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)

Endothelial activation as evidenced by increased expression of leukocyte adhesion molecules occurs during immune-mediated inflammatory processes. One such process is insulitis, the pancreatic islet inflammation that leads to autoimmune insulin-dependent diabetes mellitus (IDDM). To determine if the induction of IDDM correlates with the presence of T lymphocytes capable of activating endothelial cells (EC), we studied the diabetes resistant BB (DR) rat. These animals become diabetic after in vivo depletion of T cells expressing the RT6 alloantigen. Various populations of purified DR T lymphocytes were cocultured with MHC compatible rat EC. We observed: 1) RT6- T cells from diabetic animals induced maximal endothelial MHC Ag expression. 2) The ability of RT6- T cells to activate EC increased with the duration of in vivo RT6 depletion. It was acquired before the onset of insulitis but subsided after the onset of diabetes. 3) In contrast, neither unsorted total T cells nor in vitro-purified RT6- T cells activated EC. 4) Older DR rats depleted of RT6+ T cells did not become diabetic and their RT6- T cells did not activate EC. 5) T cell IFN-gamma production correlated with the intensity of EC activation. 6) direct T cell-EC contact was required for maximal IFN-gamma production and EC activation. We conclude that RT6- T cells capable of activating EC are generated during the induction of IDDM in DR rats. We hypothesize that such T cell activity may lead to endothelial activation in vivo and contribute to immune-mediated insulitis, beta-cell destruction, and IDDM.
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PMID:T lymphocytes capable of activating endothelial cells in vitro are present in rats with autoimmune diabetes. 842 30

Although T lymphocytes are the ultimate effectors of pancreatic beta cell destruction in autoimmune insulin-dependent diabetes, previous work has established that beta cell autoreactive T cells are generated in nonobese diabetic (NOD) mice as a result of APC dysfunctions. To determine if APC dysfunctions could result from developmental defects, we analyzed if macrophages (M phi) develop normally from NOD bone marrow stimulated with CSF-1 in the presence and absence of IFN-gamma. Due to interactions between the diabetogenic H-2g7 haplotype and background modifiers, NOD bone marrow cells were found to proliferate poorly to CSF-1 stimulation. IFN-gamma aberrantly increased CSF-1-stimulated proliferation of H-2g7 expressing bone marrow cells, although decreasing proliferation of bone marrow cells expressing diabetes resistant MHC haplotypes. FACS analysis indicated the diminished sensitivity of NOD hematopoietic precursors to CSF-1 was associated with a quantitative inability to generate phenotypically mature M phi. In addition to developmental defects, NOD M phi were also found to be functionally defective. Total MHC class I expression was aberrantly down-regulated in a tissue specific fashion in IFN-gamma-treated M phi from NOD mice, whereas MHC class I expression increased as expected in M phi from C57BL/KsJ (BKs) control mice. Total MHC class I expression also increased in IFN-gamma-treated M phi from NOR mice, a diabetes-resistant control strain that shares the H-2g7 haplotype of NOD, but contains BKs-derived genomic elements on chromosomes 2, 4, 11, and 12. This demonstrates differential trans-regulation of class I loci within the diabetogenic H-2g7 haplotype in NOD vs diabetes-resistant NOR mice. Aberrant down-regulation of MHC class I content in IFN-gamma-treated M phi from NOD mice was associated with decreased ability to activate CTL function. We propose these defects in M phi differentiation and function may interact with H-2g7 to generate APC in NOD mice that are unable to activate tolerogenic mechanisms, but remain capable of activating low level effector responses.
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PMID:Defects in the differentiation and function of antigen presenting cells in NOD/Lt mice. 845 Feb 29

Ciclosporine (CS) caused rapid improvement of anemia and increase of CD 4/8 ratio in two patients with pure red cell aplasia (PRCA). One case was a 45 year old female who were unresponsive to steroids, plasmapheresis and high dose cyclophosphamide, and another was a 61 years old man with diabetes mellitus (DM) without any treatment for PRCA. In both cases hemoglobin increased soon after the initiation of CS and CD 4/8 ratio also rose from 0.80 to 1.47 and 1.78 to 1.98, respectively. There was no side effects to interrupt the course of the therapy. CS seems to inhibit the production of cytokines such as IL-2 and IFN-gamma, and it damages the activated suppressor/cytotoxic T cells. CS is an effective drug for not only refractory cases but the first step therapy for the untreated patients.
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PMID:[Cyclosporin for pure red cell aplasia caused rapid improvement of anemia and increase of CD4/8 ratio]. 849 14

The adoptive transfer of splenocytes from diabetic NOD mice to NOD-scid/scid (NOD-scid) recipients results in diabetes. This model was used to test the effect of cotransfer of splenocyte subsets from young nondiabetic NOD mice. As shown previously in other NOD models, the CD4+ subset from young nondiabetic mice significantly delayed the onset of diabetes in splenocyte cotransfers (P < 0.001). The data presented here showed that the development of diabetes in NOD-scid recipients correlated with a rapid increase in peripheral CD45RB(low) CD4+ cells. However, the CD45RB(low) subset of CD4+ cells from young nondiabetic mice protected from diabetes transfer in this model. We therefore examined whether CD45RB(low) CD4+ cells from diabetic mice were pathogenic rather than protective. CD45RB(low) CD4+ splenocytes from diabetic NOD mice were transferred along with CD8+ splenocytes from diabetic mice into NOD-scid recipients, and all of the recipients became diabetic within 5 weeks posttransfer. In contrast, no recipients (0 of 10) of CD45RB(high) CD4+ cells along with CD8+ splenocytes from diabetic mice became diabetic within 5 weeks posttransfer (P < 0.001). A correlate for the difference between CD45RB(low) CD4+ cells from diabetic NOD mice and CD45RB(low) CD4+ cells from nondiabetic mice, which showed protective effect in splenocyte cotransfers, was found in cytokine production after stimulation with anti-CD3 antibodies in vitro. CD45RB(low) CD4+ cells from diabetic mice showed a significantly higher ratio (approximately fivefold) of gamma-interferon (IFN-gamma) to interleukin (IL)-4 when compared with CD45RB(low) CD4+ cells from nondiabetic mice (P < 0.001). In conclusion, the function of the CD45RB(low) population of CD4+ cells changes from a protective to a pathogenic one during the development of disease in the NOD mouse. This change in function correlates with cytokine production in vitro; increased IFN-gamma-to-IL-4 ratio is associated with pathogenic potential and occurs coincident with (or after) the onset of diabetes.
Diabetes 1996 Jan
PMID:Pathogenic and protective roles of CD45RB(low) CD4+ cells correlate with cytokine profiles in the spontaneously autoimmune diabetic mouse. 852 63

Inflammatory cytokines, particularly those produced by Th1 type lymphocytes, are hypothesized to play a major role in the pathogenesis of autoimmune diseases. The present studies investigated this hypothesis in the BB rat. Diabetes-prone (DP) BB rats develop spontaneous hyperglycemia and thyroiditis. Coisogenic diabetes-resistant (DR) BB rats do not develop either disorder spontaneously, but both diseases are induced by depletion of RT6+ T cells. Reverse transcriptase-PCR was used to measure mRNA encoding type 1 and type 2 cytokines. In both DP and RT6-depleted DR rats, IFN-gamma mRNA was present in islets before and during disease onset. IL-2 and IL-4 mRNAs were minimal or undetectable in infiltrated islets but present in activated peripheral T cells. IL-10 mRNA was present at low abundance in infiltrating T cells. These observations suggested a Th1 type inflammatory response, and consistent with this interpretation, we observed that mRNA encoding the p40 chain of IL-12 was also present before and during disease onset. Similar cytokine mRNA profiles were observed in the thyroids of RT6-depleted DR rats and in the islets of DP rats treated with prophylactic parenteral insulin to prevent diabetes. We conclude that IFN-gamma and IL-12 may play a major role in the expression of insulitis and thyroiditis in the BB rat, that Th1 lymphocytes may predominate over Th2 lymphocytes in these inflammatory lesions, and that prevention of diabetes by insulin is not associated with an alteration in the cytokine gene profile of islet infiltrating cells.
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PMID:Cytokine gene expression in islets and thyroids of BB rats. IFN-gamma and IL-12p40 mRNA increase with age in both diabetic and insulin-treated nondiabetic BB rats. 855 12

In 28 adult Ins-IFN-gamma transgenic mice, injection of high doses of streptozotocin (STZ; first injection, 300 microgram/g body weight; second injection, 200 microgram/g body weight 4 h later) failed to induce severe hyperglycemia. To the contrary, 28 BALB/c mice developed diabetes mellitus after identical injections of STZ. Because the STZ-induced islet damage was partially inhibited in Ins-IFN-gamma transgenic mice, their glycemia levels became normal 4 days after STZ administration. Both transgenic and BALB/c mice lost weight after receiving STZ, but the body weights of transgenic mice then returned to pretreatment levels in a nearly parallel manner with the glycemia. Immunolabeling with insulin identified an unusual spreading pattern of insulin immunoreactivity. Ultrastructural observations confirmed that beta-cell necrosis and degranulation were more severe in STZ-treated BALB/c than in Ins-IFN-gamma transgenic mice. Moreover, regeneration of pancreatic duct cells and islet neogenesis were observed in the transgenic mice. Therefore, after STZ treatment, the Ins-IFN-gamma transgenic mice apparently were resistant to the induction of severe diabetes, whereas their BALB/c age-matched counterparts succumbed to the disease.
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PMID:Transgenic mice expressing IFN-gamma in pancreatic beta-cells are resistant to streptozotocin-induced diabetes. 857 1

Monocytes from patients with poorly controlled non-insulin-dependent diabetes mellitus (NIDDM) show a decrease in intracellular bactericidal function. To determine whether this reduced bactericidal function is mediated by an impaired oxygen-dependent mechanism, we assayed the production of superoxide (O2-) and hydrogen peroxide (H2O2) by monocytes from poorly controlled NIDDM patients (n = 12), well controlled NIDDM patients (n = 12) and healthy subjects (n = 16). Using phorbol myristate acetate (PMA) as stimulant, the production of O2- by fresh monocytes was significantly decreased in poorly controlled NIDDM patients (231 +/- 30 nmol/mg protein/2-h) as compared with that of well controlled NIDDM patients (430 +/- 81 nmol/mg protein/2-h) and that of healthy subjects (399 +/- 61 nmol/mg protein/2-h), respectively (P < 0.05). Using opsonized zymosan (OZ) as stimulant, the production of O2- by fresh monocytes was also notably decreased in patients with poorly controlled NIDDM (312 +/- 42 nmol/mg protein/2-h) as compared with that of patients with well controlled NIDDM (688 +/- 92 nmol/mg protein/2-h) and that of healthy subjects (539 +/- 96 nmol/mg protein/2-h), respectively (P < 0.05). Poorly controlled NIDDM patients had a significant decrease in the production of H2O2 by monocytes, either stimulated by PMA or OZ, as compared with that of well controlled NIDDM patients and that of healthy subjects, respectively (P < 0.05). Enhancement of the production of O2- and H2O2 occurred in healthy subjects (150% increase) as well as NIDDM patients (170% increase) after a preincubation of monocytes with interferon-gamma (IFN-gamma 100 U/ml) for 48 h. The respiratory burst activity of both fresh and cultured monocytes from well controlled NIDDM patients was not significantly different from that of healthy subjects. This study suggests that both, strict metabolic control and in vitro culture with IFN-gamma may improve the monocyte oxygen-dependent bactericidal mechanism in NIDDM patients.
Diabetes Res Clin Pract 1995 Aug
PMID:Respiratory burst activity of monocytes from patients with non-insulin-dependent diabetes mellitus. 859 99

Cytokines have been shown to play an important role in regulating tolerance to islet Ags and provoking destructive islet lesions. However, data from a number of experimental systems have been conflicting, and the role of cytokines produced by T lymphocytes at various stages of diabetes has not been clearly defined. We have studied the production of cytokines in the pancreas during the development of autoimmune diabetes induced in mice by administration of (5) low doses of streptozotocin (STZ) (MDSDM). Diabetes in this model is T lymphocyte dependent. We used techniques of semiquantitative PCR to identify and quantitate cytokines that are produced. We have found that IL-2, IL-4, TNF-alpha, and IFN-gamma are expressed by the time the fourth dose of STZ is given. In the same pancreas, all of these cytokines (including IL-4) may be found. However, expression of IFN-gamma, but not IL-4, was limited to intrapancreatic lymphocytes and was not detectable at extrapancreatic lymphoid sites. Moreover, mAbs against IFN-gamma, but not against IL-4 or IL-2, prevent hyperglycemia and insulitis in MDSDM, suggesting that IFN-gamma regulates development of disease. Cells in the pancreases of nondiabetic mice treated with anti-IFN-gamma mAb and STZ show enhanced expression of IL-4, but the prevention of disease is due to blockade of the IFN-gamma itself, and not due to secretion of IL-4, because systemic administration of IL-4 does not prevent MDSDM. Thus, our findings indicate that cytokines produced by Th1 (or T cytolytic 1) and Th2 (or T cytolytic 2) cells are found in the pancreases of mice developing autoimmune diabetes. IFN-gamma is responsible for progression to diabetes, and its production is limited to lymphocytes only at that site.
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PMID:Regulation of cytokine production during development of autoimmune diabetes induced with multiple low doses of streptozotocin. 861 81

Cytokines produced by islet-infiltrating mononuclear leukocytes may be involved in islet beta-cell destruction and IDDM. To determine which cytokine(s) might be involved in islet beta-cell destruction, we used a reverse transcriptase-polymerase chain reaction assay to compare levels of cytokine mRNA expression in mononuclear leukocytes freshly isolated from islets of four groups of BB rats aged 60-75 days: diabetes-prone (DP) rats, DP rats protected from diabetes by injection of complete Freund's adjuvant (CFA) at age 25 days, acutely diabetic rats, and diabetes-resistant (DR) rats. We found that islet mononuclear leukocyte levels of gamma-interferon (IFN-gamma) mRNA were significantly higher in DP and diabetic rats than in DR rats, whereas CFA-treated DP rats had similar IFN-gamma mRNA levels to DR rats. Also, interleukin (IL)-2 mRNA levels tended to be higher in islet leukocytes from DP and diabetic rats than from DR rats. Tumor necrosis factor-alpha, IL-4, and IL-10 mRNA levels were not significantly different in islet leukocytes from the four groups of rats. These findings suggest that production of T-helper 1 (Th1)-type cytokines, IFN-gamma and IL-2, by islet-infiltrating cells in BB rats is associated with beta-cell destruction and IDDM development.
Diabetes 1996 Jun
PMID:Cytokine gene expression in pancreatic islet-infiltrating leukocytes of BB rats: expression of Th1 cytokines correlates with beta-cell destructive insulitis and IDDM. 863 48

A possible role of transporter associated with antigen processing (TAP)-1 in the pathogenesis of IDDM has been investigated by examining the level of TAP-1 expression in the islets of IDDM pancreas and by studying in vitro the effect of interferon (IFN)-gamma, IFN-alpha, and tumor necrosis factor-alpha in TAP-1 expression by cultured islet cells. A remarkable hyperexpression of TAP-1 has been found in the endocrine cells (beta and non-beta) of IDDM islets, which constitutes first evidence of hyperexpression of this molecule in the target organ of an autoimmune disease. TAP-1 hyperexpression correlated clearly with HLA class I hyperexpression but only very partially with HLA class II ectopic expression. IFN-gamma and IFN-alpha, both cytokines putatively implicated in IDDM pathogenesis, were capable of inducing TAP-1 protein (as assessed by immunofluorescence flow cytometry) and message (by Northern blot analysis and reverse transcription polymerase chain reaction). These findings suggest that under the influence of cytokines (most probably IFN-alpha) beta-cells may express in their surface a high density of HLA class I-peptide complexes that may facilitate their recognition and lysis by low-affinity CD8+ T-cells.
Diabetes 1996 Jun
PMID:Expression of transporter associated with antigen processing-1 in the endocrine cells of human pancreatic islets: effect of cytokines and evidence of hyperexpression in IDDM. 863 53


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