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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulitis occurs by 5 wk of age in all NOD mice. However, diabetes is detectable only after 3-5 mo of age and only in approximately 50% of females and 10% of males in our colony. Therefore, it is predictable that changes in the T-lymphocyte repertoire of diabetes-prone mice occur and predispose them to disease. We demonstrate here that an altered (with respect to control BALB/cJ mice) thymic T-lymphocyte maturation reflected by a depletion (approximately 12%) of CD4+CD8+ T lymphocytes and a reciprocal increase in CD4-CD8- T lymphocytes precedes the onset of diabetes. This depletion was detected only approximately 3 mo after insulitis and is manifested by a specific loss (approximately 3%) of immature T lymphocytes bearing V beta 8lo (lo is a relative level of expression) T-lymphocyte receptor. By onset of diabetes, an even greater decrease (approximately 35%) of CD4+CD8+ and a reciprocal increase of CD4-CD8- T lymphocytes were apparent and accompanied by the same depletion (3%) of V beta 8 lo T lymphocytes. Administration of cyclophosphamide (CY), which accelerates the appearance of diabetes in NOD mice, caused similar depletions of CD4+CD8+ and V beta 8lo thymic T lymphocytes. The same alterations in the distribution of these thymic T-lymphocyte subsets were evident even earlier in insulitis- and diabetes-free NON mice, indicating that these changes in thymic T-lymphocyte development may be necessary but not sufficient to give rise to diabetes. Despite the common genetic origin of NOD and NON mice, differences at their MHC-linked and -unlinked loci may account for their differential susceptibility to diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Apr
PMID:Altered thymic and peripheral T-lymphocyte repertoire preceding onset of diabetes in NOD mice. 182 79

The expression of MHC class II molecules on beta-cells of the pancreatic islet has been proposed to play a role in the genesis of insulin-dependent diabetes mellitus in the NOD mouse. We investigated this by immunofluorescent double labeling of islet cells with anti-MHC and anti-CD45 to identify cells of hematopoietic origin. MHC class I expression increased with age on CD45- islet cells. MHC class II expression was not observed on CD45- islet cells at any age; the only cells in the islet that were MHC class II positive were also CD45+. This indicates that all MHC class II-positive cells in the islet are lymphoid cells that infiltrate the islet, whereas the islet endocrine cells express no MHC class II molecules. However, an increase in MHC class I expression occurred on beta-cells, and this may play a role in immunopathogenesis.
Diabetes 1991 May
PMID:Exclusive expression of MHC class II proteins on CD45+ cells in pancreatic islets of NOD mice. 182 81

It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express antigen receptors of limited diversity. It has been suggested that the T cells responsible for the pathogenesis of type I diabetes mellitus might similarly demonstrate restricted T cell receptor (TCR) usage. Recently, attempts have been made to identify the V beta subset(s) that initiates and/or perpetuates the antiislet response in a mouse model of spontaneous autoimmune diabetes (non-obese diabetic [NOD] mice). In studies reported here, we have bred NOD mice to a mouse strain that congenitally lacks approximately one-half of the conventional TCR V beta alleles. Included in this deletion are TCR V beta gene products previously implicated as being involved in the pathogenesis of NOD disease. By studying second backcross-intercross animals, we were able to demonstrate that this deletion of TCR V beta gene segments did not prevent the development of insulitis or diabetes.
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PMID:Genetic dissection of T cell receptor V beta gene requirements for spontaneous murine diabetes. 183 91

The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction.
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PMID:Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease. 183 97

With the aim of clarifying the mechanism of the suppressive action of BCG against insulitis and overt diabetes in NOD mice, we studied the effects of BCG on spleen cell populations and on the in vitro immune responses of spleen cells. The spleen cells of BCG-vaccinated mice showed much lower responsiveness to various mitogens such as Con A, PHA, PWM, and LPS than those of saline-treated mice. Low responsiveness to alloantigens was also observed. Flow cytometric analysis of the spleen cells revealed that Mac-1+ and Mac-2+ cells had increased while T and B cells had decreased in the BCG-vaccinated mice compared with the saline-treated mice at the time when the maximum level of inhibition of mitogen responses of BCG-vaccinated mice was observed. This suggests that the decreased in vitro immune response was due to the increase in macrophages which suppress lymphocyte functions. Support for this interpretation comes from the following two findings: (1) the restoration of mitogen responses of spleen cells when macrophages were eliminated by plastic adhesion or FACS sorting and (2) resuppression of PHA and Con A responses of plastic-nonadherent spleen cells by addition of adherent cells or flow cytometrically sorted Mac-1+ cells obtained from BCG-vaccinated mice. These results indicate the generation of suppressor macrophages after BCG vaccination and suggest that these macrophages prevent the autoimmune pathogenesis leading to diabetes in NOD mice.
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PMID:Possible mechanism of the preventive effect of BCG against diabetes mellitus in NOD mouse. I. Generation of suppressor macrophages in spleen cells of BCG-vaccinated mice. 183 72

Our previous reports showed that a single injection of live BCG, one of the biological response modifiers, prevents insulitis and overt diabetes in NOD mice and that the suppression could be due to the generation of some type of suppressor cells in the BCG-treated mice. Furthermore, a more recent study has revealed that macrophages suppressive against a variety of lymphocyte functions can be induced by BCG, which suggests that these macrophages are involved in the suppression of the pathogenesis. To obtain valid evidence for this speculation, the effects of transfer of macrophage and T-cell fractions on the pathogenesis were examined in the present study. Transfer of macrophage-enriched spleen cell fraction harvested from the BCG-treated females to young females abolished the occurrence of spontaneous diabetes up to the age of 25 to 30 weeks. Also, macrophage transfer prevented the progress of insulitis. In contrast, transfer of a T-cell-enriched fraction did not suppress insulitis and overt diabetes. From these results, it could be concluded that the suppression of the autoimmune pathogenesis of diabetes by BCG is due to the generation of suppressor macrophages.
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PMID:Possible mechanism of the preventive effect of BCG against diabetes mellitus in NOD mouse. II. Suppression of pathogenesis by macrophage transfer from BCG-vaccinated mice. 183 73

Measurements were made of the levels of metabolic intermediates and activities of enzymes of the glycolytic route, pentose phosphate pathway, and polyol pathway in livers and kidneys of NOD mice. A 34% decrease in UDP-glucose, a 40% decrease in glucose-6-phosphate (G6P) and fructose-6-phosphate, and a 75% decrease in fructose-2,6-bisphosphate (F2,6P) were found in the livers of NOD mice. The fall in the level of F2,6P (the important regulator of glycolysis) is accompanied by a 20% reduction in the activity of phosphofructokinase. These changes are in agreement with previously reported liver depletion of glycogen and reduced synthesis of proteins and nucleic acids in the diabetic state. In the kidney, the increase in hexokinase activity is consistent with increased levels of G6P and glycogen content of kidney in diabetes. The decreased level of phosphoribosyl pyrophosphate was reported to be a regulator of kidney growth in the initial period of diabetes but can still be found in NOD mice 6 wk after development of hyperglycemia. The reported changes are similar to those seen in alloxan- or streptozocin-induced diabetic animals, but certain changes are more marked in NOD mice, especially those directed to increase nucleic acid and protein synthesis in the diabetic kidney.
Diabetes 1991 Nov
PMID:Regulation of glucose metabolism in livers and kidneys of NOD mice. 183 2

Diabetes in NOD mice is an autoimmune disease which is characterized by the infiltration of islets of Langerhans by large numbers of T cells. Some of these infiltrating T cells are clearly islet-cells-specific; however, many or most of these T cells could be attracted nonspecificity into these lesions. To study NOD pancreas-infiltrating T cells, we fused these cells with BW5147 to make T cell hybridomas. Ninety-four pancreas-derived T hybrids were analyzed of which 12 responded specifically to islet cells by secreting IL-2. Only CD3+, CD4+ hybrids responded to islet cells in our assay, and a large proportion of these hybrids were islet-cell reactive. T cell receptor (TCR) V beta element usage was heterogeneous in islet-reactive hybridomas.
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PMID:Analysis of pancreas-infiltrating T cells in diabetic NOD mice: fusion with BW5147 yields a high frequency of islet-reactive hybridomas. 183 36

We examined the hypothesis that the hypocholesterolemic agent, probucol (4,4'-(isopropylidenedithiol) bis (2,6-di-tert-butyl-phenol)), can attenuate development of hyperglycemia in NOD mice. The female NOD mice were fed 1% probucol containing (PROB) or standard diet (CONT) from 5 weeks of age. Development of hyperglycemia was checked by urine glucose levels using stick paper for 35 weeks. At 40 weeks of age, all animals were sacrificed and plasma glucose and serum immunoreactive insulin (IRI) levels were measured. At 40 weeks of age, 80.0% of mice showed hyperglycemia (greater than 200 mg/dl) or death in CONT group. In contrast, only 46.7% showed hyperglycemia in PROB group. Plasma glucose levels of PROB group tended to be lower than those of CONT group. The percentage of Thy 1.2-positive splenocytes were significantly lower in PROB group than that in CONT group. In addition, the splenocytes positive with Lyt. 2 were also reduced by probucol administration. These data suggest that probucol can partially prevent development of diabetes in NOD mice. It is possible that the observed changes of T-cell subsets in the spleen may be involved in the prevention of diabetes.
Diabetes Res 1991 Jul
PMID:Probucol partially prevents development of diabetes in NOD mice. 184 Oct 28

Diabetes is a T cell-mediated process in NOD/Lt mice, with a major genetically recessive component of susceptibility linked to homozygous expression of the unique H-2g7 MHC haplotype. Heterozygous expression of the H-2nb1 haplotype derived from the NON/Lt strain confers diabetes resistance both in (NOD x NON)F1 hybrids and in NOD mice congenic for the H-2nb1 haplotype. However, diabetes resistance is abrogated in F1 hybrids by NOD/Lt bone marrow reconstitution. To establish whether the generation of beta cell autoreactive T cells from NOD/Lt bone marrow-derived precursors required at least heterozygous expression of the H-2g7 haplotype on thymic epithelium, adolescent thymectomized (NOD x NON)F1 mice were implanted with neonatal NON/Lt thymus grafts before lethal radiation and reconstitution with NOD/Lt bone marrow. Peripheral T cells maturing through this ectopic thymic implant exclusively expressed the NOD H-2g7 haplotype and were tolerant to H-2nb1 skin grafts. Nevertheless, diabetes developed in 32% of the NON/Lt thymus-grafted chimeras vs 38% of the sham-thymectomized NOD bone marrow chimeras. Thus, homozygous expression of the diabetes-resistant H-2nb1 haplotype on thymic epithelium failed to block development of a diabetogenic T cell repertoire. To examine if expression of H-2nb1 on hemopoietically derived APC could alter the diabetogenic potential of NOD/Lt marrow, diabetes-resistant NOD.NON-H-2nb1 congenic mice were mated with NOD/Lt mice to produce NOD-H-2g7/H-2nb1 heterozygous recipients. These were lethally irradiated and reconstituted with either NOD/Lt marrow alone, NOD.H-2nb1 homozygous congenic marrow alone, or a 1:1 mixture of the two marrow populations. By 25 wk of age, all of the MHC heterozygous recipients of NOD.NON-H-2nb1 marrow remained diabetes-free whereas 75% of the MHC heterozygous recipients of NOD/Lt marrow developed diabetes. A striking decrease in diabetes was observed when T cell precursors derived from NOD/Lt marrow interacted with H-2nb1 gene products on hemopoietically derived APC, inasmuch as only 7% of the MHC heterozygous recipients reconstituted with a 1:1 mixture of NOD/Lt and NOD.NON-H-2nb1 marrow developed diabetes. Peripheral leukocytes in all reconstitution classes expressed the MHC phenotype(s) of the marrow donor(s). Skin grafting confirmed that all reconstitution classes of MHC heterozygous recipients were tolerant to the H-2nb1 haplotype.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development of diabetogenic T cells from NOD/Lt marrow is blocked when an allo-H-2 haplotype is expressed on cells of hemopoietic origin, but not on thymic epithelium. 186 20


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