Prevention of insulitis and diabetes in Β2-microglobulin-deficjent non-obese diabetic mice

Abstract

beta 2-Microglobulin (beta 2m)-deficient non-obese diabetic (NOD) mice were established by crossing beta 2m-deficient 129/Sv mice with NOD mice, and used to examine the possible involvement of MHC class I molecules and CD8+ T cells in the development of insulitis and diabetes. In these mice, MHC class I molecules were not expressed, resulting in no generation of CD8+ T cells. None of eight lines of beta 2m-deficient NOD mice (-/-) established developed overt diabetes by 32 weeks, while control littermates (+/+) became diabetic by 22 weeks. histological studies showed no significant lymphocyte infiltration of the islets (insulitis score: 0.03 +/- 0.03) in any of the beta 2m-deficient NOD mice (-/-) compared with littermate NOD mice (+/+) with overt insulitis (1.42 +/- 0.28). These findings support the notion that the expression of MHC class I molecules and/or CD8+ T cells plays an essential role in the infiltration of CD4+ T cells in islets as well as the development of diabetes in NOD mice.

Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

“…4 B and D). In type 1 diabetes the development of disease has usually been ascribed to a T H 1 or T C response (19)(20)(21)(22)(23)(24)(25). On the other hand, the exact role of T H 17 cells in the pathogenesis of T1D is not well understood.…”

“…The islet autoreactive CD4 + helper T (T H ) cells and CD8 + cytotoxic T (T C ) cells are involved in the immune pathogenesis of human T1D and NOD mice (19)(20)(21)(22)(23)(24)(25). Recently we showed that IL-7 can promote the development of IFN-γ-producing T H 1 cells, but not IL-17-producing T H 17 cells, from the naïve T cells of humans and of the C57BL/6 mice (26).…”

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

“…Moreover, a direct role for class I genes has been demonstrated in CD8 þ T-cell mediated destruction of b-cells in the nonobese diabetic mouse model of T1D. [28][29][30][31][32][33] These reports indicate that HLA-A and/or -B, or other loci in high LD with the associated alleles, may be particularly important in the processes between initiation of autoimmunity and progression to overt disease. Furthermore, HLA class II-independent associations with HLA-A and -B have also been reported with other AIDs.…”

Beta cell MHC class I is a late requirement for diabetes

“…T cells specific for an insulin peptide (amino acids [15][16][17][18][19][20][21][22][23] in the context of H-2K d were stained for using the tetramer G9, and the Listeria monocytogenes-specific tetramer LLO was used as a control (32). Analysis was then performed with a FACScan (BD Biosciences).…”

“…It has also been shown that depletion of CD8 T cells by treatment with monoclonal antibody prevents insulitis (18) and diabetes development in cyclophosphamide-treated NOD mice (19). In addition, ␤2-microglobulin (␤2M) Ϫ/Ϫ NOD mice, which lack MHC class I expression and CD8 T cells, do not develop insulitis (20)(21)(22)(23). However, despite numerous studies, the precise role of CD8 T cells in the disease process has remained unclear and confusing.…”