Use of recombinant congenic and congenic strains of NOD mice to identify a new insulin-dependent diabetes resistance gene.

Serreze, David; Procházka, Michal; Reifsnyder, Peter C.; Bridgett, Margot M.; Leiter, Edward H.

doi:10.1084/jem.180.4.1553

Cited by 133 publications

(129 citation statements)

References 28 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…It was also found in the NOR strain, which has segments of B6 and DBA/2-derived chromosome regions on the NOD background; the NOR proximal mouse chromosome 11 containing segments derived from all of these strains. 18 The genotype data indicate that the region immediately surrounding Il12b in the NOR strain was derived from B6. Although they share most of their genome with NOD, NOR mice do not develop diabetes.…”

Section: Discussionmentioning

confidence: 97%

“…Although they share most of their genome with NOD, NOR mice do not develop diabetes. 18 It may be significant that these two strains differ in their Il12b alleles, given the importance of the product of this gene in regulating diabetes susceptibility. 2,12,13 It was quite striking that all other autoimmune-prone strains tested, including NZB, NZW, and SJL, with the exception of DBA/1, also shared the same Il12b allele as NOD.…”

Section: Discussionmentioning

confidence: 99%

“…No T1D susceptibility gene has as yet been mapped to the vicinity of Il12b in backcrosses of NOD mice with B6 19,20 or F2 crosses to NOR. 18 For example, the Idd4 gene 19 is on mouse chromosome 11 but was mapped to a region over 20 cM distal to the reported location 14 of Il12b. However, the B6 backcrosses would not have detected a NOD-dominant gene effect, while in the NOR crosses a potentially protective effect of the NOR allele may not be sufficiently strong to be detected in the presence of all the other susceptibility alleles shared between the NOD and NOR strains.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

et al. 2002

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

et al. 2002

View full text Add to dashboard Cite

show abstract

“…A recombinant congenic strain, which is NOD-resistant (NOR) and derives *88% of its genome from the NOD strain, including the I-A g7 MHC haplotype, was produced adventitiously at the Jackson Laboratory [14], and can be used as a control strain, since NOR mice are insulitis resistant and diabetes free. At least five major genetic regions, designated insulin-dependent diabetes (Idd) 4, 5, 9, 11, 13, differ between the NOD and NOR strains [15,16]. Multiple immune-related genes involving different biological functions, from antigen processing and presentation to T cell activation, migration and apoptosis, have been suggested as candidates for these Idd loci [17].…”

Section: Introductionmentioning

confidence: 99%

“…At least five major genetic regions, designated insulin-dependent diabetes (Idd) 4, 5, 9, 11, 13, differ between the NOD and NOR strains [15,16]. Multiple immune-related genes involving different biological functions, from antigen processing and presentation to T cell activation, migration and apoptosis, have been suggested as candidates for these Idd loci [17].…”

Section: Introductionmentioning

confidence: 99%

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

Dai¹,

Jensen²,

Marrero³

et al. 2008

Eur J Immunol

View full text Add to dashboard Cite

A diabetes-associated peptide in the glutamic acid decarboxylase 65 (GAD65) molecule, p524-543, activates two distinct populations of T cells, which apparently play opposite roles in the development of diabetes in NOD mice. By comparing the fine specificity of these two T cell repertoires using a nested set of truncated peptides that cover the p524-543 region, we found, surprisingly, that all clones recognized the same core within this peptide, p530-539. The core itself was non-immunogenic, but the residues flanking this shared sequence played the crucial role in selecting T cells to activate. A peptide missing N-terminal flanking residues at position 528 and 529 was stimulatory in NOD but not in MHC-matched, NODresistant (NOR) mice, suggesting that a protective response in the resistant mice may require T cell recognition of one or more of the N-terminal flanking residues. T cell repertoire studies demonstrated selective clonal expansions within the BV4 TCR family that dominates the p524-543 response in NOD but not in NOR mice. These data suggest that processing or trimming events affecting T cell recognition of very few flanking residues of diabetes-associated determinants might be involved in the protective response in NOR mice.Key words: Antigens/peptides/epitopes Á Autoimmune Á GAD65 Á T cell repertoire IntroductionProcessing and presentation of islet antigens on I-A g7 molecules is a crucial aspect in the emergence of spontaneous type 1 diabetes (T1D) in NOD mice. How the peptide-binding motif of I-A g7 relates to the selection and processing of peptide determinants and subsequent repertoire choice in this mouse strain and its related strains remains unresolved. Several autoantigens have been defined in type 1 diabetes (T1D) using antigen-specific antibody and/or T cell assays, including glutamic acid decarboxylase 65 (GAD65), proinsulin and insulin, insulinoma-like antigen 2 (IA-2), and insulin-specific glucose-6-phosphatase catalytic subunitrelated protein (IGRP). In NOD mice, several peptides from these autoantigens have been identified as targets of T cell responses. These include GAD65 p524-543 and p246-266 [1, 2], GAD65 p206-220 and p286-300 [3], insulin B chain p9-23 [4,5], proinsulin p24-33 (proinsulin II p48-57) [6],, and insulin-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) p206-214 [8]. Extensive analysis of TCR BV gene usage and CDR3 sequences have demonstrated that the early islet-infiltrating T cell clonal expansion is restricted to distinct BV families, e.g., BV4 [9], BV2, BV12, BV14 [10], BV13 [11], BV8.2 [12], and BV1 [13]. This indicates that selective clonal expansion of antigen-specific T cells is one characteristic of the initial inflammatory response in the islets. A recombinant congenic strain, which is NOD-resistant (NOR) and derives *88% of its genome from the NOD strain, including the I-A g7 MHC haplotype, was produced adventitiously at the Jackson Laboratory [14], and can be used as a control strain, since NOR mice are insulitis resistant and diabetes ...

show abstract

The NOD Mouse: A Model for Insulin‐Dependent Diabetes Mellitus

Leiter

1997

CP in Immunology

107

View full text Add to dashboard Cite

Nonobese diabetic (NOD) mice spontaneously develop autoimmune T cell-mediated insulin-dependent diabetes mellitus (IDDM). This unit presents a protocol for maintaining NOD mice under conditions permissive to full expression of their autoimmune potential. Methods are also described for diagnosing IDDM on the basis of glycosuria and glycosemia as well as for the semiquantitation of insulitis, a valuable subphenotype diagnostic of prediabetes in these mice, including a procedure for aldehyde fuchsin staining to identify beta granules in beta islet cells for diagnostic purposes. An adoptive-transfer method is also included in which leukocytes, purified T cells, or T cell infiltrates obtained from the insulitic pancreas tissue of NOD mice are injected into prediabetic NOD or diabetes-resistant F1 mice, which then develop disease in an accelerated fashion. This protocol also includes alternative steps in which bone-marrow cells from NOD mice are transferred to syngeneic, irradiated NOD mice, allowing for reconstitution with a diabetogenic immune system. Steps for isolating pancreatic islet cells, which can then be used for a variety of purposes (e.g., as a source of islet antigens to establish and maintain autoreactive T cell lines) are included. Finally, steps are outlined that can be used to introduce transgenes into NOD mice. This protocol also discusses important considerations for introduction of targeted mutations produced in embryonic stem cells derived from other inbred strains, or introduction of other genes from non-diabetes-prone strains.

show abstract

Use of recombinant congenic and congenic strains of NOD mice to identify a new insulin-dependent diabetes resistance gene.

Cited by 133 publications

References 28 publications

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains

N‐terminal flanking residues of a diabetes‐associated GAD65 determinant are necessary for activation of antigen‐specific T cells in diabetes‐resistant mice

The NOD Mouse: A Model for Insulin‐Dependent Diabetes Mellitus

Contact Info

Product

Resources

About