LEW.1WR1 Rats Develop Autoimmune Diabetes Spontaneously and in Response to Environmental Perturbation

Abstract

We describe a new rat model of autoimmune diabetes that arose in a major histocompatibility complex congenic LEW rat. Spontaneous diabetes in LEW.1WR1 rats (RT1 u/u/a ) occurs with a cumulative frequency of ϳ2% at a median age of 59 days. The disease is characterized by hyperglycemia, glycosuria, ketonuria, and polyuria. Both sexes are affected, and islets of acutely diabetic rats are devoid of ␤-cells, whereas ␣-and ␦-cell populations are spared. The peripheral lymphoid phenotype is normal, including the fraction of ART2 ؉ regulatory T-cells. We tested the hypothesis that the expression of diabetes would be increased by immunological perturbation of innate or adaptive immunity. Treatment of young rats with depleting anti-ART2.1 monoclonal antibody increased the frequency of diabetes to 50%. Treatment with the toll-like receptor 3 ligand polyinosinic:polycytidylic acid increased the frequency of diabetes to 100%. All diabetic rats exhibited end-stage islets. The LEW.1WR1 rat is also susceptible to collagen-induced arthritis but is free of spontaneous thyroiditis. The LEW.1WR1 rat provides a new model for studying autoimmune diabetes and arthritis in an animal with a genetic predisposition to both disorders that can be amplified by environmental perturbation. Diabetes 54: 2727-2733, 2005

Prevention of Virus-Induced Type 1 Diabetes with Antibiotic Therapy

“…Infection of rats with Kilham rat virus (KRV) leads to T1D within 2-4 wk after viral inoculation in 50% of the infected rats (22). LEW1.WR1 rats have normal T lymphocyte levels and function (23), and the disease is characterized by a selective loss of islet b cells, glycosuria, ketonuria, and polyuria (23,24). We recently hypothesized that the innate immune system plays a key role in virus-induced T1D (25,26), and demonstrated that TLR-mediated innate immune activation synergizes with viral infection to promote disease induction (26).…”

The Role of Toll-Like Receptor Pathways in the Mechanism of Type 1 Diabetes

“…For example, upregulation of TLR3 and RLH pathways with Poly I:C induces diabetes in PVG, WAG, and WF rats [ 190,191], with PVG rats the most susceptible to disease induction [191]. Of note, breaking immunological tolerance in these animals requires repeated activation of the innate immune system over a period of two weeks and sometimes the use of relatively high doses of Poly I:C [190][191][192][193], probably due to the presence of low frequencies of beta cell-specific T cells [180]. The induction of diabetes by TLR3 upregulation is thought to be controlled by iddm4 [192], is restricted to strains expressing Class II u molecules and is not evident in rats expressing Class II a or Class II c [191], consistent with the critical role of Class II antigens in human diabetes [54,61].…”

Innate immunity in type 1 diabetes

“…We have therefore used the biobreeding diabetes resistant (BBDR) and LEW1.WR1 rat models to delineate how infection with Kilham rat virus (KRV) leads to islet destruction. These animals have normal Tcell proportions and function [16]. Disease triggered by KRV is immune mediated, as diabetes can be prevented by a treatment with antibodies directed against the Tcell receptor, CD5, and CD8 [17,18], and the transfer of spleen cells from virus-infected rats to class II u compatible rats adoptively transfers insulitis and diabetes [17,18].…”

“…Disease triggered by KRV is immune mediated, as diabetes can be prevented by a treatment with antibodies directed against the Tcell receptor, CD5, and CD8 [17,18], and the transfer of spleen cells from virus-infected rats to class II u compatible rats adoptively transfers insulitis and diabetes [17,18]. Infection with KRV leads to insulitis and diabetes characterized by selective loss of islet beta cells (Figure 1), glycosuria, ketonuria, and polyuria in the LEW1.WR1 and BBDR rats, but not other rat strains [16][17][18][19][20]. Susceptibility to virus-induced diabetes is dependent on the presence of class I A u and class II B/D u [17,18].…”