Protection From Type 1 Diabetes in the Face of High Levels of Activated Autoaggressive Lymphocytes in a Viral Transgenic Mouse Model Crossed to the SV129 Strain

Abstract

In comparing the incidence of virally induced type 1 diabetes in F 1 crosses of RIP-LCMV mice to three different mouse strains identical at the major histocompatibility complex H-2D b locus, we surprisingly found that disease development was reduced by 80% in F 1 crosses to the SV129 genetic background and by 60% after eight backcrosses to the original C57BL/6 RIP-LCMV mice. In this model, diabetes is strongly dependent on a virally induced H-2D b -restricted cytotoxic T-cell (CTL) response. Importantly, numbers and effector functions of autoaggressive CD4 and CD8 lymphocytes were not decreased in the protected mice, and CTLs were still able to kill syngeneic islet cells in vitro with equal efficacy compared with CTLs from the original RIP-LCMV strain. Furthermore, CTLs were able to extravasate into islets in vivo, and no evidence for induction of regulatory cells was observed. However, regeneration of ␤-cells in islets under "attack" occurred only in the protected SV129-crossed animals, whereas it was not evident at any time in any mice that developed diabetes. Thus, genetic factors can "override" the diabetogenic potential of high numbers of autoaggressive lymphocytes through, for example, increased islet regeneration. This finding has important implications for interpreting numbers and pathogenicity of autoreactive lymphocytes in prediabetic patients of genetically diverse backgrounds.

A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes

“…This experiment was repeated three times and mean values (± SEM) are displayed. *P < 0.05. onic stem cells from knockout lines are known to protect from T1D in RIP-LCMV mice (42). In contrast to RIP-LCMV-NP × K b (+) littermates, RIP-LCMV-NP × K b (-) mice did not have accelerated T1D after secondary PV infection.…”

Recovery of Islet β-Cell Function in Streptozotocin- Induced Diabetic Mice

“…In the RIP-LCMV model of autoimmune diabetes, von Herrath et al (46) reported that the ability to resist the development of diabetes differed drastically between the 129 and the C57BL/6 strain, and they speculated that this difference was the result of differences in the abilities of these two strains of mice to regenerate ␤-cells. It has also been reported that partial pancreactectomy enhanced resistance to STZ-induced diabetes (11) and that neonatal rats are able to spontaneously recover from STZ-induced diabetes (47).…”

“…Measurement of intracellular calcium concentration. Dual-wavelength excitation spectrophotometry was used to measure intracellular calcium concentration ([Ca 2ϩ ] i ) as described previously (46). Briefly, isolated pancreatic islets were loaded with Fura-2 by a 25-min incubation at 37°C in Krebs-Ringer buffer containing 2 mmol/l glucose and 5 mol/l Fura 2-AM (Molecular Probes, Eugene, OR).…”

Soluble Factors Secreted by T Cells Promote β-Cell Proliferation

“…For example, Sreenan et al (4) have reported increased β-cell proliferation in NOD mice that exhibit infiltration of pancreatic islets prior to the onset of diabetes. In addition, von Herrath et al (5) reported that nondiabetic RIP-LCMV x SV129 mice, where the numbers and effector functions of autoaggressive CD4 + and CD8 + lymphocytes were not decreased, have increased β-cell regeneration compared with nondiabetic C57BL/6 controls. In other studies, Sherry et al (6) suggested the increased β-cell proliferation that occurs after arresting the autoimmune process is secondary to effects of the inflammatory infiltrate.…”