Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus (IDDM) is caused by the progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the pathogenesis of autoimmune IDDM has been extensively studied, the precise mechanisms involved in the initiation and progression of beta cell destruction remain unclear. Animal models used in the study of IDDM, such as the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, have greatly enhanced our understanding of the pathogenic mechanisms involved in this disease. In these animals, macrophages and/or dendritic cells are the first cell types to infiltrate the pancreatic islets. Macrophages must be involved in the pathogenesis of IDDM early on, since inactivation of macrophages results in the near-complete prevention of insulitis and diabetes in both NOD mice and BB rats. The presentation of beta cell-specific autoantigens by macrophages and/or dendritic cells to CD4+ T helper cells, in association with MHC class II molecules, is considered the initial step in the development of autoimmune IDDM. The activated macrophages secrete IL-12, which stimulates Th1 type CD4+ T cells. The CD4+ T cells secrete IFN-gamma and IL-2. IFN-gamma activates other resting macrophages, which, in turn, release cytokines, such as IL-1beta, TNF-alpha, and free radicals, which are toxic to beta cells. During this process, IL-2 and other cytokines induce the migration of CD8+ peripheral T cells to the inflamed islets, perhaps by inducing the expression of a specific homing receptor. The precytotoxic CD8+ T cells that bear beta cell-specific autoantigen receptors differentiate into cytotoxic effector T cells upon recognition of the beta cell-specific peptide bound to MHC class I molecules in the presence of beta cell-specific CD4+ T helper cells. The cytotoxic CD8+ T cells then effect beta cell damage by releasing perforin and granzyme, and by Fas-mediated apoptosis. In this way, macrophages, CD4+ T cells, and CD8+ T cells synergistically destroy beta cells, resulting in the onset of autoimmune IDDM.
 ...
PMID:Cellular and molecular mechanisms for the initiation and progression of beta cell destruction resulting from the collaboration between macrophages and T cells. 958 42

Spontaneously diabetic nonobese diabetic (NOD/Lt) mice were treated with anti-T-cell monoclonal antibodies (mAbs) at the time of grafting with vascularized segmental pancreas isografts. Recipients were either untreated or given anti-CD4 and/or anti-CD8 mAbs (0.5 mg/20-g mouse on each of 4 consecutive days), which reduced target cell levels to <5% of normal. Graft function was monitored by measuring blood glucose (BG) levels. Transplants were removed for histological examination when BG returned to >20 mmol/l for two consecutive readings. Isografts from 3- to 4-week-old prediabetic mice placed in untreated diabetic NOD mice ceased functioning in 9-13 days with a mean survival time (MST) +/- SD of 10 +/- 2. Treatment with anti-CD4 prolonged survival significantly (MST = 61 +/- 35 days, P < 0.05 compared with untreated control mice). Anti-CD8 treatment was less effective, but it still significantly improved graft survival (MST = 24 +/- 9 days, P < 0.05 compared with untreated control mice). Anti-CD8 plus anti-CD4 treatment was highly effective in inhibiting autoimmune destruction of the grafts (MST = 97 +/- 8 days). This clearly demonstrates that transient inactivation of most T-cells with anti-CD4 plus anti-CD8 mAbs effectively controls autoimmune disease in the isograft, despite recovery of CD4 and CD8 T-cells to normal levels. Although insulitis developed in the long-term grafts, insulitis scores did not increase between 33 and 100 days, and none of the mice progressed to IDDM in 100 days. Histology showed a predominantly peri-islet T-cell and macrophage infiltrate with ductal expression of the cytokines interleukin (IL)-4, IL-2, and interferon-gamma. There was little infiltrate or expression of cytokines within the islets. Thus, mAb treatment at the time of grafting allowed isograft survival and prevented progression from insulitis to beta-cell destruction.
 ...
PMID:Long-term survival of segmental pancreas isografts in NOD/Lt mice treated with anti-CD4 and anti-CD8 monoclonal antibodies. 972 27

Recent evidence suggests that autoimmune animal diabetes is associated with an imbalance between the Th1 and Th2 arms of the cellular immune system. However, limited data is available regarding the Th1/Th2 imbalance in human Insulin dependent diabetes mellitus (IDDM) patients. Therefore, we examined the peak levels, secretory pattern and total cytokine production (calculated as the area under the curve, AUC) of the Th1 cytokines, IL-2 and IFN-gamma, and Th2 cytokines, IL-4 and IL-10, from stimulated peripheral blood mononuclear cells, from 17 IDDM patients and 24 normal controls. In contrast to controls, diabetic patients were characterized by an early, uniformly low secretion of Th2 cytokines, followed by a late increased secretion of Th1 cytokines. This resulted in significant differences in secretory patterns of IFN-gammaIL-2, IL-4 and IL-10 between the two groups; P<0.001, P<0.005, P<0.005 and P<0.001, respectively. No correlation was found in the diabetic patients between any profiles of the cytokines and their various clinical parameters, including age, gender, disease duration, insulin requirements or glycated hemoglobin levels. In conclusion, our data provides the first comprehensive evidence for an independent and persistent impairment of both Th1 and Th2 cytokine secretory patterns in IDDM patients.
 ...
PMID:Decreased secretion of Th2 cytokines precedes Up-regulated and delayed secretion of Th1 cytokines in activated peripheral blood mononuclear cells from patients with insulin-dependent diabetes mellitus. 987 85

Changes in serum levels of cytokines in organ-specific autoimmune diseases were reviewed. Serum levels of IL-12, critical for the development of Th1 cells, were increased in thyrotoxic patients with Hashimoto's thyroiditis and Graves' disease. Serum levels of IL-5, secreted from Th2 cells, were increased in thyrotoxic patients with Graves' disease, but not in thyrotoxic patients with Hashimoto's thyroiditis. In patients with IDDM, serum levels of Th1 cytokines (IFN-gamma and IL-2) were increased but serum levels of Th2 cytokines (IL-4 and IL-10) were not increased. These findings suggest that measuring the serum concentration of various cytokines is useful to analyze Th1/Th2 balance in autoimmune diseases.
 ...
PMID:[Organ-specific autoimmune diseases and cytokines]. 1034 7

Both IDDM and NIDDM are characterized by deviations in peripheral T and B lymphocyte count, Thelper: Tsuppressor ratio, as well as by impaired Tsuppressor function. These abnormalities may promote insulin antibody and other antibody production, contributing to overt diabetes mellitus development in early stage of the disease. In the present study we explored the effects of cerebrocrast(1, 4-dihydropyridine derivative) administration on Con A- and IL-2-stimulated tissue lymphocyte blast transformation activity and on the thymus and lymph node mass in normal and streptozotocin (STZ)-induced diabetic rats. It was established that cerebrocrast, administered four times at the doses of 0.05 and 0.5 mg kg-1, has long-term (up to 14 days) effects on the immune system and protects against the toxic effect of STZ in STZ-induced diabetic rats, preventing thymus and lymph node mass loss. We conclude that cerebrocrast administration leads to the increase in number and activity of Thelper and Tsuppressor lymphocytes. Glycolysis and DNA synthesis in these cells is augmented under the influence of cerebrocrast administration. We propose that the increase in lymphocyte suppressive activity caused by cerebrocrast administration may prevent the development of IDDM and NIDDM in patients with pre-diabetes, but in patients with early and overt diabetes mellitus the drug administration may prevent the overexpression of insulin antibodies and other antibodies. The effect of cerebrocrast on the de novo production of insulin and IL-2 receptors may be beneficial for IDDM and NIDDM patients.
 ...
PMID:Effect of cerebrocrast on the lymphocyte blast transformation activity in normal and streptozotocin-induced diabetic rats. 1037 54

We have analysed the frequency of cytokine-producing T cells in different dialysis groups (haemodialysis; HD and peritoneal dialysis; PD) over time. Although we saw no difference in type 1 cytokine production (IL-2 and IFN-gamma) in either dialysis group, there was a clear increase in the percentage of T cells spontaneously producing the type 02 cytokines in the PD group (IL-4, r = 0.558, P < 0.05; IL-10, r = 0.527, p < 0.05). Our patient group was carefully selected to include patients with an ongoing autoimmune disease, insulin dependent diabetes mellitus (IDDM) (DN group) and chronic glomerulonephritis (GN), which are common reasons of end stage renal failure. As expected there was no increase in the spontaneous production of either IL-4 or IL-10 in either disease group with patients undergoing HD treatment. However, there was a clear correlation with the frequency of T cells producing IL-4 (r = 0.755, P < 0.05) and IL-10 (r = 0.725, P < 0.05) and time on dialysis in the PD patients with DN, but not those with GN. Much work has suggested that the pathogenesis of IDDM is associated with a Th1 dominated response. We show here that this response is skewed towards a Th2 response after long term treatment with PD. This work demonstrates that the immunological effects of different dialysis modalities on patients with different diseases vary. This may go some way to explain why certain patient groups have more complications with different dialysis modalities.
 ...
PMID:The frequency of Th2 type cells increases with time on peritoneal dialysis in patients with diabetic nephropathy. 1040 Aug 28

IDDM is a T cell-mediated autoimmune disease which is paradoxically associated with T cell functional deficiencies. The proliferative response of PBMC under CD3-, Vbeta2-, Vbeta8- and Vbeta7-stimulation was investigated in IDDM and NIDDM patients, non-diabetic first-degree relatives and control subjects. Despite normal surface expression of the TCR/CD3 complex, the TCR/CD3-mediated proliferation of PBMC from IDDM patients was significantly impaired compared to control subjects (P<0.05). This defect was specific for the autoimmune disease, constitutive and not linked to the class II MHC genotype, to metabolic disturbances or to presence of specific autoantibodies. Inefficient activation of T cells was not related to a lower capacity of CD28 to transduce co-stimulative signals because proliferative responses under CD2/CD28 stimulations were similar in IDDM and control groups. The IL-2/IL-2 receptor system was functional because unstimulated PBMC proliferated in response to increasing amounts of IL-2. Nevertheless, despite normal expression of CD25, addition of IL-2 did not normalize the proliferative defect linked to IDDM. In conclusion, excluding a faulty co-stimulation pathway, these results are in favour of a constitutive defect in the CD3/TCR transduction machinery, increasing sensitivity to apoptosis or anergy in T cells from IDDM patients.
 ...
PMID:Constitutive impaired TCR/CD3-mediated activation of T cells in IDDM patients co-exist with normal co-stimulation pathways. 1047 93

Although CD8+ T cells play a major role in beta cell destruction in insulin-dependent diabetes in the non-obese diabetic mouse, the T cell autoantigen(s) recognized by such cells remains to be identified. Therefore, an islet-reactive, CD8+ T cell line was generated from islet-infiltrating cells and hybridized by fusion with a CD8+ alphabeta TCR- BW5147 thymoma. In the presence of islets, none of the 12 CD3+ CD8+ T cell hybridomas isolated secreted IL-2/IL-4 or IFNgamma but three were islet specific, as shown by activation induced cell death. Subclone 4A7.7.15 recognized only islets expressing H-2Kd, demonstrated islet-specific inhibition of proliferation and concomitant partial arrest in the G2/M phase of the cell cycle. Further analysis using a panel of cell lines, expressing H-2Kd, and transfected with the cDNA for various putative autoantigens in type 1 diabetes showed that 4A7.7.15 recognizes insulin as an antigen.
 ...
PMID:An islet-specific CD8+ T cell hybridoma generated from non-obese diabetic mice recognizes insulin as an autoantigen. 1074 64

Early graft failure, graft rejection, and autoimmune recurrence remain unresolved issues in islet xenotransplantation in type 1 diabetes. The first aim of this study was to examine the existence of early graft failure in spontaneously diabetic autoimmune NOD mice after rat islet transplantation under technically controlled circumstances. The second aim was to examine the mediators of this early xenograft dysfunction. First, we demonstrated a higher percentage of early xenograft failure (48%) in spontaneously diabetic NOD mice as compared with chemically diabetic old NOD (13%, P < 0.05) and C57Bl/6 (7%, P < 0.01) mice. In addition, in spontaneously diabetic NOD mice, xenogeneic islets displayed early graft failure more frequently than allogeneic (23%, P < or = 0.05) or isogeneic islets (7%, P < 0.01). No early graft failure was observed in allotransplantation or isotransplantation in chemically diabetic mice. Reverse transcriptase-polymerase chain reaction analysis of cytokine mRNA in islet xenografts 8 h after transplantation showed higher levels of interleukin (IL)-1 mRNA in autoimmune diabetic mice compared with chemically diabetic old NOD mice (1.40 +/- 0.32 vs. 0.90 +/- 0.14 IL-1 copies/beta-actin copies, P < 0.05). In contrast, mRNA levels of transforming growth factor (TGF)-beta were lower in spontaneously diabetic NOD mice than in chemically diabetic old NOD mice (0.67 +/- 0.16 vs. 1.36 +/- 0.50 TGF-beta copies/beta-actin copies, P < 0.05). No differences in tumor necrosis factor-alpha, IL-6, and inducible nitric oxide synthase were seen between autoimmune and nonautoimmune diabetic mice. T-cell cytokines (IL-2, IL-4, IL-10, and gamma-interferon) were absent in all mice until 48 h after transplantation. These data suggest that early islet xenograft failure is more common in spontaneously diabetic NOD mice and could be due to a nonspecific inflammatory reaction locally in the grafts.
 ...
PMID:Early graft failure of xenogeneic islets in NOD mice is accompanied by high levels of interleukin-1 and low levels of transforming growth factor-beta mRNA in the grafts. 1111 99

Cytotoxic T lymphocytes (CTL) against pancreatic beta-cells probably play a major role in the etiology of type 1 diabetes mellitus (DM). CTLs recognize a complex formed between MHC class I and antigenic peptides fragments derived from intracellular processing of proteins. However, the exogenous peptides, which show strong affinities to MHC class I, can be presented. In this study, we focused on the cytotoxic activity of peripheral lymphocytes in patients with type 1 DM against the peptides of glutamic acid decarboxylase (GAD) and insulin, which can bind MHC class 1 A24. Lymphocytes were isolated from peripheral blood of 12 type 1 DM patients and eight healthy control subjects. The effector cells were cultured with peptides, IL-2 and IL-7, restimulated weekly by autologous antigen presenting cells, which were cultured with IL-4 and GM-CSF. On day 21, CTL activities of cultured effector cells were tested against autologous EB-blast cells as target cells pulsed with the stimulating peptides using 51Cr release assay. The results showed that cytotoxicity against insulin peptide binding to MHC class I A24 was observed in lymphocytes of four out of ten patients with type 1 DM. The mean cytotoxicity was 46.0% of the maximum release. The antibody against HLA-class I inhibited this effect. Cytotoxicity against GAD peptide which bind MHC class I A24 was not observed in seven patients. None of healthy controls showed cytotoxicity against GAD or insulin peptides was observed. This is the first report describing the cytotoxic activity of CD8+ T lymphocytes against insulin in type 1 DM.
 ...
PMID:Peptide-specific cytotoxicity of T lymphocytes against glutamic acid decarboxylase and insulin in type 1 diabetes mellitus. 1126 89


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>