NOD/LtSz-<i>Rag1</i><i>null</i>Mice: An Immunodeficient and Radioresistant Model for Engraftment of Human Hematolymphoid Cells, HIV Infection, and Adoptive Transfer of NOD Mouse Diabetogenic T Cells

Shultz, Leonard D.; Lang, Pamela A.; Christianson, Sherri W.; Gott, Bruce; Lyons, Bonnie L.; Umeda, Satoshi; Leiter, Edward H.; Hesselton, RuthAnn M.; Wagar, Eric J.; Leif, Jean; Kollet, Orit; Lapidot, Tsvee; Greiner, Dale L.

doi:10.4049/jimmunol.164.5.2496

Cited by 148 publications

(103 citation statements)

References 56 publications

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“…This is consistent with our previous findings, where adhesion of NOD/ShiLtJ T cells was reduced in the presence of full length SDF-1, whereas adhesion of C57BL/6J T cells was enhanced [4]. We then used the stabilised peptide agonist CTCE-0214 in an adoptive transfer model of type 1 diabetes, which is much more rapidly progressing than the spontaneous development of diabetes in NOD/ShiLtJ mice [24]; we found that CTCE-0214 significantly delayed the onset of hyperglycaemia. Together, these data clearly demonstrate that modulation of SDF-1 signalling responses for diabetogenic T cell recruitment can affect disease development in a model that is destined to develop diabetes, suggesting that a similar approach might be useful in altering T cell recruitment during spontaneous diabetes development.…”

Section: Discussionsupporting

confidence: 90%

SDF-1–CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1–SLIT2 interactions in mice

et al. 2013

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Aims/hypothesis We had previously reported that stromal cellderived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2-roundabout, axon guidance receptor, homologue 1 (Drosophila) (ROBO1) interactions. Methods C-X-C receptor (CXCR)4 and ROBO1 protein expression was measured in mouse and human T cells. Parallel plate flow chamber adhesion and detachment studies were performed to examine the molecular importance of ROBO1 and SLIT2 for SDF-1-mediated T cell chemorepulsion. Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1 −/− mice to examine the effect of the SDF-1 mimetic CTCE-0214 on adoptive transfer of diabetes. Results CXCR4 and ROBO1 protein expression was elevated in diabetic NOD/ShiLtJ T cells over time and coincided with the onset of hyperglycaemia. CXCR4 and ROBO1 expression was also increased in human type 1 diabetic T cells, with ROBO1 expression maximal at less than 1 year post diagnosis. Cell detachment studies revealed that immunoneutralisation of ROBO1 prevented SDF-1-mediated chemorepulsion of NOD T cell firm adhesion to TNFα-stimulated islet endothelial cells. SDF-1 increased NOD T cell adhesion to recombinant adhesion molecules, a phenomenon that was reversed by recombinant SLIT2. Finally, we found that an SDF-1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo. Conclusions/interpretation These data reveal a novel molecular pathway, which regulates diabetogenic T cell recruitment and may be useful in modulating autoimmune diabetes.

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Section: Discussionsupporting

confidence: 90%

SDF-1–CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1–SLIT2 interactions in mice

et al. 2013

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“…The normal diabetes incidence of the NOD Adprt1 Ϫ/Ϫ mice could indeed result from a concomitant exacerbation of these two parameters. Because PARP-1 deficiency has been reported to rescue the lymphopenia in NOD scid/scid mice (35), we decided to use NOD Rag1 Ϫ/Ϫ mice as recipients (36). Figure 4A shows the ability of prediabetic NOD Adprt1 Ϫ/Ϫ splenocytes to transfer diabetes to NOD Rag1 Ϫ/Ϫ recipients from 8 weeks of age as efficiently as NOD control splenocytes.…”

Section: Resultsmentioning

confidence: 99%

Unexpected Sensitivity of Nonobese Diabetic Mice With a Disrupted Poly(ADP-Ribose) Polymerase-1 Gene to Streptozotocin-Induced and Spontaneous Diabetes

et al. 2002

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Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. Its excessive activation seems particularly deleterious to pancreatic ␤-cells, as exemplified by the complete resistance of PARP-1-deficient mice to the toxic diabetes induced by streptozotocin. Because of the possible implication of this enzyme in type 1 diabetes, many human trials using nicotinamide, an inhibitor of PARP-1, have been conducted either in patients recently diagnosed or in subjects highly predisposed to this disease. To analyze the role of this enzyme in murine type 1 diabetes, we introgressed a disrupted PARP-1 allele onto the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain. We showed that these mice were protected neither from spontaneous nor from cyclophosphamide-accelerated diabetes. Surprisingly they were also highly sensitive to the diabetes induced by a single high dose of streptozotocin, standing in sharp contrast with C57BL/6 mice that bear the same inactivated PARP-1 allele. Our results suggest that NOD mice are characterized not only by their immune dysfunction but also by a peculiarity of their islets leading to a PARP-1-independent mechanism of streptozotocin-induced ␤-cell death.

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“…Freshly isolated spleen cells obtained from animals injected i.p. with 100 g of polyinosinic:polycytidylic acid (poly I:C) 24 h earlier were added at E:T cell ratios of 100, 50, 25, and 12.5:1 and incubated for 4 h at 37°C in a humidified atmosphere of 95% air-5% CO 2 (31) Total releasable radioactivity (cpm maximal ) was determined by incubating an aliquot of 51 Cr-labeled target cells with 5% Triton X-100. After incubation, cells were pelleted by centrifugation, and 100 l of aliquots of supernatant were transferred to a separate microtiter plate containing 100 l of Optiphase Supermix ␤-scintillation fluid (Wallac, Gaithersburg, MD) and counted (cpm test ) using a 1450 Microbeta Trilux instrument (Wallac).…”

Section: Nk Cell Cytotoxicity Assaymentioning

confidence: 99%

Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice

Pearson¹,

Markees

Serreze

et al. 2003

The Journal of Immunology

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Curing type 1 diabetes by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. Most islet allotransplant tolerance induction protocols have been tested in nonobese diabetic (NOD) mice, and most have failed. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Out of concern that NOD biology could be misleading in this regard, we tested the hypothesis that autoimmunity and resistance to transplantation tolerance in NOD mice are distinct phenotypes. Unexpectedly, we observed that (NOD × C57BL/6)F1 mice, which have no diabetes, nonetheless resist prolongation of skin allografts by costimulation blockade. Further analyses revealed that the F1 mice shared the dendritic cell maturation defects and abnormal CD4+ T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice can be dissociated genetically. The outcomes of tolerance induction protocols tested in NOD mice may not accurately predict outcomes in human subjects.

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NOD/LtSz-Rag1nullMice: An Immunodeficient and Radioresistant Model for Engraftment of Human Hematolymphoid Cells, HIV Infection, and Adoptive Transfer of NOD Mouse Diabetogenic T Cells

Cited by 148 publications

References 56 publications

SDF-1–CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1–SLIT2 interactions in mice

SDF-1–CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1–SLIT2 interactions in mice

Unexpected Sensitivity of Nonobese Diabetic Mice With a Disrupted Poly(ADP-Ribose) Polymerase-1 Gene to Streptozotocin-Induced and Spontaneous Diabetes

Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice

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