It can be induced by as disparate means as tuberculin antigen administration, by interleukin-4 treatments, by transfer of T-cell lines generated in autologous mixed lymphocyte responses, and by immunization to insulin B-chain, whereas oral islet cell antigens, such as insulin, can delay diabetes onset in the NOD mouse.(ABSTRACT TRUNCATED AT 250 WORDS)
G6pc2(-/-) mice were generated on the NOD/ShiLtJ genetic background, and glycemia was monitored weekly up to 35 weeks of age to determine the onset and incidence of diabetes.
While both isoforms of glutamic acid decarboxylase (GAD) function as important autoantigens in autoimmune diabetes mellitus-GAD65 in humans and GAD67 in the NOD mouse-GAD67 is not synthesized in human pancreatic islets and is thought not to be an autoantigen in human diabetes.
Because type 1 diabetes is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse, we investigated the role of the vitamin D receptor (VDR) gene as a candidate for type 1 diabetes susceptibility.
As proof of concept, we report that diabetes is completely suppressed in a knock-in NOD strain with a serine to aspartic acid substitution at position 57 in the MHC class II Aβ.
First, to see which immunomodulating molecule-secreting islet grafts can most powerfully prevent diabetes development in NOD mice without immunosuppressant, NOD islets were transfected with one of the following adenoviral vectors: Ad.IL-12p40, Ad.TGF-beta, Ad.CTLA4-Ig, or Ad.TNF-alpha after which they were transplanted under the renal capsule of acutely diabetic NOD mice.
Subsequent analyses found syngeneic splenocytes bearing the combination of the two ECDI-coupled IGRPs but not INS peptides (IGRP-SPs or INS-SPs) effectively inhibited diabetes development in NOD.β2m(null).HHD mice.
NOR mice are insulitis resistant and diabetes free despite genetic identity with NOD at numerous chromosomal regions containing previously described insulin-dependent diabetes (Idd) genes, including the strongly diabetogenic H2g7 major histocompatibility complex (MHC) haplotype.
Thus, CD11c(+)CD11b(+) DC and pDC have countervailing actions in NODdiabetes, with myeloid DC providing critical antigenic stimulation to naive CD4(+) T cells and pDC providing regulatory control of CD4(+) T cell function in the target tissue.
We conclude that IA-2beta is involved in insulin secretion, but despite its importance as a major autoantigen in human type 1 diabetes, it is not required for the development of diabetes in NOD mice.
We found that the CD19+IgM+ cell is the primary subpopulation of B cells that delayed transfer of diabetes mediated by diabetogenic T cells from NOD mice (P = 0.002).
In the resulting 3A9 TCR:iHEL NOD.H2(k)-Chr12 mice, we observed a significant decrease in diabetes incidence as well as a decrease in both the quantity and affinity of HEL-specific IgG autoantibodies relative to 3A9 TCR:iHEL NOD.H2(k) mice.
Despite the well known role of nucleotide oligomerization domain (NOD) receptor proteins in innate immunity, their association with diabetes is less explored.
This was demonstrated by greater ability to cause recurrent diabetes in NOD-RIP-CD86 diabetic mice transplanted with 6-wk-old NOD islets and adoptively transferred diabetes from diabetic NOD-RIP-CD86 mice to NOD.scid mice.
Because exogenous IL-4 and IL-10 exert antidiabetogenic effect in NOD mice and early blockade of endogenous tumor necrosis factor-alpha prevents NOD mouse diabetes, these phenomena may be causally related to the antidiabetogenic effect of HGG-pulsed DC treatment.