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

The involvement of tyrosine phosphorylation in insulin action led us to hypothesize that increased activity of protein tyrosine phosphatases (PTPases) might contribute to insulin resistance in alloxan diabetes in the rat. Hepatic PTPase activity was measured using two artificial substrates phosphorylated on tyrosine: reduced, carboxyamidomethylated, and maleylated lysozyme (P-Tyr-RCML) and myelin basic protein (P-Tyr-MBP), as well as an autophosphorylated 48-kD insulin receptor tyrosine kinase domain (P-Tyr-IRKD). Rats that were made alloxan diabetic exhibited a significant increase in hepatic membrane (detergent-soluble) PTPase activity measured with P-Tyr-MBP, without a change in activity measured with P-Tyr-RCML or the P-Tyr-IRKD. The PTPase active with P-Tyr-MBP behaved as a high molecular weight peak during gel filtration chromatography. Characterization of this enzyme indicated it shared properties with CD45, the prototype for a class of transmembrane, receptor-like PTPases. Our results indicate that alloxan diabetes in the rat is associated with an increase in the activity of a large, membrane-associated PTPase which accounts for only a small proportion of insulin receptor tyrosine dephosphorylation. Nonetheless, increased activity of this PTPase may oppose tyrosine kinase-mediated insulin signal transmission, thus contributing to insulin resistance.
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PMID:Differential regulation of multiple hepatic protein tyrosine phosphatases in alloxan diabetic rats. 132 40

The demonstration that functionally different T-cell subsets can be defined by the isoforms of the leukocyte-common antigen, CD45, that they express, has prompted studies on the roles of these subsets in autoimmunity. The results have led to the identification of a particular subset of CD4+ T cells that have the ability to inhibit autoimmune disease. Further, it has been shown that diabetes in the B-B rat can be transferred by in vitro activation of T cells by Staphylococcal enterotoxin suggesting that superantigens may play a role in the pathogenesis of this disease. However, in this system too, it appears that a subset of T cells can inhibit the induction of autoaggressive cells. In other experimental autoimmune diseases there is evidence that CD8+ T cells can be protective and that these cells may mediate this protection by the synthesis of transforming growth factor-beta.
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PMID:T-cell subsets in autoimmunity. 146 96

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

NOD mice spontaneously develop organ-specific autoimmunity and are widely used as a model for diabetes. NOD mice also exhibit some features of non-organ specific autoimmune rheumatic disease such as thymocytotoxic and anti-nuclear autoantibodies and they develop haemolytic anaemia in senescence. A single dose of 2.6 x 10(7) heat-killed Bacillus Calmette-Guerin (BCG) i.v. in 8-week-old NOD mice prevented diabetes but precipitated a syndrome similar to systemic lupus erythematosus (SLE), in which treated mice rapidly developed haemolytic anaemia, high titre anti-DNA and anti-Sm antinuclear autoantibodies, perivascular lymphocytic infiltration in the kidneys and glomerular immune complex deposition. Here, we examined the mechanism of action by which BCG precipitated rheumatic autoimmune disease in NOD mice. Two weeks after injection, reticuloendothelial cell function was dramatically increased in BCG-treated NOD mice. By 4 weeks, treated mice had a three- to four-fold increase in Mac-1+ and class-II+, B220-negative splenocytes and in vitro antigen-presentation capacity was enhanced two- to four-fold. In vivo responses to SRBC confirmed enhancement of DTH 4 weeks after BCG injection, consistent with an adjuvant-like activity.
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PMID:Mycobacteria precipitate autoimmune rheumatic disease in NOD mice via an adjuvant-like activity. 800 75

Individuals with insulin-dependent diabetes mellitus, as well as high-risk prediabetic subjects who are identified prior to the onset of hyperglycaemia by abnormal autoantibodies to both insulin and islet cells have an autologous antigen presenting cell (APC) defect that results in sluggish T cell proliferation in the in vitro autologous mixed lymphocyte reaction (AMLR). In contrast, lower-risk relatives, who produce autoantibodies restricted to insulin and fail to develop overt hyperglycaemia, show apparently normal autologous antigen presenting cell function and paradoxically demonstrate excessive T cell proliferation in the AMLR. We have now characterized this lower-risk vigorous T cell response in the autologous mixed by lymphocyte reaction as a predominant and excessive proliferation of CD4+ T cells to self-antigens (n = 10, p < 0.001). In addition, the normal autologously driven transition of the expanding CD45RA+ subset of CD4+ cells into transient CD45RA+RO+ cells with subsequent progression to CD45RA-RO+ cells is partially blocked in the lower-risk autologous response compared to controls (n = 5, p = 0.01, respectively). Autologously driven T cell developmental transitions also appear to be blocked in these individuals in vitro; the peripheral blood of lower-risk relatives contains an increased number of CD4+ cells abnormally coexpressing CD45RA and CD45RO (p = 0.01). Interestingly, in two twin sets reconstitution of T cells from the diabetic twin of an identical twin-pair that is discordant for Type 1 diabetes with the APCs of the nondiabetic twin resulted in overly vigorous T cell proliferation dominated by CD4+ cells; phenotypically, these CD4+ cells at the end of the reaction were similar to those of lower-risk relatives in that the CD45RA+RO+ transition into CD45RA-RO+ cells was now observed to be defective. Therefore, T cells from lower-risk relatives and individuals with Type 1 diabetes appear to possess similar intrinsic T cell developmental defects in CD45 transitions that are apparent after normal autologous antigen stimulation.
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PMID:Occult CD45 T cell developmental defect in type 1 diabetes. 805 25

Islet cell Ag 512 (ICA512) is a recombinant human Ag that was isolated from an islet cDNA expression library by screening with human insulin-dependent diabetes mellitus sera. Specificity of reaction with diabetic sera was demonstrated initially by immunoprecipitation with a small number of diabetic and normal serum samples. To permit quantitative and rapid serum testing, ICA512 was purified and adapted to an ELISA format. In this way, a sensitivity of 48% with newly diagnosed diabetic sera has been measured with a panel of 80 sera. DNA sequencing of ICA512-3, a cDNA that contains a 1644 bp open reading frame, suggests that it codes for a transmembrane protein having a single membrane-spanning segment and a cytoplasmic domain that is closely related to the first intracellular (catalytic) domain of the T cell protein tyrosine phosphatase, CD45. Northern blot analysis of poly(A)+ RNAs from several human tissues indicates that ICA512 mRNA is expressed in brain and pancreas.
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PMID:Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases. 814 12

The non-obese diabetic (NOD) mouse spontaneously develops a T cell-mediated autoimmune disease, sharing many features with human insulin-dependent diabetes mellitus (IDDM), leading to insulin-secreting beta cell destruction. The role of CD4+ T cells has been evidenced at two levels. First, CD4+ T cells from diabetic animals are required to transfer diabetes to non-diabetic recipients in conjunction with CD8+ effector T cells. Second, suppressive CD4+ T cells have been characterized in non-diabetic NOD mice. T cells with different functions can thus share the CD4+ phenotype. Since CD4+ T cells can be divided into at least two subgroups on the basis of CD45 isoform expression, we evaluated the distribution of CD4+ T cells expressing the CD45RA isoform on NOD mouse thymocytes and peripheral T cells. The percentage of CD45RA+ cells was dramatically increased among the most mature CD3bright thymocytes and among CD4+ T cells in lymph nodes of the NOD mouse as compared with control strains. This increase was related to the development of insulitis. Interestingly, the CD45RA isoform was expressed on most CD4+ T cells invading the islets. In vivo treatment with an anti-CD45RA mAb prevented the development of insulitis and spontaneous diabetes in female animals but not the transfer of diabetes by T cells collected from diabetic NOD donors. These results indicate that anti-CD45RA mAb is only effective if given before the full commitment of effector T cells to the destruction of islet beta cells. Thus CD4+CD45RA+ T cells play a key role in early activation steps of anti-islet immunity.
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PMID:Role of CD4+CD45RA+ T cells in the development of autoimmune diabetes in the non-obese diabetic (NOD) mouse. 831 52

The monoclonal antibodies 2H4 (anti-CD45RA) and UCHL1 (anti-CD45RO) were used to subdivide the CD4 and CD8 T-cell subsets into naive and memory cells. The peripheral blood lymphocytes of 34 patients with recent-onset IDDM, 21 patients with long-standing IDDM, and healthy control subjects of similar age and sex were analyzed by a three-color immunofluorescence technique. CD4 and CD8 lymphocytes expressed the CD45 isoforms alone (CD45RA+ or CD45RO+) or in combination CD45RA+RO+). Simultaneous coexpression of both CD45RA and CD45RO (CD45RA+RO+) on CD4 and CD8 lymphocytes in patients with recent-onset IDDM was higher than in control subjects (P < 0.001). The proportion of CD4 lymphocytes expressing CD45RA alone (CD45RA+RO-) was similar in these groups, but the percentage of CD8 lymphocytes that were CD45RA+RO- was significantly higher in the patients with recent-onset IDDM (P < 0.05). The result of these changes is a significant increase in expression of naive phenotypes (CD45RA+ and CD45RA+RO+) on CD4 and CD8 lymphocytes in recent-onset IDDM (P < 0.005 and P < 0.0001). In long-standing IDDM, total CD45RA+ expression on CD4 and CD8 lymphocytes was reduced compared with control subjects (P < 0.05) as a result of a tendency of CD45RA+RO- and CD45RA+RO+ subsets to be lower. This increase in total naive (CD45RA+) lymphocytes and in coexpression of naive (CD45RA) and memory (CD45RO) markers on CD4 and CD8 lymphocytes subsets in patients with recent-onset IDDM suggests that abnormal regulation of T-cell activation and maturation is important in the pathogenesis of the disease.
Diabetes 1993 Jan
PMID:Increase in simultaneous coexpression of naive and memory lymphocyte markers at diagnosis of IDDM. 842 Aug 10

Transplantation of human fetal pancreas (HFP) is being considered as a potential treatment for insulin-dependent diabetes mellitus (IDDM). Therefore, it is necessary to have an experimental model of HFP-specific allograft rejection in order to understand all the fators that contribute to allograft rejection, and in which to test potential immunomodulatory protocols. The severe combined immunodeficient (SCID) mouse provides such a model. Previously, it has been reported that human allograft rejection can be observed in SCID mice engrafted with human lymphocytes. However, graft rejection is inconsistent and depends on both the number of lymphocytes injected and on the activation state. Here, we describe a model in which SCID mice are injected intraperitoneally with donor-specific lymphocytes generated by an in vitro culture period with irradiated donor splenocytes. Injection of the donor-sensitized PBL results in an acute rejection of HFP allografts (as early as 4 days post-transplant). This model does not require the establishment of chimerism. in the SCID mice, as demonstrated by the lack of detectable human CD45 cells in the peripheral blood of rejecting mice. Allograft rejection was due to human CD4+ and CD8+ cells, as determined by immunohistochemical analysis of graft-infiltrating cells. The advantages of this model include the potential to specifically manipulate either the phenotype of the responding cells or the mechanism in which the responding population is generated. This model can provide a rapid method to test the efficacy of immunomodulatory regimens designed to protect allografts from an acute rejection response.
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PMID:Acute graft rejection of human fetal pancreas allografts using donor-specific human peripheral blood lymphocytes in the SCID mouse. 863 71

Gene transfer into the pancreas would be useful for the treatment of a variety of disorders, including cystic fibrosis, diabetes, cancer, and immunomodulation of pancreatic allografts. A hypothesis that various cell populations in the pancreas could be targeted by recombinant adenoviruses was developed and tested. Gene transfer into the rat ductal epithelium, acinar cells, and islets of Langerhans was accomplished with a recombinant adenovirus containing bacterial beta-galactosidase by retrograde delivery of adenovirus into the pancreaticobiliary duct. Maximal gene expression was observed at 3 days and correlated with DNA blot analysis. Histologic analysis of sections from pancreatic tissue in the adenovirus-treated rats demonstrated severe pancreatitis. Immunophenotyping of the inflammatory infiltrate with rat lymphocyte-specific markers showed CD45-, CD8-, and CD4-positive cells. Tissue injury resolved as gene expression was lost, with both features absent by 21 days. Pancreatic regeneration was documented by the presence of 5-bromo-2'-deoxyuridine-positive staining cells. Pancreatic gene transfer with first-generation recombinant adenoviruses can be accomplished by techniques applicable to clinical situations. The use of first-generation recombinant adenoviruses for pancreas-directed gene transfer is limited by the development of inflammation and transient expression.
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PMID:Adenovirus-mediated in vivo gene transfer and expression in normal rat pancreas. 874 Apr 9


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