Adenovirus E3 MHC inhibitory genes but not TNF/Fas apoptotic inhibitory genes expressed in β cells prevent autoimmune diabetes

Abstract

To mimic events and molecules involved in type 1 insulin-dependent diabetes mellitus (T1D), we previously designed a transgenic (tg) mouse model where the viral nucleoprotein (NP) gene of lymphocytic choriomeningitis virus (LCMV) was expressed in the thymus to delete high affinity antiself (virus) T cells and in insulin-producing ␤ cells of the islets of Langerhans. Such tg mice, termed RIP-LCMV, fail to spontaneously develop diabetes. In contrast, when these mice are challenged with LCMV, they develop diabetes as they display hyperglycemia, low to absent levels of pancreatic insulin, and abundant mononuclear cell infiltrates in the islets. However, expressing the adenovirus early region ( adenovirus E3 regulatory region ͉ Type 1 diabetes T ype 1 diabetes (T1D) results from destruction of insulinproducing ␤ cells located in the pancreatic islets of Langerhans. Most often destruction of ␤ cells occurs over a prolonged period, and disease is characterized by hyperglycemia, hypoinsulinemia, and mononuclear cell infiltration in the islets. To dissect the molecular and biologic events involved, we created a transgenic (tg) mouse model of T1D inducible by virus infection, where a unique protein of that virus was expressed in the thymus and in the ␤ cells of the islets of Langerhans. As the virus transgene was passaged in the germ line of progeny mice, the mouse immune system treated the viral protein as a self antigen. Such unmanipulated mice had a negligible spontaneous incidence of T1D of less than 1% over their normal life span (1, 2). However, when immunologic tolerance to the virus (self) protein was broken by infection with the virus or a different virus that shared cross-reactive T cell epitopes, diabetes developed with an incidence of Ͼ90% within 1 to several months depending on the host's genetic background (1-5). Such mice displayed the triad of hyperglycemia, hypoinsulinemia, and mononuclear cell infiltrates in the islets.

Molecular Anatomy and Number of Antigen Specific CD8 T Cells Required to Cause Type 1 Diabetes

“…As anticipated from our prior reports [12], [25], [28], [29], inoculation of RIP-LCMV GP tg mice with 1×10 5 PFU of LCMV ARM i.p. induced T1D in all mice (Fig.…”

Extraneural manifestations of prion infection in GPI-anchorless transgenic mice

“…Plasma glucose was determined using a One-Touch Ultra glucose meter (Life Scan) as reported (Horwitz et al, 2009). Glucose tolerance tests were performed on mice deprived of food for 18 hours.…”

A unique secreted adenovirus E3 protein binds to the leukocyte common antigen CD45 and modulates leukocyte functions

“…For example, E3/19K retains MHC class I molecules and MHC class I-related chain A and B in the endoplasmic reticulum of infected cells, thereby suppressing recognition by cytotoxic T lymphocytes (13)(14)(15) and activation of natural killer (NK) cells (16,17). Other common E3 proteins (E3/10.4K-14.5K) down-regulate various apoptosis receptors from the cell surface or affect TNF-α-induced signaling (9,18,19).…”