NOD.B6-(D1Mit18-D1Mit445)(D11Nds1-D11Mit41)/DelJ

Stock number: 005311
Product name: NOD.Idd4A
Research areas: Diabetes and Obesity Research, Immunology, Inflammation and Autoimmunity Research

Description

Mice of this strain display resistance to diabetes.

Detailed description

The donating investigator reports diabetes onset of female NOD.B6-(D1Mit18-D1Mit445) (D11Nds1-D11Mit41)/DelJ (commonly called NOD.B6-Idd4A, Chromosome 11, 43.8-49cM) is delayed, with 15% of the females and 5% of the males becoming diabetic by 30 weeks of age. In the same colony, diabetes rates in NOD controls are 75% in females and 45% in males by 30 weeks of age. Histological examination of 12-week-old NOD.B6-Idd4A mice indicates 70% of the islets are normal compared with 50% in NOD controls. At 25-30 weeks of age, 10% of NOD.B6-Idd4A islets are infiltrated compared to 80% in NOD controls. Until 25-30 weeks of age, NOD.B6-Idd4A mice only develop periductal infiltrates with mild non-destructive insulitis. Additionally, immunohistochemical assays indicate normal amounts of stored insulin. Purified splenic T-cells from 12-week-old, non-diabetic NOD.B6-Idd4A females alone are able to induce diabetes in NOD.Prkdc^scid female recipients. Diabetes onset is slightly delayed in recipients of NOD.B6-Idd4A T-cells only, with 50% becoming diabetic by 70 days post transfer compared to 80% diabetic in recipients receiving either diabetic NOD T-cells alone or recipients co-transferred with diabetic NOD/ non-diabetic NOD.B6-Idd4A T-cells.TCR stimulated T-cell proliferative responses or anti-CD3 stimulated splenic T-cells express CD69, CD25, and produce IL2 at similar levels to NOD controls, while producing more IL4 and less interferon gamma than NOD controls (Grattan et al. 2002). 005311 incidence study and fine mapping data.

Surprisingly, Genetic Quality Control completed at the Jackson Laboratory indicates Chromosome 1 markers in the Idd5 region are of C57BL/6 origin and QC of Idd4 congenic stocks.

The reported conclusion of diabetes resistance has been re-evaluated since the C57BL/6 contaminating genome on Chromosome 1 has been eliminated in Stock No. 006809. Diabetes incidence studies performed at The Jackson Laboratory show an accelerated onset and incidence of diabetes in Stock No. 006809 females when compared with NOD/ShiLtJ controls and the original Stock No. 005311, while the diabetes onset and incidence in males is accelerated compared to the original Stock No. 005311 and is slightly less compared to NOD/ShiLtJ controls. 006809 incidence study and fine mapping data.

This strain may be useful for identifying genes involved with diabetes resistance located within the Idd4 region of Chromosome 11.

Development

The three Idd4 subloci map to Chr. 11. Chr. 11 genomic segments from C57BL/6 were transferred to NOD by outcross to an NODxC57BL/6J F2 mouse followed by 3 backcross cycles to NOD/Del with selection for B6 markers on Chr 11 prior to inbreeding. T.L. Delovitch established three congenic strains based on their congenic intervals, D11Nds1-D11Mit325 (43.8-49cM), D11Mit38-D11Mit325 (49cM) and D11Mit38 (49cM). The 5.2cM region located between D11Nds1 - D11Mit325 of Chr 11 is known to contain Nos2 (45.6cM) Mpmv4 (48cM), Xmv42 (53cM), Mpo, (49cM, D11Mit38) and the beta-chemokine gene family, including, Ccl1 (Tcr3, 47cM), Ccl2(Mcp1, 46.5cM), Ccl3 (Mip1a, 47.59cM), Ccl4 (Mip1b, 47.6cM) (Gill et al, 1995 and Grattan et al, 2002). Additional microsatellite analysis confirm all other known Idd's are NOD in origin (Grattan, et al., 2002). In 2005, The Jackson Laboratory received NOD.B6-(D11Nds1-D11Mit325)/DelJ (NOD.Idd4A) at generation N3F18.

Genetic Quality Control data completed at the Jackson Laboratory indicates the following Chromosome 11 markers are of B6 origin: D11Nds1 (43.8cM), D11Mit245 (44.8cM), D11Mit325 (49cM), D11Mit38 (49cM) and D11Mit41 (49cM), while D11Mit339 (31.7cM) and D11Mit358 (52.5cM) are of NOD origin. Surprisingly, Chromosome 1 markers (Idd5 region) of C57BL/6 origin include: D1Mit18 (29.7cM), D1Mit180 (41cM), D1Jmp12 (47-51.4cM), D1Jmp23 (54.6cM) and D1Mit445 (70cM), while D1Mit411 (18.5cM), D1Mit143 (86.6cM) and D1Mit26 (62.1cM) are of NOD origin.

Allele

Symbol: Idd4^C57BL/6
Name: C57BL/6
MGI accession ID: MGI:3036666
Generation method: QTL
Marker symbol: Idd4
Marker name: insulin dependent diabetes susceptibility 4
Chromosome: 11
Strain of origin: C57BL/6
Molecular note: This allele confers increased T-cell proliferation compared to DBA/2 and NOD.

Allele

MGI accession ID: MGI:89125
Marker symbol: D11Mit41
Marker name: DNA segment, Chr 11, Massachusetts Institute of Technology 41
Chromosome: 11

Allele

MGI accession ID: MGI:101974
Marker symbol: D1Mit445
Marker name: DNA Segment, Chr 1, Massachusetts Institute of Technology 445
Chromosome: 1

Allele

MGI accession ID: MGI:91556
Marker symbol: D1Mit18
Marker name: DNA segment, Chr 1, Massachusetts Institute of Technology 18
Chromosome: 1

Allele

MGI accession ID: MGI:89264
Marker symbol: D11Nds1
Marker name: DNA segment, Chr 11, Nuffield Department of Surgery 1
Chromosome: 11