Abstract
PurposeThe LEW.1AR1-iddm rat is an animal model of human type 1 diabetes mellitus (T1DM), which arose through a spontaneous mutation within the MHC-congenic inbred strain LEW.1AR1 (RT1r2). In contrast to the diabetes-resistant LEW.1AR1 background strain in LEW.1AR1-iddm rats a highly variable T-cell frequency could be observed in peripheral blood lymphocytes (PBLs).MethodsIn this study we therefore characterised the T-cell repertoire within the PBLs of the two strains by flow cytometry analysis and identified the CD3+ T-cell phenotype and its possible linkage to diabetes susceptibility. To map loci conferring susceptibility to variable CD3+ T-cell frequency, backcross strains (N2) were generated with the genetically divergent BN and PAR rats for microsatellite analysis.ResultsThe LEW.1AR1-iddm rat strain was characterised by a higher variability of CD3+ T-cells in PBLs along with a slightly decreased mean value compared to the LEW.1AR1 background strain. The reason for this reduction was a decrease in the CD4+ T-cell count while the CD8+ T-cell proportion remained unchanged. However, both T-cell subpopulations showed a high variability. This resulted in a lower CD4+/CD8+ T-cell ratio than in LEW.1AR1 rats. Like LEW.1AR1-iddm rats all animals of the backcross populations, N2 BN and N2 PAR rats, also showed large variations of the CD3+ T-cell frequency. The phenotype of variable CD3+ T-cell frequency mapped to the telomeric region of chromosome 1 (RNO1), which is identical with the already known Iddm8 diabetes susceptibility region. The data indicate that a variable CD3+ T-cell frequency in PBLs is genetically linked to diabetes susceptibility in the LEW.1AR1-iddm rat.ConclusionThe T-cell variability in PBLs could be related to the previously reported imbalance between regulatory and effector T-cell populations which results in beta-cell autoimmunity. Since similar T-cell phenotypes have also been described in human T1DM the identification of the functional role of the observed variable CD3+ T-cell frequency may help to understand the mechanisms of autoimmunity in T1DM.
Highlights
Type 1 diabetes mellitus (T1DM) is a multifactorial disease in which a predisposing genetic background as well as environmental factors lead to an autoimmune destruction of the pancreatic beta cells [1]
Strain LEW.1AR1 The percentage of CD3+ T-cells in peripheral blood lymphocytes (PBLs) within the LEW.1AR1 background population varied between 63% and 74% (mean 6 SEM: 6961%, CV: 5.3) (Fig. 1A)
The percentage of CD3+ T-cells in PBLs within the diabetic LEW.1AR1-iddm group was in the range of 34% to 63% (5161%, p,0.001, CV: 15.8), while within the non-diabetic LEW.1AR1iddm group this value varied between 36% and 80% (5962%, p,0.02, CV: 22.9)
Summary
Type 1 diabetes mellitus (T1DM) is a multifactorial disease in which a predisposing genetic background as well as environmental factors lead to an autoimmune destruction of the pancreatic beta cells [1]. Animal models play an important role for the understanding of the pathogenesis of T1DM because they permit combining genetic and functional characterisation of the syndrome [2]. The LEW.1AR1-iddm rat is a model for human T1DM, which arose through a spontaneous mutation in the intra-MHC recombinant inbred strain LEW.1AR1 (RT1r2, RT1-Aa, RT1-B/Du, RT1-Cu) [3]. This model shows an apoptotic beta-cell destruction, induced by proinflammatory cytokines released from islet infiltrating immune cells [4]. The MHC haplotype plays a pivotal role in permitting T1DM development [9]
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