Kooperativer Bibliotheksverbund

Berlin Brandenburg

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  • 1
    In: Transplantation, 1996, Vol.62(9), pp.1371-1374
    Description: In this study, we investigated the effects of the intracellular metal chelator desferrioxamine (DFO) and the extracellular metal chelator diethylenetriamine penta-acetic acid (DTPA), which were previously shown to have strong anticytomegalovirus potencies, on their ability to elicit immunomodulatory effects in vitro[fcn,3]. The results showed that nontoxic and in vivo attainable concentrations of both DFO and DTPA inhibited mitogen- and allogen-induced proliferation of peripheral blood lymphocytes. The immunomodulatory effects of DFO/DTPA seem to be due to the impaired expression of interleukin-2 receptor and the reduced secretion of interleukin-2. However, metal chelators were more effective than cyclosporine or tacrolimus (FK506) in our in vitro experiments. Moreover, cytotoxicity mediated by lymphokine-activated killer cells and natural killer cells and the expression of HLA and adhesion molecules on cytokine-stimulated endothelial cells were differentially impaired by DFO/DTPA. These results warrant further study of the immunological effects of metal chelators in vivo.
    Keywords: Immunopharmacology ; Immunoregulation ; Metal Chelators ; Desferrioxamine ; Diethylenetriamine Penta-Acetic Acid ; Desferrioxamine ; Diethylenetriamine Penta-Acetic Acid ; Immunoregulation ; Metal Chelators;
    ISSN: 0041-1337
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  • 2
    In: Transplantation, 1996, Vol.61(12), pp.1763-1770
    Description: Transplantation-related pathogenic factors such as ischemia or allograft-directed inflammation are associated with oxidative changes that might lead to cellular oxidative stress. The aim of this study was to investigate the impact of oxidative stress on: (1) CMV replication in cultured human endothelial cells and (2) the stimulation of endothelial cells by proinflammatory cytokines. Both pathomechanisms are known to contribute to graft rejection crises in vivo. Oxidative stress was induced in endothelial cell cultures with 10-200 μM buthionine sulfoximine. Western blotting showed a significant increase in the production of CMV-specific immediate early and late proteins in buthionine sulfoximine-treated cultures. Immunocytochemical staining suggested that this effect was caused by increased numbers of CMV antigen expressing cells (66% immediate early; 78%, late). Quantitative polymerase chain reaction for CMV-specific DNA and virus titration revealed that enhanced viral replication levels correlated with increased virion production. As a measure for the endothelial cell activation status, the surface expression of HLA-ABC and HLA-DR and adhesion molecules(ICAM-1, ELAM-1, VCAM-1) was quantified by fluorometric methods. Whereas oxidative stress alone did not modulate any surface molecule expression, the IFN-γ-mediated expression of HLA-ABC and HLA-DR and the IL-1-mediated expression of ICAM-1, but not of ELAM-1 and VCAM-1 (IL-1+TNF-α), was amplified. Interestingly, the amplification of HLA molecule expression was even higher in CMV-infected endothelial cells. This study provides evidence that oxidative stress contributes to the regulation of CMV replication, virus shedding, and the activation of endothelial cells by proinflammatory cytokines as it is observed in transplant recipients.
    Keywords: Human Cytomegalovirus ; Human Cytomegalovirus ; Endothelium ; Replication ; Oxidation ; Stress ; Man ; Endothelium ; Replication ; Oxidation ; Stress ; Man ; Viruses ; Immune Response & Immune Mechanisms ; Cytokines ; Cytokines ; Cytokines;
    ISSN: 0041-1337
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  • 3
    In: Transplantation, 1999, Vol.68(11), pp.1753-1761
    Description: BACKGROUND.: Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model. METHODS.: One day after liver transplantation, PVG (RT1) into BN(RT1), the rats were infected with rat CMV (RCMV, Maastricht strain; 10 plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined. RESULTS.: In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-α and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells. CONCLUSIONS.: Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.
    Keywords: Adjuvants, Immunologic–Pharmacology ; Animals–Pharmacology ; Antiviral Agents–Metabolism ; Cell Adhesion Molecules–Physiology ; Cytomegalovirus–Immunology ; Cytomegalovirus Infections–Virology ; Deferoxamine–Pharmacology ; Graft Rejection–Complications ; Liver–Drug Effects ; Liver Transplantation–Immunology ; Nephritis–Pathology ; Rats–Virology ; Rats, Inbred Bn–Etiology ; Rats, Inbred Strains–Pathology ; Transplantation, Homologous–Metabolism ; Tumor Necrosis Factor-Alpha–Drug Effects ; Virus Replication–Drug Effects ; Adjuvants, Immunologic ; Antiviral Agents ; Cell Adhesion Molecules ; Tumor Necrosis Factor-Alpha ; Deferoxamine;
    ISSN: 0041-1337
    E-ISSN: 15346080
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  • 4
    In: Transplantation, 2000, Vol.69(4), pp.588-597
    Description: BACKGROUND.: Cyclosporine A (CsA) and tacrolimus prevent proliferation but not transendothelial migration of alloreactive lymphocytes into donor organs. As a result, serious adverse effects, such as nephrotoxicity and neurotoxicity, have been observed under CsA/tacrolimus therapy. The incorporation of new drugs with infiltration blocking properties might enhance the efficacy of the current immunosuppressive protocol, allowing lower CsA/tacrolimus dosage. Because Ca plays a critical role in cell-cell interaction, the Ca-channel blocker verapamil might be a good cany.didate for supporting CsA/tacrolimus-based therap METHODS.: A T-cell endothelial cell coculture model or immobilized immunoglobulin G globulin chimeras were employed to investigate how S- and R- verapamil interfere with the lymphocytic infiltration process. The expression and arrangement of membranous adhesion receptors and cytoskeletal F-actin filaments were analyzed by fluorometric method in the presence of. verapamil. RESULTS.: Both verapamil enantiomers strongly inhibited lymphocyte infiltration. CD4 and CD8 T-cells were influenced to a similar extent with regard to horizontal locomotion (CD4=CD8), but to a different extent with regard to adhesion and penetration (CD4 〉 CD8). Moreover, penetration was blocked to a higher extent than was adhesion. ID50-values were 31 μM (CD4-adhesion) and 11 μM (CD4-penetration). Verapamil reduced P-selectin expression on endothelial cells and effectively down-regulated binding of T-cells to immobilized P-selectin immunoglobulin G globulins (ID50=4.4 μM; CD4). A verapamil-induced reduction of intracellular F-actin in T-lymphocytes was proven to be mainly responsible for diminished cell locomotion. CONCLUSIONS.: The prevention of CD4 T-cell penetration by verapamil might argue for its use as an adjunct to CsA/tacrolimus-based immunosuppressive therapy.
    Keywords: Immunosuppression ; Endothelium ; Lymphocytes T ; Immunosuppressive Agents ; Cell Motility ; Verapamil ; Calcium Channel Blockers ; Experimental ; Function ; Immunology ; Calcium Channel Blockers ; Cell Motility ; Immunology ; Verapamil;
    ISSN: 0041-1337
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