Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human myeloid DC were generated from peripheral blood mononuclear cells by monocyte adhesion and subsequent culture with rhGM-CSF and rhIL-4. We transduced immature (day 5 of culture) myeloid DC with an E1-deleted replication-deficient adenoviral vector encoding the cytokine IL-10 (AdV IL-10) and a control adenovirus MX-17 (AdV MX 17). Human DC transduced with AdV IL-10 showed inhibition of the mixed leukocyte culture, reduced cell surface expression of co-stimulatory molecules (CD80/CD86) and were unable to produce the potent allo-stimulatory cytokine, interleukin-12. In order to test the in vivo properties of these cells a humanized immunodeficient mouse skin transplantation model was developed. Immunodeficient NOD-scid mice were engrafted with human skin, reconstituted via intraperitoneal injection with allogeneic mononuclear cells (MNC) mixed with 1 x 10(6) DC that were autologous to the skin donor and that had been transduced with either AdV IL-10 or AdV MX-17. Skin grafts were removed at day 7 and 14 after reconstitution and studied histologically for evidence of rejection. In animals that received DC modified with AdV IL-10 there was reduced skin graft rejection as characterized by reduced mononuclear cell infiltration and less dermo-epidermal junction destruction compared with those animals that received DC modified with the control virus alone. Injection of equivalent numbers of donor-derived fibroblasts transduced with AdV IL-10 were ineffective at modifying rejection of skin grafts. Immunosuppressive cytokine gene therapy targeting human DC is a novel means of inhibition of the alloimmune response.
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PMID:Human myeloid dendritic cells transduced with an adenoviral interleukin-10 gene construct inhibit human skin graft rejection in humanized NOD-scid chimeric mice. 1150 55

Oral tolerance to myelin basic protein (MBP) is an effective antigen-specific method to suppress experimental allergic encephalomyelitis (EAE). Glatiramer acetate [copolymer 1 (Cop1)] is a synthetic copolymer designed to mimic MBP which suppresses EAE, is used parenterally to treat multiple sclerosis (MS) and is being tested orally for efficacy in MS. We investigated the immunologic properties of Cop1 to determine the degree to which its effects were antigen specific using MBP TCR transgenic mice. Immunization of MBP TCR transgenic mice fed Cop1, MBP or MBP Ac1-11 resulted in decreased proliferation, and IL-2, IL-6 and IFN-gamma production, and increased secretion of IL-10 and transforming growth factor (TGF)-beta in Cop1-fed animals. IFN-gamma was decreased, and IL-10 and TGF-beta were increased in non-immunized mice fed Cop1 and stimulated in vitro with MBP. No such effects were observed in ovalbumin TCR transgenic mice. To determine if the effects of Cop1 were specific to MBP TCR-bearing cells, MBP TCR transgenic Rag2(-/-) mice were immunized and re-stimulated in vitro with Cop1. We found a marked increase in IL-4 and similar increases in IL-4 after feeding Cop1. In disease models, feeding Cop1 suppressed EAE in MBP TCR transgenic mice, (PL/J x SJL)F(1) mice, and in myelin oligodendrocyte glycoprotein-induced EAE in NOD mice. Oral Cop1 had no effect on collagen-induced arthritis. These results demonstrate that Cop1 is active orally in an antigen-specific fashion, and may function as an altered peptide ligand for MBP-specific TCR-bearing cells by decreasing pro-inflammatory cytokines (IFN-gamma) and increasing anti-inflammatory cytokines (IL-4, IL-10 and TGF-beta).
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PMID:Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. 1180 32

Sirolimus is an immunosuppressant that inhibits interleukin (IL)-2 signaling of T-cell proliferation but not IL-2-induced T-cell apoptosis. Therefore, we hypothesized that administration of IL-2, together with sirolimus, might shift T-cell proliferation to apoptosis and prevent autoimmune destruction of islet beta-cells. We found that sirolimus and IL-2 therapy of female NOD mice, beginning at age 10 weeks, was synergistic in preventing diabetes development, and disease prevention continued for 13 weeks after stopping sirolimus and IL-2 therapy. Similarly, sirolimus and IL-2 were synergistic in protecting syngeneic islet grafts from recurrent autoimmune destruction after transplantation in diabetic NOD mice, and diabetes did not recur after stopping sirolimus and IL-2 combination therapy. Immunocytochemical examination of islet grafts revealed significantly decreased numbers of leukocytes together with increased apoptosis of these cells in mice treated with sirolimus and IL-2, whereas beta-cells were more numerous, and significantly fewer were apoptotic. In addition, Th1-type cells (gamma-interferon-positive and IL-2(+)) were decreased the most, and Th2-type cells (IL-4(+) and IL-10(+)) and Th3-type cells (transforming growth factor-beta1(+)) were increased the most in islet grafts of sirolimus and IL-2-treated mice. We conclude that 1) combination therapy with sirolimus and IL-2 is synergistic in protecting islet beta-cells from autoimmune destruction; 2) diabetes prevention continues after withdrawal of therapy; and 3) the mechanism of protection involves a shift from Th1- to Th2- and Th3-type cytokine-producing cells, possibly due to deletion of autoreactive Th1 cells.
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PMID:Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. 1187 61

We have reported previously that oral administration of pig cells to NOD mice modified xenogeneic cellular response against pig islet cells (PICs), and hypothesized that it may have induced active suppression. This preliminary report evaluated only the effect of feeding pig cells by 'primary' proliferation, i.e. when splenocytes from fed mice are confronted with pig cells in vitro. The present study also considered 'secondary' proliferation and cytokine production after feeding and subsequent in vivo graft of pig cells. Additionally, serum IgM and IgG isotypes were quantified by ELISA using pig target cells. Induction of active mechanism by feeding was hypothetical, which led us here to transfer splenocytes from mice fed pig spleen cells (PSC) and evaluate 'primary' (after transfer) and 'secondary' (after transfer and subsequent graft of pig cells) proliferations and cytokine secretions in recipient mice. We also determined whether the effects of feeding pig cells persisted after depression of suppressor mechanisms by cyclophosphamide. Mice fed with PSC displayed increased 'primary' splenocyte proliferation to PSC or PIC (P < 0.0001), while 'secondary' responses were decreased (P < 0.03) in those fed PSC and subsequently grafted with PSC. The increased 'primary' and decreased 'secondary' proliferations were reduced (P < 0.04) by pretreatment with cyclophosphamide. The IL-10/ and IL-4/IFNgamma ratios produced in response to PSC increased (P < 0.04) in mice fed and grafted with PSC compared to those grafted only with PSC. IgM and IgG levels against pig cells were, respectively, increased (P < 0.04) and decreased (P < 0.04) in mice fed and grafted with PSC. IgG2a and IgG2b, but not IgG1, levels were lower (P < 0.01). These effects of feeding PSC on 'secondary' proliferation, cytokine and antibody productions, were not detected when mice were fed PSC only after graft with PSC. Transfer with splenocytes from mice fed PSC increased 'primary' proliferation of splenocytes from recipient mice in response to PSC (P < 0.02) or PIC (P < 0.05). After transfer with splenocytes from PSC-fed mice and graft with PSC, 'secondary' proliferation to pig cells were reduced (P < 0.04), and the IL-10/IFNgamma ratio produced in response to PSC was increased fourfold. Thus, oral administration of PSC induces active transferable mechanisms, characterized by a biphasic pattern with early increased 'primary' xenogeneic cellular reactions to both PSC and PIC, followed by decreased 'secondary' responsiveness and a concomitant shift of the Th1/Th2 balance towards greater Th2 influence. Decreased responsiveness may be due to active suppression, even though induction of anergy or deletion cannot be excluded.
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PMID:Feeding NOD mice with pig splenocytes induces transferable mechanisms that modulate cellular and humoral xenogeneic reactions against pig spleen or islet cells. 1196 56

Autoimmune diabetes recurrence is in part responsible for islet graft destruction in type 1 diabetic individuals. The aim of the present study was to design treatment modalities able to prevent autoimmune diabetes recurrence after islet transplantation in spontaneously diabetic NOD mice. In order to avoid confusion between autoimmune diabetes recurrence and allograft rejection, we performed syngeneic islet transplantations in spontaneously diabetic NOD mice. Mice were treated with mouse interferon-beta (IFN-beta, 1 x 105 IU/day), a new 14-epi-1,25-(OH)2D3-analogue (TX 527, 5 microg/kg/day) and cyclosporin A (CsA, 7.5 mg/kg/day) as single substances and in combinations. Treatment was stopped either 20 days (IFN-beta and CsA) or 30 days (TX 527) after transplantation. Autoimmune diabetes recurred in 100% of control mice (MST 11 days). None of the mono-therapies significantly prolonged islet graft survival. Combining CsA with TX 527 maintained graft function in 67% of recipients as long as treatment was given (MST 31 days, P < 0.01 versus controls). Interestingly, 100% of the IFN-beta plus TX 527-treated mice had normal blood glucose levels during treatment, and even had a more pronounced prolongation of graft survival (MST 62 days, P < 0.005 versus controls). Cytokine mRNA analysis of the grafts 6 days after transplantation revealed a significant decrease in IL-2, IFN-gamma and IL-12 messages in both IFN-beta plus TX 527- and CsA plus TX 527-treated mice, while only in the IFN-beta with TX 527 group were higher levels of IL-10 transcripts observed. Therefore, we conclude that a combination of IFN-beta and TX 527 delays autoimmune diabetes recurrence in islet grafts in spontaneously diabetic NOD mice.
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PMID:Treatment of autoimmune diabetes recurrence in non-obese diabetic mice by mouse interferon-beta in combination with an analogue of 1alpha,25-dihydroxyvitamin-D3. 1198 11

Adhesion molecules are important for leukocyte extravasation and for the delivery of costimulatory signals in T cell activation. We therefore interfered in the immune process leading to islet inflammation in diabetes prone NOD mice by oral vaccination with plasmid DNA encoding soluble ICAM-1. Female NOD mice were treated orally with ICAM-1, TGF-beta, or control plasmid DNA and received a single injection of cyclophosphamide for synchronization and acceleration of the disease process in the pancreas. Quantitative RT-PCR analysis of pancreatic mRNA showed that cyclophosphamide induced the expression of Th1 cytokines (IFN-gamma and IL-12p40) in vehicle- or control plasmid-treated mice. Treatment with ICAM-1 and TGF-beta DNA resulted in increased levels of IL-10 mRNA in the pancreas, indicating an anti-inflammatory regulatory immune response. Histological analysis of pancreatic islets showed that the DNA treatment did not alter islet infiltration in response to cyclophosphamide. Hence vaccination with the ICAM-1 plasmid had not suppressed leukocyte migration but rather modulated lymphocyte activity, similarly as seen for the TGF-beta-encoding plasmid. Neither of the three plasmids caused recognizable changes in cytokine expression in the small intestine, Peyer's patches, or mesenteric lymph nodes. We conclude that oral vaccination with DNA encoding immunoregulatory molecules such as ICAM-1 and TGF-beta represents an approach for modulating the ongoing inflammatory process in the pancreas of diabetes prone NOD mice.
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PMID:Oral DNA vaccination with a plasmid encoding soluble ICAM-1 modulates cytokine expression profiles in nonobese diabetic mice. 1202 42

Linomide prevents the development of autoimmune insulitis and insulin-deficient diabetes mellitus in female NOD mice. Linomide prevents development of autoimmune manifestations in other experimentally induced and spontaneous autoimmune diseases as well, but the mechanism of action is unknown. The present report summarizes our investigations on the effect of Linomide on different functional T cell subsets in NOD mice analyzed according to their cytokine profile. Supernatants from cultured splenocytes and peritoneal cells taken from Linomide-treated mice contained lower levels of TNFalpha, IL-1 beta, IFN gamma and IL-12 versus higher levels of IL-4, IL-6 and IL-10 in comparison with supernatants from cultures of untreated mice. Our results suggest that regulation of autoimmunity following oral Linomide administration in NOD mice induces a shift from Th(1) to Th(2) phenotype response, thereby preventing the development of diabetes by active cytokine-induced immunoregulation of T cell subsets, including downregulation of Th(1) and upregulation of Th(2).
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PMID:Cytokine production in Linomide-treated nod mice and the potential role of a Th (1)/Th(2) shift on autoimmune and anti-inflammatory processes. 1218 43

Islet transplantation represents a potential cure for type 1 diabetes, yet persistent autoimmune and allogeneic immunities currently limit its clinical efficacy. For alleviating the autoimmune destruction of transplanted islets, newly diagnosed NOD mice were provided a single intramuscular injection of recombinant adeno-associated viral vector encoding murine IL-10 (rAAV-IL-10) 4 weeks before renal capsule delivery of 650 syngeneic islets. A dose-dependent protection of islet grafts was observed. Sixty percent (3 of 5) of NOD mice that received a transduction of a high-dose (4 x 10(9) infectious units) rAAV-IL-10 remained normoglycemic for at least 117 days, whereas diabetes recurred within 17 days in mice that received a low-dose rAAV-IL-10 (4 x 10(8) infectious units; 5 of 5) as well as in all of the control mice (5 of 5 untreated and 4 of 4 rAAV-green fluorescent protein-transduced). Serum IL-10 levels positively correlated with prolonged graft survival and were negatively associated with the intensity of autoimmunity. The mechanism of rAAV-IL-10 protection involved a reduction of lymphocytic infiltration as well as induction of antioxidant enzymes manganese superoxide dismutase and heme oxygenase 1 in islet grafts. These studies support the utility of immunoregulatory cytokine gene therapy delivered by rAAV for preventing autoimmune disease recurrence in transplant-based therapies for type 1 diabetes.
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PMID:Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice. 1260 12

A short-term administration of antibodies against ICAM-1/LFA-1 or CD8 molecules during a critical period of younger age resulted in complete protection of autoimmune diabetes in NOD mice. In this study, we attempted to elucidate the tolerance mechanisms. Transfer of splenocytes from both antibody-treated NOD mice to NOD-SCID mice failed to develop diabetes. On the other hand, when splenocytes from diabetic mice were transferred to the antibody-treated mice, 40% of both mAb-treated recipients became diabetic. In vitro response of T cells from these protected mice exhibited strong proliferation against syngeneic islet cells or ConA. Furthermore, semiquantitative RT-PCR analysis of cytokines showed that T cells from anti-CD8-treated mice could express IFN-gamma, IL-4, IL-10 and TGF-beta1 in response to islet antigen. In contrast, T cells from anti-ICAM-1/LFA-1-treated mice expressed IFN-gamma, IL-10 and TGF-beta1 but not IL-4. These results suggest that tolerance mechanisms like clonal deletion, anergy, immunoregulatory T cells or Th1 to Th2/Th3 cytokine shifting are not responsible for the tolerance induction, indicating the presence of other unrevealed mechanism responsible for the loss of capability of autoreactive T cells to infiltrate and destroy the pancreatic beta-cells in vivo.
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PMID:Tolerance mechanisms in murine autoimmune diabetes induced by anti-ICAM-1/LFA-1 mAb and anti-CD8 mAb. 1265 34

Thiazolidinediones acting as PPAR-gamma agonists are a new generation of oral antidiabetics addressing insulin resistance as a main feature of type-2 diabetes. In accordance to our results, pre-clinical studies have demonstrated that the thiazolinedione troglitazone prevents the development of insulin-dependent autoimmune type-1 diabetes. To investigate whether TGZ acts by affecting the ICAM-1/LFA-1 pathway and/or the Th1/Th2 cytokine balance in NOD mice, we analysed the IL-1beta-induced ICAM-1 expression on islet-cells and the LFA-1, CD25, IL-2, IFN-gamma, IL-4, and IL-10 expression on splenocytes. After 200 days of oral TGZ administration, islet cells from TGZ-treated NOD mice showed a reduced ICAM-1 expression in response to the pro-inflammatory cytokine IL-1beta. The expression of the ligand LFA-1 on CD4(+) and CD8(+) T-cells was comparable to that of placebo- and untreated controls. Also, the expression of Th1/Th2 cytokines was comparable in groups receiving TGZ or Placebo. Nevertheless, the investigated NOD mice segregated into IFN-gamma low- and IFN-gamma high producers as revealed by cluster analysis. Interestingly, the majority of TGZ-treated mice belonged to the cluster of IFN-gamma low producers. Thus, the prevention of autoimmune diabetes in NOD mice by TGZ seems to be associated with suppression of IL-1beta-induced ICAM-1 expression leading to a reduced vulnerability of pancreatic beta-cells during the effector stage of beta-cell destruction. In addition, IFN-gamma production was modulated, implicating that alteration of the Th1/Th2 cytokine balance might have contributed to diabetes prevention. The findings of this study suggest that TGZ exerts its effects by influencing both the beta-cells as the target of autoimmune beta-cell destruction and the T-cells as major effectors of the autoimmune process.
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PMID:Prevention of autoimmune diabetes in NOD mice by troglitazone is associated with modulation of ICAM-1 expression on pancreatic islet cells and IFN-gamma expression in splenic T cells. 1271 26


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