Disease relevance of Mice, Inbred NOD

• In an attempt to protect nonobese diabetic mice (NOD) from autoimmune diabetes, we made FasL transgenic NOD mice using the beta cell-specific rat insulin-1 promoter [1].
• Immune deviation of T-cell responses to the beta-cell autoantigen glutamate decarboxylase (GAD65), induced an active form of self-tolerance that was associated with an inhibition of disease progression in prediabetic mice and prolonged survival of syngeneic islet grafts in diabetic NOD mice [2].
• Spontaneous diabetes mellitus was blocked in nonobese diabetic mice by treatment with a monoclonal antibody against the L3T4 determinant present on the surface of T-helper lymphocytes [3].
• Development of spontaneous autoimmune peripheral polyneuropathy in B7-2-deficient NOD mice [4].
• By using such reassortants and both parental strains of virus to infect NOD mice, the prevention of IDDM was mapped to the S RNA segment of LCMV Pasteur [5].

Psychiatry related information on Mice, Inbred NOD

• A short-term administration of antibodies against ICAM-1/LFA-1 or CD8 molecules during a critical period of younger age resulted in complete protection of autoimmune diabetes in NOD mice [6].

High impact information on Mice, Inbred NOD

• We show that islet-associated CD8+ T cells in nonobese diabetic mice recognize numerous IGRP epitopes, and that these cells have a role in the outcome of protocols designed to induce IGRP206-214-specific tolerance [7].
• NKT cells are less frequent and display deficient IL-4 responses in both NOD mice and individuals at risk for T1D (ref. 8), and this deficiency may lead to T1D (refs. 1,6-9) [8].
• Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells [9].
• These in vitro-generated islets showed temporal changes in mRNA transcripts for islet cell-associated differentiation markers, responded in vitro to glucose challenge, and reversed insulin-dependent diabetes after being implanted into diabetic non-obese diabetic mice [10].
• Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice [11].

Chemical compound and disease context of Mice, Inbred NOD

• These observations provide strong evidence for a dacryoadenitis-promoting role of male gonadal hormones in NOD mice, a finding that contrasts the known androgen-mediated protective effects on insulitis and submandibulitis in the same strain and on dacryoadenitis in other animal models of Sjögren's syndrome [12].
• After transplantation of bone marrow plus newborn pancreas, NOD mice showed reduction of the glycosuria and a normal response in the glucose-tolerance test [13].
• Tolerance to IDDM induced by CD4 antibodies in nonobese diabetic mice is reversed by cyclophosphamide [14].
• Nicotinamide, a derivative of the B vitamin niacin, is currently under trial for the prevention of insulin-dependent diabetes mellitus after success in the NOD mouse [15].
• We, therefore, conclude that prevention of autoimmune diabetes by linomide is associated with up-regulation of the p21(ras) T cell signal transduction defect in NOD mice [16].

Biological context of Mice, Inbred NOD

• Two unusual features of the class II major histocompatibility complex (MHC) of the NOD mouse are the absence of I-E and the presence of unique I-A molecules (I-ANOD), in which aspartic acid at position 57 of the beta-chain is replaced by serine [17].
• Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain [18].
• Furthermore, beta cell apoptosis was necessary for protection since SZ did not protect RIP-CrmA transgenic NOD mice in which beta cells expressed the caspase inhibitor CrmA [19].
• We have cloned and expressed an alternatively spliced form of CTLA-4 that has genetic linkage with type I diabetes in the NOD mice [20].
• The similarity of the DQ8, DQ2 and I-A(g7) peptide-binding pockets suggests that diabetes is caused by the same antigen-presentation event(s) in humans and NOD mice [21].

Anatomical context of Mice, Inbred NOD

• Furthermore, NOD mice receiving intrathymic injections of GAD65 exhibit markedly reduced T-cell proliferative responses to GAD and to the rest of the panel, in addition to remaining free of diabetes [11].
• Insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice results from the T-lymphocyte-mediated destruction of the insulin-producing pancreatic beta-cells and serves as a model for human IDDM [22].
• Progression to destructive insulitis in nonobese diabetic (NOD) mice is linked to the failure of regulatory cells, possibly involving T helper type 2 (Th2) cells [23].
• CD4+ T cell lines were generated from the spleens of diabetic NOD mice against crude membrane preparations derived from a rat insulinoma [24].
• Expression of diabetes-resistant MHC class II I-Abeta chain molecules in NOD mice following retroviral transduction of autologous bone marrow hematopoietic stem cells prevented the development of autoreactive T cells by intrathymic deletion and protected the mice from the development of insulitis and diabetes [25].

Associations of Mice, Inbred NOD with chemical compounds

• I-Ag7 lacks this aspartate and is the only class II allele expressed by the nonobese diabetic mouse [26].
• In contrast with spleen cells from 6-mo-old naive NOD mice which transfer diabetes in irradiated 8-mo-old male recipients, spleen cells from age-matched NOD mice which received a single injection of alloxan at 3 wk of age did not transfer diabetes [27].
• Androgen treatment prevents diabetes in nonobese diabetic mice [28].
• A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice [29].
• The non-obese diabetic (NOD) mouse spontaneously develops autoimmune insulitis and diabetes which can be accelerated and synchronized by a single injection of cyclophosphamide [30].

Gene context of Mice, Inbred NOD

• In sharp contrast, spontaneous diabetes is exacerbated in both B7-1/B7-2-deficient and CD28-deficient NOD mice [31].
• Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor [32].
• NOD mice were also treated with mAbs to another CD28 ligand, B7-1 [33].
• Most significant, however, is the co-localization of Aod2 to Idd3, a susceptibility gene that plays a role in autoimmune insulin-dependent type 1 diabetes mellitus in the nonobese diabetic mouse [34].
• PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice [35].

Analytical, diagnostic and therapeutic context of Mice, Inbred NOD

• The non-obese diabetic mouse is a good spontaneous animal model of the human disease, with IDDM developing in 50-80% of female mice by the age of 6 months [36].
• Tim-3 pathway blockade accelerated diabetes in nonobese diabetic mice and prevented acquisition of transplantation tolerance induced by costimulation blockade [37].
• Adoptive transfer of splenocytes of NOD-RGP-TGF-beta1 mice to neonatal NOD mice did not transfer diabetes after CY administration [38].
• Immunotherapy with a high-affinity mimicry peptide targeting ICA69-specific T-cells reduced established Sjögren's syndrome in wild-type NOD mice in the long term [39].
• Combined treatment with nicotinamide and desferrioxamine prevents islet allograft destruction in NOD mice [40].

References