency is associated with type II diabetes in mice. Yokoi et al [20,40] reported that loss of function due to mutated CBLB is associated with type I diabetes in rodents and humans. CBLB mutation causes autoimmune disease by impairing anergy induction in T-cells.…”

Experimentação animal: ética e legislação brasileira

“…Esta constatação evidencia a necessidade de levar ao conhecimento público os códigos éticos estabelecidos para a escolha do método a ser, ou já empregado, assim como a evolução dos resultados obtidos e que propiciaram avanços importantes para o conhecimento e tratamento, por exemplo, do Diabetes mellitus tipo 2 13 .…”