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ABSTRACT: Cytomegalovirus (CMV) has evolved multiple immunological evasion strategies, including the encoding of viral interleukin (IL)-10 homologues (cmvIL-10). In this study, cmvIL-10 bound avidly to the same receptors on blood mononuclear cells and was as bio-potent as native human IL-10. Seventeen percent of plasma samples from 3200 Danish blood donors (corresponding to 28 % of the anti-CMV IgG-positive donors) contained substantial levels of anti-cmvIL-10 IgG antibodies, as measured by a radioimmunoassay for human anti-cmvIL-10 antibodies. The antibodies neither cross-reacted with native human IL-10 nor with Epstein-Barr virus-encoded IL-10. Anti-cmvIL-10 antibodies potently inhibited the binding of cmvIL-10 to cellular receptors, and they specifically inhibited cmvIL-10-induced JAK-STAT signalling. Ultimately, anti-cmvIL-10 antibodies blocked the inhibitory effect of cmvIL-10 on lipopolysaccharide-induced tumour necrosis factor alpha and IL-1β from blood mononuclear cells. Taken together, our data signify that cmvIL-10 has been produced during CMV infection, and that anti-cmvIL-10 IgG antibodies represent an effective immunological counter reaction against cmvIL-10.
Journal of General Virology 03/2011; 92(Pt 7):1508-18. · 3.36 Impact Factor
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ABSTRACT: IL-6 is involved in inflammation and a therapeutic target. 0.1% of Danish blood donors have nanomolar plasma concentrations of polyclonal, picomolar affinity and in vitro as well as in vivo neutralizing IgG autoantibodies to IL-6 (aAb-IL-6). Such donors are assumed to be severely IL-6 deficient; yet they appear healthy and do not exhibit overt clinical or laboratory abnormalities. We induced comparable levels of aAb-IL-6 in different mouse strains by vaccination with immunogenic IL-6 analogues. We observed that the induced aAb-IL-6 protected against collagen-induced arthritis and experimental allergic encephalitis. Furthermore, aAb-IL-6 carrying mice displayed increased plasma TNFalpha concentrations upon challenge with LPS. Taken together, induction of IL-6 autoantibodies was possible in different mouse strains. The autoantibodies influenced experimental inflammation. This immunotherapeutic principle might be a viable alternative in immune competent humans suffering from disorders driven by IL-6.
International Immunopharmacology 01/2008; 7(13):1704-13. · 2.38 Impact Factor
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New England Journal of Medicine 06/2007; 356(19):2001; author reply 2002. · 53.30 Impact Factor
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ABSTRACT: IL-6-specific autoantibodies (aAb-IL-6) have been reported in diseased and healthy individuals. We recently established a model for aAb-IL-6 in different mouse strains, based on vaccination with immunogenic IL-6 analogues, in which titers of aAb-IL-6 above 1,000 resulted in an in vivo IL-6 deficiency. Here, we examined aAb-IL-6 in 4,230 blood donors. Stable low titers of aAb-IL-6 were found in 9% of the donors, while 1% had titers ranging from 64 to greater than 10,000. Such aAb-IL-6-positive donors appeared normal with no overt signs of pathology. Natural and recombinant forms of IL-6 bound avidly to their IgG, and their plasma strongly neutralized IL-6 in vitro. Slightly elevated concentrations of IL-6 exclusively in the form of IL-6-IgG complexes were present in their circulation. The complexes did not contain soluble IL-6 receptors. Titers of 0.1% of the blood donors were as positive as the vaccination-induced IL-6-deficient mice. Such donors might be IL-6 deficient, and if so, IL-6 seems be dispensable for several months in otherwise healthy individuals. Such highly positive donors also explain why normal human IgG for pharmaceutical use may contain high anti-IL-6 activity. Finally, transfusion of plasma with a high titer of aAb-IL-6 might, temporally, render a recipient IL-6 deficient.
European Journal of Immunology 12/2004; 34(11):3267-75. · 5.10 Impact Factor
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ABSTRACT: Inappropriate expression of IL-6 plays a role in various inflammatory conditions, degenerative diseases, and cancers. Several model systems have been developed that can specifically block IL-6-receptor interactions. Here we present a simple and highly effective approach based on vaccination with a pool of specifically mutated IL-6 analogues to induce a neutralizing IL-6 antibody response in mice. Judged by the ability of the analogues to bind to heterologous anti-IL-6 antibodies and cellular IL-6 receptors the IL-6 analogues seemed to have a three-dimensional structure comparable to that of wild-type IL-6. Injection of them broke self-tolerance and induced an immune response to IL-6, presumably because of the amino acid differences between the analogues and wild-type IL-6. This resulted in a long-lasting anti-IL-6 antibody-mediated IL-6 deficiency that blocked experimentally induced IL-6-mediated pathology.
European Journal of Immunology 02/2004; 34(1):291-300. · 5.10 Impact Factor
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ABSTRACT: The increased use of recombinant cytokines and cytokine analogues in various disease therapies emphasizes the importance of antibodies to cytokines. Here, Klaus Bendtzen and colleagues discuss how immunological tolerance to cytokines may be broken, and the clinical relevance of cytokine autoantibodies. They also comment on the implications for refined passive immunization and cytokine vaccination strategies.
Immunology Today 06/1998;
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ABSTRACT: Cytokines are essential components of our defense and repair systems but also potentially harmful mediators of infectious and immunoinflammatory reactions. Clinically important cytokines function systemically as pleiotropic hormones with overlapping effects on many cell types. All engage in a complex network of agonists and antagonists. Some immunoglobulin G (IgG) antibodies have been found to be potent and specific regulators of cytokines. These antibodies bind interleukin (IL-1)α, IL-6, IL-10, leukemia inhibitory factor (LIF), and interferon (IFN)-α/β with exceptional force. They neutralize their corresponding cytokines ex vivo and perhaps in vivo, although they may also function as cytokine carriers. The biological role of autoantibodies to cytokines is not yet understood, but they may provide a level of regulation not appreciated at present. Inappropriate production/function of such antibodies could be pathogenetically involved in immunoinflammatory and other diseases. Cytokine antibodies may also contribute to the anti-inflammatory effects of human IgG therapy.
Stem Cells 12/1994; 13(3):206 - 222. · 7.78 Impact Factor
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ABSTRACT: Immunoglobulin G (IgG) antibodies to interleukin 1α (IL-1α) are frequently found in the sera of healthy human individuals. The effects of these autoantibodies on receptor binding and biological activities of human IL-1 were tested. Using the murine T-lymphocyte line NOB-1, human thyrocytes and human foreskin fibroblasts, the antibodies competitively inhibited the biological activity of human recombinant IL-1α (rIL-1α). The degree of inhibition correlated with 125I-rIL-1α binding to IgG in different immunoglobulin preparations and in individual sera. These antibodies also neutralized the IL-1 activity of isolated membrane fragments and lysates of human blood monocytes activated by lipopolysaccharide. In contrast, the supernatant IL-1 activity was not affected. Stronger inhibition of biological activity and cell binding of 125I-rIL-1α was obtained with NOB-1 cells than with human thyrocytes. The antibodies failed to interfere with the biological activity of rIL-1β. It is concluded that IgG autoantibodies to IL-1α in the sera of healthy humans selectively inhibit the biological activity of the soluble and membrane-associated forms of IL-1α in vitro, and that the degree of biological inhibition afforded by these antibodies depends upon the target cell.
Cytokine.
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ABSTRACT: High-affinity IgG autoantibodies (aAb) to IL-1α are among the most frequently found aAb to cytokines in humans. To establish an animal model with aAb to IL-1α, we immunised mice with recombinant murine IL-1α. Unprimed and Bacille Calmette-Guérin (BCG)-primed BALB/cA mice were vaccinated with IL-1α coupled to purified protein derivative of tuberculin (PPD). Both unprimed and primed animals developed IgG aAb to IL-1α. These aAb persisted at high levels more than 100 days after vaccination and did not cross-react with murine IL-1β. The induced anti-IL-1α aAb inhibited binding of IL-1α to the murine T-cell line NOB-1 by simple competition and neutralised IL-1α, but not IL-1β-induced IL-6 in vivo. The aAb did not induce visible discomfort in the animals. In conclusion, long-lasting and high levels of neutralising and specific IgG aAb to IL-1α can be induced in mice by vaccination with recombinant murine IL-1α conjugated to PPD. Studies of the effects of IL-1α aAb in such animals may help clarify the importance of naturally occurring IL-1α aAb in humans and permit the evaluation of future therapies with cytokine aAb in patients with immunoinflammatory diseases and cytokine-dependent tumours.
Journal of Immunological Methods.
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ABSTRACT: We investigated the possible influence of recombinant (r) sIL-6R on the growth of three IL-6 non-responsive or weakly IL-6 responsive long-term myeloma cell lines. The three cell lines chosen for the study (U266, L363 and Fravel) all expressed gp130 but differed in their expression of IL-6R and IL-6. mRNA analysis by northern blot and reverse transcriptase polymerase reaction showed that the cell line U266 was the only one that expressed IL-6 mRNA. Only U266 and L363 expressed IL-6R mRNA. 125I-rIL-6 binding studies and FACS analysis, using biotinylated IL-6 and antibodies directed against the IL-6R and gp130, showed corresponding results on the protein level. Addition of rsIL-6R resulted in induction of IL-6 responsiveness in L363 cells, whereas the 3H-thymidine incorporation of the cell lines U266 and Fravel was unaffected by rsIL-6R addition. In conclusion, the IL-6 unresponsive growth of several long-term myeloma cell lines in vitro can in some, but not all cases, be due to a deficiency in exogenous sIL-6R.
Leukemia Research.
