Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homozygosity for the severe combined immunodeficiency (scid) mutation results in a block in T- and B-lymphocyte development. An unusually high incidence of spontaneous thymic lymphoma development was observed after transfer of this mutation from the C.B-17 congenic strain background onto the diabetes-susceptible nonobese diabetic (NOD) background. Thymomagenesis in the NOD-scid/scid mouse was associated with expression of an NOD mouse-unique endogenous ecotropic murine leukemia provirus locus (Emv-30, mapped to proximal region of chromosome 11) not expressed in the standard substrain NOD/Lt thymus. All tumors exhibited insertions of ecotropic proviruses, whereas only a subset also exhibited proviral integrations of mink cell focus-forming retrovirus. Neither class of retrovirus was associated with consistent integration into genes previously associated with activation of oncogenesis. We propose that the unusual features of T-cell ontogeny characteristic of the NOD inbred strain synergize with the scid-imparted block in thymocyte development, leading to activation of the NOD-unique Emv-30 to initiate thymomagenesis.
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PMID:The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency. 137 93

Mice bearing a tumor necrosis factor (TNF) alpha transgene controlled by an insulin promoter developed an increasingly severe lymphocytic insulitis, apparently resulting from the induction of endothelial changes with features similar to those observed in other places of intense lymphocytic traffic. This was accompanied by dissociation of the endocrine tissue (without marked decrease in its total mass), islet fibrosis, and the development of intraislet ductules containing, by places, beta cells in their walls, suggesting a regenerative capacity. Islet disorganization and fibrosis did not result from lymphocytic infiltration, since they were also observed in SCID mice bearing the transgene. Diabetes never developed, even though a number of potentially inducing conditions were used, including the prolonged perfusion of interferon gamma and the permanent expression of a nontolerogenic viral protein on beta cells (obtained by using mice bearing two transgenes). It is concluded that (a) a slow process of TNF release in pancreatic islets induces insulitis, and may be instrumental in the insulitis resulting from local cell-mediated immune reactions, but (b) that insulitis per se is not diabetogenic, lymphocyte stimulation by cells other than beta cells being necessary to trigger extensive beta cell damage. This provides an explanation for the discrepancy between the occurrence of insulitis and that of clinical disease in autoimmune diabetes.
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PMID:Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes. 146 Apr 28

Allogeneic fetal liver cell transplantation has been shown to be able to reconstitute lymphopoietic systems of mice when these systems are defective or destroyed. Lethally irradiated mice or mice with inherited severe combined immunodeficiency disease (SCID) were grafted with 14 days gestation allogeneic fetal liver cells, then subjected to a follow-up for the immune tolerance to the donor and the normal or subnormal immune reconstitution allowing prevention of diabetes in NOD mice or cure of leukemia in AKR mice and of immunodeficiency in SCID mice. Briefly, when normal CBA mice were lethally irradiated and then grafted with allogeneic fetal liver cells from Balb/c mice, a specific immune tolerance was induced to donor skin grafts. Unrelated skin grafts were rejected and a response to antigens was observed in these chimeras. However, despite the capacity to develop hyperacute rejection of skin allografts, following hyperimmunization, these chimeric mice did not produce anti-H2 cytotoxic antibodies. In SCID mice (CB17), the immune reconstitution occurred when mice were grafted with allogeneic (C57/B16) as well as with syngeneic fetal liver cells. Human cells were found in SCID mice following implantation of human fetal liver and thymus cells. When NOD mice were irradiated, then grafted with allogeneic fetal liver cells, a large part of donor cells were found in NOD recipients, correlating with a low incidence of diabetes. Leukemic AKR mice grafted with allogeneic fetal liver cells had virtually no leukemia relapse, suggesting a strong graft-versus-leukemia effect following such a transplant.
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PMID:Fetal liver cell transplantation in various murine models. 150 74

The pathogenesis of diabetes in C57BL/KsJ-db/db mice has been proposed to entail autoimmune mechanisms. We have combined immunodeficiency genes with the db mutation to determine whether beta cell necrosis and establishment of severe diabetes would occur in the absence of normal T and/or B lymphocyte functions. Inbred mice carrying the recessive mutations, severe combined immunodeficiency (scid), X-linked immunodeficiency (xid), nude (nu), and the Y-linked autoimmune accelerator (Yaa), were crossed with strains congenic for the db mutation. The diabetes syndrome was studied in double homozygotes produced in the F2 generation. In another experiment, C57BL/KsJ-db/db males were made T cell function deficient by adolescent thymectomy followed by lethal irradiation and bone marrow reconstitution. None of these manipulations served to prevent the induction of a severe diabetes syndrome in any of the model systems analyzed. Thus, diabetogenesis characterized by massive necrosis of the pancreatic beta cells and atrophy of the pancreatic islets was observed in both the absence of normal T cell function (as assessed by absence of T cell mitogen response) and humoral autoimmunity against beta cell antigens (insulin, retroviral p73). In conclusion, our data indicate that anti-beta cell autoimmunity is not a primary event in the etiopathogenesis of diabetes in the db/db mouse.
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PMID:Effect of immunodeficiency on diabetogenesis in genetically diabetic (db/db) mice. 355 24

There is an increasing interest on one of the smallest human chromosomes as it is shown by the First International Symposium on the Human Chromosome 20 and by the genetic map prepared by EUROGEN. The conserved part of the long arm of human chromosome 20 is synthenic with the distal part of the mouse chromosome 2 allowing for some analogies between them. Human chromosome 20 contains several important genes for the human pathology. Mutations of one of them, the vasopressin-neurophysin II gene, are responsible for hereditary neurohypophyseal diabetes insipidus. Severe combined immunodeficiency due to adenosin deaminase deficiency is the first human disorder successfully treated by somatic gene therapy. Spongiform encephalopathies are related to mutation and/or polymorphisms of the PRNP amyloid gene. One form of benign familiar neonatal convulsions is mapped to a specific locus on chromosome 20. In some families, maturity onset diabetes of the young (MODY) is caused by alterations of a hypothetical gene closely linked to the ADA locus. Allegile syndrome is often associated with deletions and microdeletions of the short arm of the chromosome. Finally, deletions of the long arm of the chromosome is a frequent finding in several hematologic malignities, specifically in myeloproliferative disorders and myelodysplastic syndromes.
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PMID:[The human genome--chromosome 20]. 748 83

We have made three observations that are important for our understanding of the dynamics of presentation of diabetogenic Ags in immunologically induced diabetes. First, the APC in the islets of Langerhans were found normally to contain diabetogenic peptides on their I-Ag7 molecules. This was found in freshly harvested islet cells from prediabetic NOD mice and, importantly, from NOD.SCID mice. Second, the presence of diabetogenic lymphocytes improved the presenting function of intra-islet APC. We interpret this to mean that lymphocytes can regulate intra-islet APC function before the development of diabetes. Finally, spleen APC can be found bearing diabetogenic Ag after acute injury to islets. These APC may be important in lymphocyte stimulation outside the environment of the pancreas.
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PMID:Relationship between beta cell injury and antigen presentation in NOD mice. 756 Nov 22

When used as hosts in passive transfer experiments, a stock of NOD/Lt mice congenic for the severe combined immunodeficiency (scid) mutation have provided great insight to the contributions of various T-cell populations in the pathogenesis of autoimmune insulin-dependent diabetes mellitus (IDDM). Moreover, NOD-scid mice support higher levels of human lymphohematopoietic cell growth than the C.B-17-scid strain in which the mutation originated. However, the ability to perform long-term lymphohematopoietic repopulation studies in the NOD-scid stock has been limited by the fact that most of these mice develop lethal thymic lymphomas beginning at 20 weeks of age. These thymic lymphomas are characterized by activation and subsequent genomic reintegrations of Emv30, an endogenous murine ecotropic retrovirus unique to the NOD genome. To test the role of this endogenous retrovirus in thymomagenesis, we produced a stock of Emv30null NOD-scid mice by congenic replacement of the proximal end of chromosome 11 with genetic material derived from the closely related NOR/Lt strain. Thymic lymphomas still initiate in Emv30null NOD-scid females, but their rate of progression is significantly retarded since the frequency of tumors weighing between 170 and 910 mg at 25 weeks of age was reduced to 20.8% vs. 76.2% in Emv30% segregants. The thymic lymphomas that did develop in Emv30null NOD-scid mice were not characterized by a compensatory increase in mink cell focus-forming proviral integrations, which initiate thymomagenesis in other susceptible mouse strains. Significantly, the ability of standard NOD T-cells to transfer IDDM to the Emv30null NOD-scid stock was not impaired.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Dec
PMID:Emv30null NOD-scid mice. An improved host for adoptive transfer of autoimmune diabetes and growth of human lymphohematopoietic cells. 758 44

Diabetes was dramatically accelerated in non-obese diabetic (NOD) transgenic mice that expressed interleukin-2 (IL-2) in their beta cells. A single cross to C57BL/6 completely prevented this effect and a further backcross to the NOD genetic background showed that at least two diabetes susceptibility loci (Idd1s and Idd3/10s) were required for the diabetes acceleration T cells activated to islet antigens were not circulating in the mice. The accelerating effect of IL-2 was present; but decreased, in NOD mice that lacked CD8+ T cells as well as in NOD SCID mice. The implications are that in the NOD genetic background, the production of cytokines, such as IL-2, by islet-specific CD4+ T cells can lead to beta cell damage and diabetes and that CD8+ T cells may have a role in accelerating diabetes onset.
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PMID:Genetic requirements for acceleration of diabetes in non-obese diabetic mice expressing interleukin-2 in islet beta-cells. 792 81

A number of inherited and acquired serum protein deficiencies including hemophilias A and B, diabetes mellitus, and the erythropoietin-responsive anemias are currently treated with repeated subcutaneous or intravenous infusions of purified or recombinant proteins. The development of an in vivo gene-transfer approach to deliver physiologic levels of recombinant proteins to the systemic circulation would represent a significant advance in the treatment of these disorders. Here we describe the construction of a replication-defective adenovirus (AdEF1hEpo) containing the human erythropoietin (hEpo) cDNA under the transcriptional control of the cellular elongation factor 1 alpha (EF1 alpha) promoter and the 4F2 heavy chain (4F2HC) enhancer. Neonatal CD-1 and adult SCID mice injected once intramuscularly (i.m.) with 10(7) to 10(9) plaque-forming units (pfu) of this virus displayed significant dose-dependent elevations of serum hEpo levels and increased hematocrits, which were stable over the 4-month time course of these experiments. Adenovirus injected i.m. remained localized at the site of injection and there was no evidence of either systemic infection or a localized inflammatory response. These results suggest that i.m. injection of recombinant replication-defective adenovirus vectors may serve as a paradigm for the treatment of human serum protein deficiencies.
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PMID:Stable delivery of physiologic levels of recombinant erythropoietin to the systemic circulation by intramuscular injection of replication-defective adenovirus. 797 1

The murine severe combined immunodeficiency (scid) mutation was used to assess whether the diabetogenic effects of multiple low-dose streptozocin (MD-STZ) administration required the presence of functional T-cells. An STZ dose as low as 30 mg/kg body wt for 5 days induced hyperglycemia in young NOD/Lt-+/+ male mice, whereas a dose of 50 mg/kg for 5 days was required to elicit comparable hyperglycemia in C.B.-17-+/+ male mice. The greater NOD strain sensitivity was not a function of preexisting insulitis, because insulitis- and diabetes-free NOD male mice congenic for a diabetes-resistant major histocompatibility complex haplotype were equally susceptible to MD-STZ. This was confirmed in NOD-scid/scid and C.B.-17-scid/scid males. Both were completely insulitis-free, and despite the absence of functional T- cells and B-cells, both congenic stocks were as sensitive to MD-STZ as congenic +/+ controls. Indeed, MD-STZ-induced hyperglycemia in NOD-scid/scid male mice was significantly higher than in NOD/Lt-+/+ male mice. The NOD-scid/scid mouse as a recipient of adoptively transferred splenocytes clearly delineated a distinct pathogenesis of spontaneous insulin-dependent diabetes mellitus (IDDM) versus MD-STZ-induced hyperglycemia. Splenocytes from spontaneously diabetic NOD/Lt males, but not those from donors given MD-STZ, readily transferred IDDM, even when host beta-cells were sensitized by a single injection of STZ before adoptive transfer. We conclude that IDDM induced by MD-STZ is not mediated by T-cell- or B-cell-dependent autoimmune mechanisms in a fashion analogous to the spontaneous IDDM characteristic of NOD mice.
Diabetes 1994 Mar
PMID:Multiple low-dose streptozocin-induced diabetes in NOD-scid/scid mice in the absence of functional lymphocytes. 831 17


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