I-E+ nonobese diabetic mice develop insulitis and diabetes.

Podolin, Patricia L.; Pressey, A; DeLarato, Nicole H.; Fischer, Paul; Peterson, Laurence B.; Wicker, Linda S.

doi:10.1084/jem.178.3.793

Cited by 117 publications

(110 citation statements)

References 56 publications

(92 reference statements)

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…Alternatively, the relatively greater resistance of B cells from autoimmunity-prone mice, particularly those of NOD mice, to depletion by anti-CD20 could be due to deficient Fc␥RI binding of IgG2a anti-CD20 and/or decreased numbers of splenic monocytes in NOD mice compared with C57BL/6 mice (38). Because NOD.H-2h4 mice differ from NOD mice only at the MHC locus (2,32), the defects in Fc␥R effector functions in NOD mice (38,41,42) are presumably also present in NOD.H-2h4 mice. The relative resistance of some splenic B cells to depletion by anti-CD20 in our studies might also be explained by the fact that some NOD.H-2h4 mice given anti-CD20 IgG2a generated an immune response against the variable domain of the IgG2a anti-CD20 Ab, because circulating anti-idiotypic Abs were detected in some mice (data not shown).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

B Cell Depletion Inhibits Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice

Dunn

Kehry

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

All NOD.H‐2h4 wild type (WT) mice given NaI water develop SAT, but B cell‐deficient (B−/−) mice are resistant. B cells presumably function as APC for activation of CD4+ T cells. B −/− mice develop SAT comparable to WT mice after transient depletion of T reg, suggesting T reg are preferentially activated if autoantigen is presented by non‐B cells. Anti‐CD20 or isotype control was given to young (1–2 wk) or adult (7 wk) WT mice; all mice were given NaI water at 8 wk, and SAT was evaluated 8 wk later. WT mice given anti‐CD20 at 1 and 2 wk of age developed minimal SAT, although B cells had repopulated by 6–8 wk of age. Transient depletion of T reg during B cell depletion reversed the effects of anti‐CD20, and all mice developed SAT. SAT was also inhibited in adult mice given anti‐CD20 if B cell depletion in blood was maintained for 8 wk. Transient B cell depletion of adult mice did not inhibit SAT development. Anti‐CD20 depleted most circulating B cells, but only 60–80% of splenic B cells in adults. Most follicular B cells were depleted, but marginal zone B cells were resistant. The results suggest that in the absence of B cells, other APC activate T reg. This may be one mechanism by which B cell depletion inhibits autoimmune disease. The effects of B cell depletion and the underlying mechanisms may differ depending on when anti‐CD20 is administered. (Supported by Arthritis Natl. Res. Fdn). Anti‐CD20 was provided by Drs. M. Kehry and R. Dunn, Biogen, Idec.

show abstract

Section: Discussionmentioning

confidence: 99%

“…k , I-A k , and D d on the NOD background (1,32). They were maintained in the animal facility at the University of Missouri as previously described (2,6,7).…”

Section: Nodh-2h4 Mice Express H-2kmentioning

confidence: 99%

B Cell Depletion Inhibits Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice

Dunn

Kehry

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…NOD.H-2h4 mice are I-E-negative and express H-2K k , I-A k , and D d on the NOD background (16). IFN-␥ Ϫ/Ϫ NOD.H-2h4 mice were generated as previously described (5).…”

Section: Micementioning

confidence: 99%

Thyrocytes Responding to IFN-γ Are Essential for Development of Lymphocytic Spontaneous Autoimmune Thyroiditis and Inhibition of Thyrocyte Hyperplasia

Yu¹,

Sharp²,

Braley‐Mullen

2006

The Journal of Immunology

View full text Add to dashboard Cite

IFN-γ promotes the development of lymphocytic spontaneous autoimmune thyroiditis (L-SAT) in NOD.H-2h4 mice and inhibits the development of thyrocyte hyperplasia and proliferation (TEC H/P). The precise mechanisms by which IFN-γ promotes L-SAT and inhibits TEC H/P are unknown. To determine whether responsiveness of lymphocytes or thyrocytes to IFN-γ is important for the development of these lesions, IFN-γR−/− mice, which develop TEC H/P similar to IFN-γ−/− mice, were used as recipients for adoptive cell transfer. Wild-type (WT) splenocytes or bone marrow induced L-SAT and inhibited TEC H/P in IFN-γ−/−, but not IFN-γR−/− recipients. IFN-γR−/− recipients of WT cells developed severe TEC H/P, but did not develop L-SAT, suggesting that thyrocytes responding to IFN-γ are important for inhibition of TEC H/P. Unexpectedly, IFN-γR−/− splenocytes or bone marrow did not induce L-SAT in IFN-γ−/− or WT mice even though IFN-γR−/− lymphocyte donors produced as much IFN-γ as lymphocytes from WT donors, and thyrocytes could respond to IFN-γ. Real-time PCR indicated that recipients of IFN-γR−/− bone marrow expressed less mRNA for IFN-γ-inducible chemokines compared with recipients of WT bone marrow. This might limit the migration of IFN-γR−/− lymphocytes to thyroids. Few IFN-γR−/− lymphocytes infiltrated thyroids even in the presence of WT lymphocytes, suggesting that lymphocytes unable to respond to IFN-γ are not induced to migrate to thyroids. These results suggest that thyrocytes must be able to respond to IFN-γ for the development of L-SAT and inhibition of TEC H/P, and lymphocytes must be able to respond to IFN-γ to induce L-SAT.

show abstract

“…These mice never become diabetic, although they may develop some intraislet insulitis by 7-10 months of age (7). When used at 5 weeks of age, they therefore have a reduced frequency of the underlying defects.…”

Section: H4mentioning

confidence: 99%

The Derivation of Highly Germline-Competent Embryonic Stem Cells Containing NOD-Derived Genome

et al. 2003

View full text Add to dashboard Cite

It would be extremely advantageous to the analysis of disease mechanisms in the spontaneous mouse model of type 1 diabetes, the nonobese diabetic (NOD) strain, if genes in this strain could be modified in vivo using embryonic stem (ES) cells and homologous recombination. However, a NOD ES cell line with adequate germline transmission has not yet been reported. We report the development of highly germline-competent ES cell lines from the F1 hybrid of NOD and 129 for use in NOD gene targeting. Consequently, we developed ES cell lines derived from (NOD ؋ 129)F1 ؋ 129 backcross 1 mice, which were intercrossed to select for homozygosity of particular regions of NOD genome known to contain disease loci. Diabetes 52: [205][206][207][208] 2003 T he nonobese diabetic (NOD) mouse is a valuable model of human type 1 diabetes, particularly since the most important gene, the immune reponse gene IAb, and its human orthologue DQB1 share at least one of the same causal variants. However, allelic variation of this gene is not sufficient to explain disease and other genes are involved. Identification and functional analysis of candidate genes would be greatly facilitated if they could be altered in vivo by homologous recombination. Unfortunately, derivation of embryonic stem (ES) cells from the NOD mouse has proved extremely difficult. In addition, the modification of genes in ES cells from other strains such as 129 can lead to ambiguous results due to the unpredictable influence of linked 129-derived genes on the development of diabetes following the backcrossing of the chimeras to the NOD background. Thus far there is only one report of an NOD ES cell line that has demonstrated germline competence (1), but both its rate of growth and the level of germline transmission are too low to enable its use in gene targeting. We have had previous success in deriving ES cell lines from refractory strains of mice using microsurgery to explant epiblast of blastocysts that have been subjected to implantation delay (2). Here we present the results of using these same techniques, first with the NOD mouse and then with (NOD ϫ 129)F1 hybrid embryos.Our initial attempts to derive NOD ES cells involved ovariectomizing NOD mice on the third day of pregnancy to initiate implantation delay, and recovering the delayed blastocysts 7 days later. However, the number of blastocysts recovered was extremely low. Of 22 pregnant females, 18 yielded none and the remaining 4 gave only 17 living blastocysts. In contrast, of 38 nonovariectomized NOD females, 36 were pregnant with an average of nine blastocysts. This suggests that blastocyst viability is severely compromised by delaying implantation in the NOD mouse.In subsequent experiments, NOD conceptuses were explanted on the first, third, or fourth day of pregnancy and transferred to non-NOD host dams in which implantation delay was then induced by ovariectomy. Epiblasts from a total of 372 delayed blastocysts were placed in culture, and 9 of these gave rise to colonies of cells that had a typical ES cell ...

show abstract

I-E+ nonobese diabetic mice develop insulitis and diabetes.

Cited by 117 publications

References 56 publications

B Cell Depletion Inhibits Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice

B Cell Depletion Inhibits Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice

Thyrocytes Responding to IFN-γ Are Essential for Development of Lymphocytic Spontaneous Autoimmune Thyroiditis and Inhibition of Thyrocyte Hyperplasia

The Derivation of Highly Germline-Competent Embryonic Stem Cells Containing NOD-Derived Genome

Contact Info

Product

Resources

About