Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.148 (Thy1)
 1,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early intensive insulin treatment is thought to improve subsequent Beta-cell function in Type 1 (insulin-dependent) diabetic patients. Prophylactic insulin administration also reduced diabetes incidence in diabetes-prone animals. To study the mechanisms by which these effects occur, we tested the ability of insulin therapy in the model of non-obese-diabetic mice, to prevent the penetration of committed T cells into the islets and subsequent Beta-cell destruction. Sublethally irradiated non-obese-diabetic males of 8 weeks of age were adoptively transferred with splenocytes from diabetic donors and treated with the maximum tolerable dosage of fast-acting insulin (0.5 U, twice daily) until 30 days after cell transfer. Diabetes incidence was compared to control animals injected with the same concentration of insulin diluent. After one month of treatment, the cumulative diabetes frequency was significantly less within the insulin-treated group (4 of 15, 26.6%) than in the control group (15 of 18, 83.3%; p less than 0.01). Pancreatic histological analysis of insulin-treated animals revealed a lower severity of insulitis and Beta-cell necrosis and a higher percentage of normal islets (46.6 +/- 10% vs 2.3 +/- 2%, p less than 0.01), including five (33%) mice with no lesions. Immunoperoxydase staining of pancreatic sections indicated similar insulin and ganglioside staining of Beta cells from insulin-treated mice and control animals. Insulin-treated mice had comparable pancreatic insulin content to normal mice. Flow cytometry analysis of spleen cell populations indicated that insulin increased the number of Thy1,2+ and Lyt-2+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin prevents adoptive cell transfer of diabetes in the autoimmune non-obese diabetic mouse. 186 85

Proliferation of islet-associated leukocytes occurred when isolated islets from 20 week-old female Non-obese Diabetic (NOD) mice were cultured with 10 U/ml recombinant interleukin-2 (rIL-2) for 7 days. Co-culture of these lymphocytes with freshly-isolated islets from 6-8 week-old NOD donors in the presence of 1 U/ml rIL-2 produced islet structural deformation within 24 h and islet cytolysis within 48 h. Three lines of evidence suggest that leukocytes were cytotoxic T lymphocytes (CTL) specific for islet cells. First, these proliferating cells adhered to NOD islets at 6 h and specifically killed islets after 48 h of culture, but the cytoadherence of these cells to the other organs including thyroid, pancreatic exocrine glands and liver from NOD mice could not be observed and the shape of tissue clumps hardly deformed after culture for 48 h. The accumulated insulin release from NOD islets to the medium after 6 h of culture was significantly increased in the presence of islet-derived cells compared with the insulin release in the absence of cells. On the contrary, lactic dehydrogenase activity released from liver and amylase activity from pancreatic exocrine glands showed on difference between with and without these cells for 6h of culture. Second, a flow cytometric analysis showed that these cells consisted of 96%Thy1.2, 70%Lyt2, and 8%L3T4-positive cells. After treatment with monoclonal anti-Thy1.2 or Lyt2 antibody and complement, these cells lost their activity to destroy NOD islets. However, these cells still had a full killing activity after the depletion of L3T4-positive cells. Third, islets of NOD (H-2 genotype KdDb), B10.GD (H-2KdDb), BALB/cA (H-2d), and DBA/2N (H-2d) were susceptible to destructive activity of these cells, whereas islets of NON (H-2b), C57BL/6N (H-2b), C57BL/10J (H-2b), and C3H/He (H-2k) mice remained intact. Furthermore, anti-Kd monoclonal antibody could prevent islet-specific cytolysis of these cells. These results suggest that CTL expressing Thy1.2 and Lyt2 phenotypes appear to recognize islet cell antigen with restriction of major histocompatibility complex (MHC) class H-2Kd and then destroy pancreatic beta cells in NOD mice.
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PMID:[Studies on the pathogenesis of type I diabetes mellitus--destruction of pancreatic beta cells by cytotoxic T lymphocytes in nonobese diabetic mice]. 218 54

To assess the effects of high blood glucose concentration on glomerular changes after the acute mesangial cell injury in the rat, the monoclonal anti-Thy1.1 antibody OX-7 was injected into streptozoticin-induced diabetic rats or normal rats. The increase in proliferating cell nuclear antigen-positive cells in glomeruli at day 4 and glomerular hypercellularity at day 18 was less prominent in diabetic rats than in normal rats. The expansion of mesangial matrix area assessed by fibronectin immunostaining was more prominent, and segmental glomerulosclerosis was observed at day 60 in the diabetic rats. These data suggest that the insulin-deficient group may reflect impaired "wound-healing," leading to the prolonged ECM accumulation under the hyperglycemic condition in vivo.
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PMID:In vivo effects of hyperglycemia on the outcome of acute mesangial injury in rats. 782 41

Since the modulation of the immune system at birth may influence the course of insulin-dependent (type 1) diabetes, we investigated whether neonatal injections of cyclosporin (CsA) to newborn non-obese diabetic (NOD) mice influence diabetes during later life. Two groups of 90 mice (45 female, 45 male) were injected intraperitoneally for the first 6 days of life with CsA (10 mg/kg per day) or with vehicle. In female NOD mice, the onset of diabetes was earlier and cumulative incidence was higher after neonatal treatment with CsA (P < 0.01). The incidence of diabetes was also dramatically enhanced in male NOD mice (P < 0.01), which normally display a very low disease incidence. Concomitantly, the severity of lymphocytic infiltration of the pancreatic islets was higher in female NOD mice neonatally treated by CsA (P < 0.02), and to a lesser extent in males, than in control mice. After administration of CsA to newborn NOD mice, there was a reduction (P < 0.01) of both CD4+CD8- and CD4-CD8+ thymocytes, whereas the number of double positive CD4+CD8+ thymocytes was increased. Concomitantly, Thy1-2+ cells in spleen were decreased (P < 0.01), and spleen cells expressing either CD3 molecule or alpha beta TCR complex were diminished (P < 0.01). Both CD4+ and CD8+ spleen T cells were depleted. By contrast, the low percentage of gamma delta TCR-expressing splenocytes was not modified. Numbers of MHC class 1+ or MHC class 2+ spleen cells were also depressed (P < 0.01). After neonatal injections of CsA, spleen cells showed a reduced response to concanavalin A (Con A) (P < 0.01). On the contrary, stimulation indices of splenocytes incubated with xenogeneic insulin-producing cell extracts were enhanced (P < 0.03). Proliferation indices of splenocytes to self class 2 antigens, generating suppressor cell activity, during syngeneic mixed lymphocyte reaction (SMLR) were significantly reduced (P < 0.01). Irradiated NOD mice were used as recipients for spleen cells from CsA-neonatally treated NOD mice. They displayed enhanced insulitis 2 weeks after transfer, and diabetes was successfully produced by 1 month after transfer in 50% of the recipients. By contrast, NOD mice which received control syngeneic spleen cells remained normoglycaemic, with only moderate islet infiltration which would be expected of NOD mice of this age. Thus, neonatal injections of CsA markedly enhance diabetes in both female and male NOD mice.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neonatal injections of cyclosporin enhance autoimmune diabetes in non-obese diabetic mice. 803 11

An unexpected observation led us to investigate whether a short course (7 days) of oral cyclosporin (CsA) at different doses (5, 10, 20 or 40 mg/kg/day) in nonobese diabetic (NOD) mice could modify the expression of islet antigens related to the autoimmune process. Analysis was performed on the last day of CsA administration, and then up to 60 days after CsA withdrawal. Antigen modulation was analysed by indirect immunofluorescence using islet-cell antibody (ICA)-positive human sera for ICA antigens, and by immunoperoxidase for glutamic acid decarboxylase 67 Kd (GAD67). Concomitantly, beta-cell function was evaluated by in vivo glucose tolerance and insulin response from isolated islets. The severity of insulitis and histological damage to islets was quantified. We measured splenocyte and thymocyte subsets by cytofluorometry (CD4+ CD8-, CD4- CD8+, and double-positive thymocytes; Thy1-2+, CD3+, CD4+, and CD8+ spleen cells) and determined splenocyte mitogenesis in response to concanavalin A. Even when the lowest dose (5 mg/kg) was used, CsA concentrated in the islets. A graded reduction of ICA antigens was detected, showing no effect for 5 mg/kg/day but a significant dose-dependent reduction (P < 0.01) with 10, 20 and 40 mg/kg/day. GAD67 expression was also reduced (P < 0.03) in a CsA dose-dependent manner. On the other hand, only treatment with the highest CsA dose (40 mg/kg/day) induced glucose intolerance in vivo (P < 0.02), decreased insulin sensitivity to glucose from isolated islets (P < 0.03), reduced insulitis (P < 0.03), and altered thymocyte and splenocyte phenotypes and mitogenesis (P < 0.02). Moreover, the reversibility of the different effects was different: islet antigens were not completely recovered 2 months after CsA withdrawal, whereas other immunologic and metabolic effects obtained with the highest CsA dose were reversed within 15 days. Thus, a short course of low CsA doses in NOD mice produced a pancreatic concentration of the drug which reduced the expression of certain islet antigens for several weeks, whereas major effects on immunological parameters and islet insulin release occurred only with higher CsA doses and improved more rapidly.
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PMID:Cyclosporin depresses pancreatic islet expression of antigens for islet cell autoantibodies in non obese diabetic mice. 884 51

Abnormalities in postthymic T cell development in the BB/W rat model of autoimmune insulin-dependent diabetes mellitus (IDDM) result in part from a lymphopenia (lyp) gene defect. To better characterize these abnormalities, the phenotypes of T cells from diabetes-prone (DP) and diabetes-resistant (DR) coisogenic rats were analyzed by multiparameter flow immunocytometry (FCM). Marked decreases in the numbers of Thy1- RT6+ T cells, most of which are CD8+, were documented in DP rats by live-gating. Conversely, an approximately 3-fold increase was observed in the percentage of Thy1+ RT6- T cells, which normally serve as the precursors of both Thy1- RT6+ and Thy1- RT6- T cell subsets in rats. These results suggested that, at a minimum, an arrest in maturation of the Thy1+ precursors of RT6+ T cells occurs postthymically in DP rats. To determine more precisely the stage(s) in T cell development at which lymphopenia occurs, the export and fate of recent thymic emigrants (RTE's) and their immediate descendants in DP rats was traced after intrathymic (i.t.) labelling with fluorescein isothiocyanate (FITC). The results showed that in DP, as compared with DR, rats: 1) 5-fold fewer RTE's are exported from the thymus per 24 hr; 2) more than 80% of the RTE's are CD4+; 3) most of the immediate descendants of RTE's disappear from the peripheral lymphoid tissues within one week after export from the thymus; and 4) few of the descendants of the RTE's that do survive differentiate into RT6+ T cells. Staining with propidium iodide revealed that a significantly higher proportion of Thy1+ T cells in DP than in DR rats are in cycle (S/G2/M), thereby accounting for their disproportionately high numbers relative to RTE's. These results indicate that, in addition to defective thymic export, most of the immediate descendants of RTE's in DP rats undergo non-productive proliferation and death at the time (3-7 days postthymic) at which their counterparts in DR rats differentiate into Thy1- RT6+ T cells. The resulting deficiency of immunoregulatory T cells, acting in concert with defective intrathymic selection of effector T cell precursors, appears to conspire to markedly enhance the predisposition of DP rats to autoimmunity.
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PMID:Abnormalities in the export and fate of recent thymic emigrants in diabetes-prone BB/W rats. 893 86

Oral administration of antigens has been proposed in the prevention and treatment of autoimmune diseases. We reported that oral administration of 0.8 mg of recombinant human insulin to 6-week-old NOD mice every other day for a month generated regulatory T-cells that were able to reduce the severity of insulitis and the percentage of clinical diabetes in naive irradiated recipients when co-injected with diabetogenic T-cells. In the present study, immunohistochemical analysis of the pancreatic glands revealed that injection of T-cells from insulin-fed mice upregulated the number of interleukin (IL)-4-secreting cells within the islets. Using two strains of NOD mice congenic at the Tbeta, or Thy1, locus, we observed a higher proportion of T-cells from insulin-fed mice in both the spleen (7.73 +/- 0.3 vs. 5.57 +/- 0.2%; P < 0.001) and the pancreatic lymph nodes (10.1 +/- 0.8 vs. 7.2 +/- 0.7%; P < 0.05) of cotransferred mice. By reverse transcription-polymerase chain reaction (RT-PCR) analysis, mice reconstituted with T-cells from insulin-fed animals had detectable amounts of IL-4 mRNA, specifically in the pancreatic lymph nodes (8 of 9 experimental mice vs. 1 of 9 control mice) and the pancreas (3 of 3 experimental mice vs. 0 of 3 control mice). Gamma-interferon mRNA was detectable in all cotransferred animals, but IL-10 mRNA and transforming growth factor beta mRNA were undetectable. These results suggested a shift from a T-helper 1 (Th1) to a Th2 pattern of cytokine expression and underlined the role of pancreatic lymph nodes in the protection. Repeated injections of 500 microg s.c. of anti-IL-4 monoclonal antibody led to an accentuation of the severity of islet infiltration and to the development of clinical diabetes. We concluded that oral administration of insulin can induce the presence of regulatory T-cells in the pancreas and the corresponding draining lymph nodes, initiate the secretion of IL-4 in this microenvironment sufficiently to suppress the activity of Th1 autoreactive T-cell clones, and ultimately provide protection against autoimmune diabetes.
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PMID:Protection against autoimmune diabetes with oral insulin is associated with the presence of IL-4 type 2 T-cells in the pancreas and pancreatic lymph nodes. 942 72

Restoration of peripheral tolerance to target autoantigens during autoimmune diseases has met with several limitations because of the limited efficacy of this approach in an already immune host. To optimize the induction of tolerance, we have shown that feeding insulin conjugated to cholera toxin B-subunit (CTB), a potent mucosal adjuvant, reduced by 5,000 the amounts of antigen necessary for delaying diabetes onset in NOD mice. To analyze these protective mechanisms, we have performed cotransfer experiments using splenocytes from young females fed once with 10 microg of CTB-insulin, mixed with diabetogenic T-cells, and intravenously injected into irradiated syngeneic male recipients. We demonstrated that the delayed onset of diabetes relied on CD4+ T-cells. We studied the cytokine production from plate-bound anti-CD3-stimulated cells. Higher interleukin (IL)-4 amounts were observed in both splenocytes and pancreatic lymph node (PLN) cell cultures from CTB-insulin-fed mice as soon as 4 h after the feeding. An increase in the levels of transforming growth factor-beta was seen after 24 h only in the mesenteric lymph nodes (MLN). In both of these organs, a reduction of gamma-interferon (IFN-gamma) production occurred after CTB-insulin treatment, at 24 h in the PLN and at 7 days in the MLN. Reverse transcription-polymerase chain reaction analysis indicated an increase in the level of IL-4 and a reduction in IFN-gamma transcripts in the PLN of mice treated orally with CTB-insulin and of the recipients of regulatory T-cells. Using different strains of congenic NOD mice at the Thy1 locus, we showed that protection was associated with the accumulation of T-cells from CTB-insulin-fed mice in the lymph nodes from draining sites containing functional islets, i.e., the PLN in normal mice and the renal lymph nodes after a syngeneic islet graft under the kidney capsule of streptozotocin-treated mice. Taken together, our results clearly indicate that oral administration of CTB-insulin conjugates in NOD mice produced a shift from a T-helper type 1 to a type 2 profile with the induction of antigen-specific regulatory CD4+ T-cells in the vicinity of the mucosal barrier and close to the inflamed islets.
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PMID:Oral administration of cholera toxin B-insulin conjugates protects NOD mice from autoimmune diabetes by inducing CD4+ regulatory T-cells. 1053 48

Stem cells are interesting candidates as a new source for cell/organ culture or cell transplantation concepts. So far it is believed that the hepatoblast is the common progenitor cell during fetal liver development. In previous studies two distinct fractions of liver cells were found during development: cells co-expressing Thy1 and CK-18 (cytokeratin-18) and cells expressing CK-18 only. In this study we cultured Thy1-positive and Thy1-negative hepatic progenitors isolated from collagenase digested fetal rat livers after depletion of OX43/OX44-positive hematopoietic cells. The cells were cultured on a collagen-I matrix in a medium containing epidermal growth factor, insulin, and fetal calf serum. Thy1-positive cells isolated from ED16, ED18, or ED20 livers showed significantly enhanced cell growth compared with Thy1-negative cells during the culture period. Both cell types showed expression of the liver-specific genes CK-18, albumin and alpha-feto-protein at the beginning of the culture period, as assessed by reverse-transcription polymerase chain reaction and immunocytochemistry. The growth of Thy1-positive cells was significantly higher when compared with Thy1-negative cells and declined with maturation of the liver. The data suggest a stem cell-like growth potential of Thy1-positive fetal hepatic cells. Thus, these cells might be useful for concepts of cell-based therapies. However, further efforts must be undertaken to define the biological, ethical, and legal aspects of using fetal cells.
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PMID:Cell growth and differentiation of different hepatic cells isolated from fetal rat liver in vitro. 1649 49

Impaired glomerular endothelial integrity is pivotal in various renal diseases and depends on both the degree of glomerular endothelial injury and the effectiveness of glomerular endothelial repair. Glomerular endothelial repair is, in part, mediated by bone marrow-derived endothelial progenitor cells. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists have therapeutic actions independent of their insulin-sensitizing effects, including enhancement of endothelial progenitor cell function and differentiation. We evaluated the effect of PPAR-gamma agonist rosiglitazone (4 mg.kg(-1).day(-1)) on the course of anti-Thy1-glomerulonephritis in rats. Rosiglitazone limited the development of proteinuria and prevented plasma urea elevation (8.1 +/- 0.4 vs. 12.5 +/- 1.1 mmol/l, P = 0.002). Histologically, inflammatory cell influx was not affected, but rosiglitazone-treated rats did show fewer microaneurysmatic glomeruli on day 7 (26 +/- 3 vs. 41 +/- 5%, P = 0.01) and reduced activation of matrix production with reduced renal cortical transforming growth factor-beta, plasminogen activator inhibitor type 1, and fibronectin-1 mRNA expression. However, bone marrow-derived endothelial cell glomerular incorporation was not enhanced (3.1 +/- 0.4 vs. 3.6 +/- 0.3 cells/glomerular cross section; P = 0.31). Rosiglitazone treatment in nonnephritic rats did not influence proteinuria, urea, or renal histology. In conclusion, treatment with PPAR-gamma agonist rosiglitazone ameliorates the course of experimental glomerulonephritis in a nondiabetic model, but not through enhancing incorporation of bone marrow-derived endothelial cells in the glomerulus.
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PMID:Amelioration of anti-Thy1-glomerulonephritis by PPAR-gamma agonism without increase of endothelial progenitor cell homing. 1807 1


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