Cellular Requirements for Diabetes Induction in DO11.10xRIPmOVA Mice

Abstract

Type 1 Diabetes (T1D3) results from the immune-mediated destruction of the insulin producing β-islet cells in the pancreas. The genetic and environmental mechanisms promoting the development of this disease remain poorly understood. We have explored the cellular requirements for T1D development in DO11.10xRIP-OVA (DORmO) mice, which carry a T cell receptor transgene specific for an MHC class II-restricted epitope from ovalbumin (OVA) and express membrane-bound OVA in the pancreas under the control of the rat insulin promoter. We found that DORmO.RAG2−/− mice do not develop insulitis and are completely protected from diabetes, demonstrating that endogenous lymphocyte receptor rearrangement is required for disease development. Diabetes in DORmO mice is preceded by the development of OVA-specific autoantibodies, and is delayed in B cell-deficient DORmO.JHD−/− mice, demonstrating that B cells contribute to disease progression. In addition, transfer of CD8+ T cells from diabetic animals into DORmO.RAG2−/− mice promoted insulitis by OVA-specific CD4+ T cells. Finally, although diabetes develops in DORmO mice in the presence of a significant population of Foxp3+ OVA-specific regulatory T cells, boosting regulatory T cell numbers by injecting IL-2 immune complexes dampens autoantibody production and prevents development of insulitis and overt diabetes. These results help define the events leading to diabetes in DORmO mice, and provide new insights into the cellular interactions required for disease development in an antigen-specific model of T1D.

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

“…Of note, this treatment was initiated when the mice were 8 weeks of age, at which time insulitis is typically well established in DORmO mice. This is a strong, protective phenotype in a model in which the incidence of autoimmune diabetes is typically 100% (13). Furthermore, a short 1-week course of 4-MU treatment was sufficient to prevent diabetes progression in the canonical mouse model of T1D, the NOD mouse.…”

“…They carry a T cell receptor transgene specific for OVA (emulating autoreactive CD4 + T cells), while simultaneously expressing OVA in conjunction with the insulin gene promoter on pancreatic β cells (emulating the autoantigen). DORmO mice spontaneously develop autoimmune insulitis starting at 4 weeks of age, with nearly 100% becoming diabetic by 20 weeks of age (13).…”

Control of Regulatory T Cell Migration, Function, and Homeostasis

“…As a result, the effectiveness of IL-2 in treating disease in pre-clinical models of autoimmunity had varied greatly depending on the dose and timing of administration (68). Whereas low-doses of IL-2 given prior to or early in disease have proven effective, higher-doses of IL-2 given later have actually exacerbated or accelerated disease development (67, 69, 70). To circumvent this issue, IL-2 can be combined with immunosuppressive agents such as rapamycin that selectively inhibit effector T cell proliferation and function.…”

Prevention of experimental diabetes by Uncaria tomentosa extract: Th2 polarization, regulatory T cell preservation or both?

“…The tight association between pancreatic infiltration of the major orchestrators of ␤-cell damage, such as auto-reactive CD4 + and CD8 + lymphocytes, and destruction of insulin-secreting ␤-cell was recently reported (Wesley et al, 2010). Immune-mediated diabetes has been classically described as a predominant Th1 mediated disease, characterized by an elevated production of IFN-␥ Fig.…”