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  • 1
    Electronic Resource
    Electronic Resource
    Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells (2006)
    [s.l.] : Nature Publishing Group
    Nature medicine 12 (2006), S. 688-692 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Despite a more than 20-year experience of therapeutic benefit, the relevant molecular and cellular targets of intravenous immunoglobulin (IVIg) in autoimmune disease remain unclear. Contrary to the prevailing theories of IVIg action in autoimmunity, we show that IVIg drives signaling through ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm1416
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    Paper (German National Licenses)
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  • 2
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    MicroRNA MiR-17 retards tissue growth and represses fibronectin expression (2009)
    Springer Nature
    Details
    Publication Date: 2009-07-26
    Print ISSN: 1465-7392
    Electronic ISSN: 1476-4679
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 3
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    Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells (2006)
    Springer Nature
    Details
    Publication Date: 2006-05-21
    Print ISSN: 1078-8956
    Electronic ISSN: 1546-170X
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 4
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    Can IVIg Preparations with Specificity for Soluble Antigens Mimic the Therapeutic Effects of IVIg in the Treatment of Immune Thrombocytopenia?. (2004)
    American Society of Hematology
    Details
    Publication Date: 2004-11-16
    Description: Intravenous immunoglobulin (IVIg) mediates protection from the effects of immune thrombocytopenic purpura (ITP). In addition, an IVIg specific for a cell-associated antigen (anti-D) is also able to increase platelet counts in D positive subjects with ITP. Whether an IVIg directed to a soluble antigen can likewise be beneficial in ITP is, however, unknown. A murine model of ITP was used to determine the effectiveness of IgG specific to soluble antigens in treating immune thrombocytopenia. Ovalbumin (OVA) was selected as the primary target antigen because it can be used in its soluble form or can be coupled to syngeneic red blood cells (OVA-RBC), and the same anti-OVA antibody could be used with both OVA and OVA-RBC. Mice were injected with either preformed soluble OVA + anti-OVA, OVA-RBC’s presensitised with anti-OVA, or appropriate control preparations, followed by an anti-platelet antibody to induce thrombocytopenia. Both experimental regimes, but none of the control preparations, protected mice from ITP. Similar to IVIg, soluble OVA + anti-OVA did not have any effect on thrombocytopenia in mice lacking the inhibitory receptor FcγRIIB (FcγRIIB−/−). In contrast, injection of anti-OVA sensitised OVA-RBC’s did ameliorate thrombocytopenia in FcγRIIB−/− mice. Finally, mice injected with IgG specific for the endogenous soluble antigens, albumin and transferrin, also inhibited ITP in an FcγRIIB-dependent manner. We conclude that IgG antibodies directed to soluble antigens can inhibit or reverse immune thrombocytopenia in an FcγRIIB-dependent manner.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 5
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    Monoclonal antibodies that mimic the action of anti-D in the amelioration of murine ITP act by a mechanism distinct from that of IVIg (2005)
    American Society of Hematology
    Details
    Publication Date: 2005-02-15
    Description: The mechanism of action of intravenous immunoglobulin (IVIg) and polyclonal anti-D–mediated reversal of immune thrombocytopenia (ITP) is still unclear. However, in a murine model of ITP, the therapeutic effect of IVIg appears to be wholly dependent upon the expression of the inhibitory Fc receptor, FcγRIIB. We previously demonstrated that, similar to anti-D in humans, 2 erythrocyte-reactive monoclonal antibodies (TER119 and M1/69) ameliorated murine ITP and inhibited reticuloendothelial system (RES) function at doses that protected against thrombocytopenia. The current study evaluated the involvement of the inhibitory and activating Fc receptors, FcγRIIB and FcγRIIIA, respectively, in the TER119 and M1/69-mediated inhibition of thrombocytopenia. In contrast to IVIg, in FcγRIIB-deficient mice, both monoclonal antibodies ameliorated ITP and both significantly down-regulated the level of expression of the activating FcγRIIIA in splenic macrophages. These results indicate that anti-erythrocyte antibodies that ameliorate ITP act independently of FcγRIIB expression but are dependent upon the activating FcγRIIIA.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 6
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    IVIg-Primed Splenocytes Ameliorate Murine ITP in an MHC Class II-Unrestricted Manner. (2007)
    American Society of Hematology
    Details
    Publication Date: 2007-11-16
    Description: We have previously demonstrated that IVIg-primed leukocytes can, upon transfer to naïve mice, completley recapitulate the therapeutic effects of IVIg in treating immune thrombocytopenia in a murine model. Dendritic cells (DC) appear to be the primary cellular target of IVIg in this model. The exact pathway by which IVIg-primed DC inhibit platelet clearance remains, however, unknown. DC are professional antigen presenting cells of haematopoietic origin that are specialized for the capture, processing and presentation of antigens to T cells via their MHC Class II. This primary function of DC is absolutely dependent on MHC Class II expression. Herein, we have evaluated the efficacy of action of IVIg-primed splenocytes from MHC mismatched mice in the amelioration of murine ITP. Mice expressing the Class II haplotype I-Ab (C57BL/6) were injected intravenously with IVIg-primed splenocytes from syngeneic mice, or Balb/C mice (Class II haplotype I-Ad /I-Ed) or CD1 mice (outbred, mixed Class II haplotype I-A/E) prior to the induction of thrombocytopenia by an anti-platelet antibody. We found that IVIg-primed splenocytes from all strains of mice tested were able to successfully ameliorate thrombocytopenia in C57BL/6 mice, regardless of Class II haplotype. None of the splenocytes primed with a control protein, BSA, ameliorated thrombocytopenia. To confirm our findings that IVIg-primed splenocytes function independent of MHC haplotype, we next employed IVIg-primed splenocytes from MHC Class II deficient mice and found these splenocytes were also able to successfully ameliorate murine thrombocytopenia. These data demonstrate a non-MHC-restricted function for DC in IVIg function, and suggest that IVIg-primed DC function occurs independent of MHC Class II expression in the amelioration of murine ITP. In addition, since this potential new cell-based therapy for ITP is not MHC-restricted, we speculate that IVIg-primed DC from any donor (including autologous) could theoretically be used to treat individuals with ITP or other autoimmune diseases without the requirement for donor matching.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 7
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    Monoclonal IgG Specific for the CD44 Antigen Mimics the Action of IVIg in the Amelioration of ITP. (2005)
    American Society of Hematology
    Details
    Publication Date: 2005-11-16
    Description: Previous work in our laboratory has shown that both IVIg and “anti-D like” erythrocyte-reactive antibodies ameliorate immune thrombocytopenia (ITP) in a murine model. However, they appear to function through different mechanisms: IVIg is dependent upon the inhibitory Fc receptor, FcγRIIB in the amelioration of ITP, but the anti-erythrocyte antibodies function independently of FcγRIIB expression. We have also demonstrated that anti-erythrocyte antibodies down-modulate the expression of the activating Fc receptor, FcγRIIIA in splenic macrophages during the amelioration of ITP. A monoclonal antibody to CD44, cell surface protein involved in cell homing, cancer progression and inflammation, can also ameliorate murine ITP. Elucidation of the mechanisms of action of anti-CD44 antibodies in the amelioration of ITP would be critical to the successful application of this potential therapy. In this report, two monoclonal antibodies against CD44, KM114 and IM7 were studied in C57BL/6 and FcγRIIB−/− mice to assess their therapeutic activity in treating ITP. Both KM114 and IM7 bound well to splenic cells from all mice tested. Neither KM114 nor IM7 demonstrated any in vitro anti-idiotypic activity which could neutralize the binding of the thrombocytopenia-inducing anti-platelet antibody. At the dose that protected against thrombocytopenia, KM114 did not mediate RES blockade. In contrast, IM7, which did not at all protect against thrombocytopenia, blocked RES. Since FcγRIIB has been documented to play a key role in the function of IVIg in the amelioration of ITP, we questioned the significance of it in the function of KM114. Surprisingly, KM114 was not able to ameliorate ITP in mice genetically deficient in FcγRIIB. These results suggest that, like IVIg, monoclonal antibody against CD44 mediates amelioration of murine thrombocytopenia in a manner dependent upon the inhibitory FcγRIIB rather than via RES blockade.
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    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 8
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    IVIg-Primed Leukocytes Offer Longer Protection in the Amelioration of ITP Than IVIg. (2006)
    American Society of Hematology
    Details
    Publication Date: 2006-11-16
    Description: Using a murine model of ITP, we have previously demonstrated that both IVIg and a monoclonal antibody which reacts with red cells (TER-119), ameliorates thrombocytopenia. We have also recently demonstrated that passive transfer of IVIg-primed splenic leukocytes can completely recapitulate the effects of standard IVIg therapy in the amelioration of murine ITP, and further showed that CD11c+ dendritic cells were the primary cell mediating IVIg functions (Nat Med2006;12:688–692). However, the duration of action of IVIg, TER-119 and IVIg-primed leukocytes in the inhibition of murine ITP has not been evaluated. Herein, we have evaluated the efficacy and duration of action of IVIg-primed leukocytes compared with standard therapeutic delivery of IVIg and TER-119. On day 1, mice were pre-treated with 50 ug TER-119 or 50 mg IVIg, or with only 106 leukocytes that had been primed for 30 minutes with IVIg, followed by extensive washing to remove all extraneous IVIg. Alternatively, leukocytes were also primed as above with BSA as a negative control. On days 2, 5, 8 and 11, mice from each group were injected with an antibody directed to integrin αIIβ to induce immune thrombocytopenia and bled the following day for platelet enumeration. On days 3 and 6, platelet counts revealed that mice receiving IVIg-primed leukocytes, IVIg or TER-119 were all protected from thrombocytopenia to the same extent. Mice that were pre-treated with leukocytes primed with BSA were not protected, as expected. However, at day 9, mice that received IVIg-primed leukocytes were still completely protected from thrombocytopenia, while mice receiving IVIg or TER-119 were not protected. By day 12, none of the treatment regimens conferred protection from thrombocytopenia. We are currently repeating these experiments with IVIg-primed bone marrow-derived dendritic cells and these results will also be presented. These data confirm that in the treatment of murine immune thrombocytopenia, pre-treatment of mice with IVIg-primed leukocytes offers up to 50% longer duration of protection from thrombocytopenia than standard therapies with IVIg or TER-119.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 9
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    Inhibition of Immune Thrombocytopenic Purpura (ITP) by an Orally Bioavailable Inhibitor of Syk Kinase Activity. (2005)
    American Society of Hematology
    Details
    Publication Date: 2005-11-16
    Description: Immune Thrombocytopenic Purpura (ITP) is an autoimmune disease characterised by the destruction of platelets by pathogenic autoantibodies. Clearance of platelets by phagocytic cells such as macrophages occurs through activating receptors for the Fc portion of IgG (FcγR). A central tyrosine kinase in this activation pathway is Syk, which is required for FcγR-mediated phagocytosis; thus, we questioned whether inhibition of Syk would ameliorate ITP. R406 is an orally bioavailable Syk-kinase inhibitor which is well tolerated by human volunteers. Using a well-described murine model of ITP, we tested the ability of R788 (the prodrug of R406) to ameliorate thrombocytopenia. Mice injected with an antibody directed to integrin αIIβ were profoundly thrombocytopenic when platelets were enumerated 24 hr post injection. However, mice pre-treated with 25 or 40 mg/kg R788 were protected from thrombocytopenia. Mice pre-treated with the vehicle alone displayed no protection. It has been demonstrated that chimeric Syk deficient mice display a bleeding diathesis; it was therefore questioned whether treatment of mice would demonstrate prolonged tail vein bleeding time. In independent experiments, mice treated with the with the bioavailable inhibitor R406 had no significant difference in bleeding time compared to untreated mice or mice treated with vehicle alone. Syk is also involved in collagen-induced platelet secretion and aggregation. To further the potential use of this drug in humans, the ability of platelets derived from human volunteers treated with R788 to respond to in vitro collagen-induced aggregation was analysed. Platelets from volunteers treated with the drug displayed normal collagen (as well as ADP)-induced platelet aggregation compared to untreated volunteers or those treated with the vehicle alone. These data suggest that future investigation of Syk inhibition in autoimmune diseases such as ITP is warranted.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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