C.Cg-Tg(Ins2-NP)25-3Olds/MvhJ

Stock number: 004827
Product name: BALB.RIP NP
Research areas: Diabetes and Obesity Research, Immunology, Inflammation and Autoimmunity Research, Research Tools

Description

These BALB.RIP NP mice express a transgene containing the nucleoprotein from Armstrong's clone of the lymphocytic choriomeningitis virus (LCMV), and develop IDDM after challenge with LCMV. BALB.RIP NP mice show a slower onset of IDDM than B6.RIP NP (Stock No. 004826) when challenged with LCMV.

Detailed description

Transgenic mice were created with the Lymphocytic choriomeningitis virus (LCMV) nucleoprotein(NP) or glycoprotein(GP) under the control of the rat insulin promoter. Northern blot analysis identifies a 3kb band expected of the transgene and SV40 processing signals in the pancreas (Oldstone et al., 1991). Ins2-NP expression was determined in the pancreas and thymus by RT-PCR (von Herrath et al 1994). Tg(Ins2-NP)25-3Olds untreated mice rarely develop insulin-dependent diabetes mellitus (IDDM). When challenged with LCMV they develop IDDM. The B6.Cg -Tg(Ins2-NP)25-3Olds mice (H2^b) exhibit a slower (30-120 days) onset of IDDM than the C.Cg-Tg(Ins2-NP)25-3Olds mice (H2^d) (10-21 days) or the B6.Cg-Tg(Ins2-GP) 34-20Olds mice (H2^b) (10-14 days) (Oldstone et al.,1991, Homann et al.,1999). Thymic expression of nucleoprotein has been shown to be responsible for this delayed onset of IDDM. Thymi from newborn B6.Cg-Tg(Ins2-NP)25-3Olds transplanted into hosts homozygous for Prkdc^scid fail to produce a primary CTL response when challenged with LCMV, although thymi transplanted from C.Cg-Tg(Ins2-NP)25-3Olds mice mount a response. CD8 T cells are required for IDDM development in both nucleoprotein and glycoprotein transgenic mice, as is interferon gamma. In interferon gamma deficient transgenicsstimulated with LCMV, CTLs were present in the pancreas and around the islets of Langerhans, but did not infiltrate the islets. Additionally, nucleoprotein transgenic animals require the presence of CD4 T cells. (von Herrath, et al, 1994 and 1997)

Diabetes can be prevented in the C.Cg-Tg(Ins2-NP)25-3Olds (H2^dmice after its induction by LCMV infection through oral insulin treatment and this model has proven that bystander suppression of autoaggressive CD8 T cells can occur in the pancreatic draining lymph node (Homann et al., 1999).

A single dose injection of anti CD80, anti CD86 or anti CD80/anti CD86 antibodies does not prevent LCMV induced diabetes in either the NP or GP transgenic mice. LCMV challenged GP transgenic mice are partially protected from diabetes by anti CD80 antibodies and completely protected by anti CD86 or anti CD80/CD86 antibodies injected daily for 14 days. However, LCMV challenged NP transgenic mice have accelerated diabetes onset when treated with anti CD80/CD86 antibodies injected daily for 14 days. LCMV induced diabetes is prevented in NP and GP transgenic mice treated with anti TNFRSF5 when treated within a defined time window. Splenocytes from these protected mice adoptively transferred disease resistance to LCMV- challenged pre diabetic GP transgenic mice. The cells thatconfer protection express ITGAX5, NK1.1 and DX5. The spleens of anti TNFRSF5 protected mice have an increased population of ITGAX5 expressing cells. When this population of cells is further fractionated into ITGAX5⁺, DX5⁺ cells, the recipient mice acquire protection from diabetes. (Homann et al., 2002)

Development

C.Cg-Tg(Ins2-NP)25-3Olds/MvhJ expresses the lymphocytic choriomeningitis virus (LCMV) nucleoprotein (NP) under control of the rat insulin promoter, (Ins2, commonly designated RIP). The transgene was first inserted by Oldstone, et al (1991) into C57BL/6 (H2^b) x Balb/WEHI (H2^d) F2 oocytes. Line 25-3, maintained by Herrath et al., (1994, 2000) has been backcrossed to BALB/c (H2^d) for at least 10 generations. This strain arrived at The Jackson Laboratory in 2003 and is maintained as hemizygous.

Allele

Symbol: Tg(Ins2-NP)25-3Olds
Name: transgene insertion 25-3, Michael BA Oldstone, MD
MGI accession ID: MGI:3573697
Generation method: Transgenic
Attributes: Inserted expressed sequence
Marker symbol: Tg(Ins2-NP)25-3Olds
Marker name: transgene insertion 25-3, Michael BA Oldstone, MD
Chromosome: UN
Strain of origin: C57BL/6 x BALB/c
Expressed genes: NP,lymphocytic choriomeningitis virus nucleoprotein,viral
Molecular note: This transgene encodes the nucleoprotein (NP) from Armstrong's clone of the lymphocytic choriomeningitis virus (LCMV) regulated by the rat insulin promoter. Upstream of the NP cDNA are 660 base pairs of regulatory elements in addition to the rat insulin promoter. Downstream of the NP c-DNA is the SV40 small T-antigen intron and late polyadenylation signal. A stable transcript of the expected size was present in the pancreas, as determined by Northern blot analysis. RT-PCR analysis demonstrated that the transcript was expressed in pancreas and thymus, but not the spleen, brain, liver, kidney, heart, muscle or lung. In a T cell recognition assay, LCMV-specific cytotoxic T lymphocytes were shown to migrate specifically to the islets of Langerhans of transgenic mice, but not in control mice.