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Khusru Asadullah - One of the best experts on this subject based on the ideXlab platform.
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Immunomodulation by Interleukin-10 therapy decreases the incidence of relapse and prolongs the relapse-free interval in Psoriasis.
The Journal of investigative dermatology, 2002Co-Authors: Markus Friedrich, Wolfram Sterry, Hans-dieter Volk, Wolf-dietrich Döcke, Anja Klein, Sandra Philipp, Khusru AsadullahAbstract:The ability of Interleukin-10 therapy to reduce the severity of exacerbated psoriasis has been demonstrated recently. Considering the immunobiologic properties of this cytokine we investigated the effects of long-term Interleukin-10 application on the immune system and duration of psoriasis remission. We performed a placebo-controlled, double-blind, phase II trial using Interleukin-10 in patients with chronic plaque psoriasis in remission. Patients received subcutaneous injections with either Interleukin-10 (10 µg per kg body weight; n = 7) or placebo (n = 10) three times per week until relapse or study termination after 4 months. The treatment was well tolerated. In the placebo group almost all patients (90%) showed a relapse during the observation period. In contrast to this, only two of seven patients (28.6%) relapsed in the Interleukin-10-treated group. Kaplan–Meier analysis revealed a significantly lower relapse incidence in the Interleukin-10 than in the placebo group (p = 0.02). The mean relapse-free interval time was 101.6 ± 12.6 d in the Interleukin-10 group in comparison with 66.4 ± 10.4 d in the placebo group. Immunologic activity of Interleukin-10 application was indicated by an increase in soluble Interleukin-2 receptor plasma levels and higher ex vivo Interleukin-4 secretion capacities. Remarkably, a significant negative correlation was demonstrated between the Interleukin-4 secretion capacity and Psoriasis Area and Severity Index score (r = -0.36, p
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Interleukin-10 promoter polymorphism in psoriasis.
The Journal of investigative dermatology, 2001Co-Authors: Khusru Asadullah, Joyce Eskdale, Anja Wiese, Grant Gallagher, Markus Friedrich, Wolfram SterryAbstract:Beneficial effects of Interleukin-10 therapy and lower endogenous Interleukin-10 formation compared with atopic dermatitis and cutaneous T cell lymphomas indicated that Interleukin-10 is a key cytokine in psoriasis. The Interleukin-10 promoter is highly polymorphic, with two informative microsatellites, Interleukin-10.G and Interleukin-10.R. In order to understand whether Interleukin-10 itself is a predisposing gene for the psoriasis susceptibility we analyzed Interleukin-10 promotor polymorphism in patients. The distribution of Interleukin-10.G and Interleukin10.R microsatellite alleles did not vary between patients (n = 78) and healthy controls (n = 80). In addition, when the psoriasis patients were stratified according to age of onset (younger than 40 y of age, or age 40 and older), no difference in allele distribution was observed; however, a clear differential distribution was revealed at the Interleukin10.G locus when patients were stratified according to whether they had a positive family history of psoriasis (p = 0.04). This difference was due to an over-representation of the Interleukin10.G13 allele in those patients with familial disease (40.4% vs 19.6%, Chi-square = 7.292, p = 0.007). The positive association of allele Interleukin10.G13 with familial psoriasis was especially true when patients with an early onset (< 40 y of age) of the disease were compared with those patients with early onset against a nonfamilial background (39.6% vs 14.5%, Chi-square = 8.959, p = 0.003). Patients with age-of-onset of less than 40 were 4-fold [odds ratio = 3.85 (1.55--9.62)] more likely to have a psoriatic family background if they carried this Interleukin10.G13 allele. These data suggest that the Interleukin-10 locus contributes to the heritability of psoriasis susceptibility.
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Effects of systemic Interleukin-10 therapy on psoriatic skin lesions: histologic, immunohistologic, and molecular biology findings.
The Journal of investigative dermatology, 2001Co-Authors: Khusru Asadullah, Markus Friedrich, Hans-dieter Volk, Sandra Hanneken, Christoph Rohrbach, Heike Audring, Athanasios Vergopoulos, Merle Ebeling, Wolf-dietrich Döcke, Wolfram SterryAbstract:Interleukin-10 is an important anti-inflammatory and immunosuppressive cytokine with major impact on several immune reactions, including regulatory mechanisms in the skin. Recently, we performed a phase II trial in psoriatic patients receiving subcutaneously Interleukin-10 over 7 wk. The clinical response suggested that Interleukin-10 might represent a novel anti-psoriatic drug. In order to understand better the mode of action and to elucidate the effects of systemic Interleukin-10 treatment on the skin immune system, skin punch biopsies from sites different from Interleukin-10 injection were analyzed. Biopsies were obtained from the patients before, at the end, and 3 wk after Interleukin-10 therapy. The results are reported here. Histologic examination showed a decrease of several parameters reflecting the psoriatic disease activity as acanthosis and extension of the horny layer. Immunohistologic examination demonstrated decreasing numbers of infiltrating T cells, dermal CD1a + cells, and a diminished proliferation of epidermal cells. Using a novel, quantitative reverse transcriptase–polymerase chain reaction approach a significant shift within the cytokine pattern was found. Interleukin-10 therapy led to a decrease of cutaneous Interleukin-8 and Interleukin-10 mRNA expression. Whereas no significant changes of Interleukin-6, tumor necrosis factor-α, and interferon-γ expression were found, Interleukin-4 was strongly upregulated suggesting a shift from a type 1 towards a type 2 cytokine pattern. The changes within the local cytokine pattern seem to be disease-related, as an inverse course was found in a single Interleukin-10 nonresponding patient. Our findings demonstrate considerable effects of systemic Interleukin-10 application on the skin immune systems, which might contribute to the anti-psoriatic activity of Interleukin-10.
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sympathetic activation triggers systemic Interleukin 10 release in immunodepression induced by brain injury
Nature Medicine, 1998Co-Authors: Christian Woiciechowsky, Khusru Asadullah, Dirk Nestler, Beatrice Eberhardt, Cornelia Platzer, Britta Schoning, Frauke Glockner, Wolfgang Lanksch, Hans-dieter VolkAbstract:The mechanism of immunodepression after brain injury is not yet clear. Here we demonstrate rapid systemic release of the immunoinhibitory cytokine Interleukin-10, monocytic deactivation and a high incidence of infection in patients with 'sympathetic storm' due to acute accidental or iatrogenic brain trauma. In vitro studies showed that within minutes catecholamines trigger the secretion of Interleukin-10 from unstimulated monocytes through a beta-adrenoreceptor-mediated, cAMP/protein kinase A-dependent pathway. We found that in a rat model of acute brain injury, the beta-receptor antagonist propranolol prevented the increase of Interleukin-10 plasma levels. Rapid monocytic Interleukin-10 release after sympathetic activation may represent a common pathway for immunodepression induced by stress and injury.
Wolfram Sterry - One of the best experts on this subject based on the ideXlab platform.
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Immunomodulation by Interleukin-10 therapy decreases the incidence of relapse and prolongs the relapse-free interval in Psoriasis.
The Journal of investigative dermatology, 2002Co-Authors: Markus Friedrich, Wolfram Sterry, Hans-dieter Volk, Wolf-dietrich Döcke, Anja Klein, Sandra Philipp, Khusru AsadullahAbstract:The ability of Interleukin-10 therapy to reduce the severity of exacerbated psoriasis has been demonstrated recently. Considering the immunobiologic properties of this cytokine we investigated the effects of long-term Interleukin-10 application on the immune system and duration of psoriasis remission. We performed a placebo-controlled, double-blind, phase II trial using Interleukin-10 in patients with chronic plaque psoriasis in remission. Patients received subcutaneous injections with either Interleukin-10 (10 µg per kg body weight; n = 7) or placebo (n = 10) three times per week until relapse or study termination after 4 months. The treatment was well tolerated. In the placebo group almost all patients (90%) showed a relapse during the observation period. In contrast to this, only two of seven patients (28.6%) relapsed in the Interleukin-10-treated group. Kaplan–Meier analysis revealed a significantly lower relapse incidence in the Interleukin-10 than in the placebo group (p = 0.02). The mean relapse-free interval time was 101.6 ± 12.6 d in the Interleukin-10 group in comparison with 66.4 ± 10.4 d in the placebo group. Immunologic activity of Interleukin-10 application was indicated by an increase in soluble Interleukin-2 receptor plasma levels and higher ex vivo Interleukin-4 secretion capacities. Remarkably, a significant negative correlation was demonstrated between the Interleukin-4 secretion capacity and Psoriasis Area and Severity Index score (r = -0.36, p
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Interleukin-10 promoter polymorphism in psoriasis.
The Journal of investigative dermatology, 2001Co-Authors: Khusru Asadullah, Joyce Eskdale, Anja Wiese, Grant Gallagher, Markus Friedrich, Wolfram SterryAbstract:Beneficial effects of Interleukin-10 therapy and lower endogenous Interleukin-10 formation compared with atopic dermatitis and cutaneous T cell lymphomas indicated that Interleukin-10 is a key cytokine in psoriasis. The Interleukin-10 promoter is highly polymorphic, with two informative microsatellites, Interleukin-10.G and Interleukin-10.R. In order to understand whether Interleukin-10 itself is a predisposing gene for the psoriasis susceptibility we analyzed Interleukin-10 promotor polymorphism in patients. The distribution of Interleukin-10.G and Interleukin10.R microsatellite alleles did not vary between patients (n = 78) and healthy controls (n = 80). In addition, when the psoriasis patients were stratified according to age of onset (younger than 40 y of age, or age 40 and older), no difference in allele distribution was observed; however, a clear differential distribution was revealed at the Interleukin10.G locus when patients were stratified according to whether they had a positive family history of psoriasis (p = 0.04). This difference was due to an over-representation of the Interleukin10.G13 allele in those patients with familial disease (40.4% vs 19.6%, Chi-square = 7.292, p = 0.007). The positive association of allele Interleukin10.G13 with familial psoriasis was especially true when patients with an early onset (< 40 y of age) of the disease were compared with those patients with early onset against a nonfamilial background (39.6% vs 14.5%, Chi-square = 8.959, p = 0.003). Patients with age-of-onset of less than 40 were 4-fold [odds ratio = 3.85 (1.55--9.62)] more likely to have a psoriatic family background if they carried this Interleukin10.G13 allele. These data suggest that the Interleukin-10 locus contributes to the heritability of psoriasis susceptibility.
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Effects of systemic Interleukin-10 therapy on psoriatic skin lesions: histologic, immunohistologic, and molecular biology findings.
The Journal of investigative dermatology, 2001Co-Authors: Khusru Asadullah, Markus Friedrich, Hans-dieter Volk, Sandra Hanneken, Christoph Rohrbach, Heike Audring, Athanasios Vergopoulos, Merle Ebeling, Wolf-dietrich Döcke, Wolfram SterryAbstract:Interleukin-10 is an important anti-inflammatory and immunosuppressive cytokine with major impact on several immune reactions, including regulatory mechanisms in the skin. Recently, we performed a phase II trial in psoriatic patients receiving subcutaneously Interleukin-10 over 7 wk. The clinical response suggested that Interleukin-10 might represent a novel anti-psoriatic drug. In order to understand better the mode of action and to elucidate the effects of systemic Interleukin-10 treatment on the skin immune system, skin punch biopsies from sites different from Interleukin-10 injection were analyzed. Biopsies were obtained from the patients before, at the end, and 3 wk after Interleukin-10 therapy. The results are reported here. Histologic examination showed a decrease of several parameters reflecting the psoriatic disease activity as acanthosis and extension of the horny layer. Immunohistologic examination demonstrated decreasing numbers of infiltrating T cells, dermal CD1a + cells, and a diminished proliferation of epidermal cells. Using a novel, quantitative reverse transcriptase–polymerase chain reaction approach a significant shift within the cytokine pattern was found. Interleukin-10 therapy led to a decrease of cutaneous Interleukin-8 and Interleukin-10 mRNA expression. Whereas no significant changes of Interleukin-6, tumor necrosis factor-α, and interferon-γ expression were found, Interleukin-4 was strongly upregulated suggesting a shift from a type 1 towards a type 2 cytokine pattern. The changes within the local cytokine pattern seem to be disease-related, as an inverse course was found in a single Interleukin-10 nonresponding patient. Our findings demonstrate considerable effects of systemic Interleukin-10 application on the skin immune systems, which might contribute to the anti-psoriatic activity of Interleukin-10.
Cutler David L - One of the best experts on this subject based on the ideXlab platform.
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Pharmacodynamics of subcutaneous recombinant human Interleukin‐10 in healthy volunteers
Clinical pharmacology and therapeutics, 1997Co-Authors: Richard D. Huhn, Elaine Radwanski, Jose Gallo, Melton B. Affrime, Ron Sabo, Gerilyn Gonyo, April Monge, Cutler David LAbstract:Interleukin-10 inhibits T-lymphocyte activation and proliferation and lipopolysaccharide-induced monocyte production of proinflammatory cytokines. Fifty-four healthy volunteers received single doses of recombinant human Interleukin-10 (1.0, 2.5, 5.0, 10, 25, or 50 micrograms/kg) or placebo by subcutaneous injection (randomized double-blind assignment). Clinical adverse events were infrequent at doses below 50 micrograms/kg (five of six subjects had mild flu-like syndrome). Mean serum Interleukin-10 concentrations were dose related. The mean terminal-phase half-life ranged from 2.7 to 4.5 hours, and the apparent volume of distribution ranged from 0.70 to 1.35 L/kg. Hematologic changes included transient mild to moderate increases of neutrophil counts, decreases of lymphocyte counts, and a delayed decrease of platelet counts. Recombinant human Interleukin-10 significantly suppressed production of the proinflammatory cytokines Interleukin-1 beta and tumor necrosis factor-alpha by whole blood stimulated ex vivo with Escherichia coli lipopolysaccharide.
Markus Friedrich - One of the best experts on this subject based on the ideXlab platform.
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Immunomodulation by Interleukin-10 therapy decreases the incidence of relapse and prolongs the relapse-free interval in Psoriasis.
The Journal of investigative dermatology, 2002Co-Authors: Markus Friedrich, Wolfram Sterry, Hans-dieter Volk, Wolf-dietrich Döcke, Anja Klein, Sandra Philipp, Khusru AsadullahAbstract:The ability of Interleukin-10 therapy to reduce the severity of exacerbated psoriasis has been demonstrated recently. Considering the immunobiologic properties of this cytokine we investigated the effects of long-term Interleukin-10 application on the immune system and duration of psoriasis remission. We performed a placebo-controlled, double-blind, phase II trial using Interleukin-10 in patients with chronic plaque psoriasis in remission. Patients received subcutaneous injections with either Interleukin-10 (10 µg per kg body weight; n = 7) or placebo (n = 10) three times per week until relapse or study termination after 4 months. The treatment was well tolerated. In the placebo group almost all patients (90%) showed a relapse during the observation period. In contrast to this, only two of seven patients (28.6%) relapsed in the Interleukin-10-treated group. Kaplan–Meier analysis revealed a significantly lower relapse incidence in the Interleukin-10 than in the placebo group (p = 0.02). The mean relapse-free interval time was 101.6 ± 12.6 d in the Interleukin-10 group in comparison with 66.4 ± 10.4 d in the placebo group. Immunologic activity of Interleukin-10 application was indicated by an increase in soluble Interleukin-2 receptor plasma levels and higher ex vivo Interleukin-4 secretion capacities. Remarkably, a significant negative correlation was demonstrated between the Interleukin-4 secretion capacity and Psoriasis Area and Severity Index score (r = -0.36, p
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Interleukin-10 promoter polymorphism in psoriasis.
The Journal of investigative dermatology, 2001Co-Authors: Khusru Asadullah, Joyce Eskdale, Anja Wiese, Grant Gallagher, Markus Friedrich, Wolfram SterryAbstract:Beneficial effects of Interleukin-10 therapy and lower endogenous Interleukin-10 formation compared with atopic dermatitis and cutaneous T cell lymphomas indicated that Interleukin-10 is a key cytokine in psoriasis. The Interleukin-10 promoter is highly polymorphic, with two informative microsatellites, Interleukin-10.G and Interleukin-10.R. In order to understand whether Interleukin-10 itself is a predisposing gene for the psoriasis susceptibility we analyzed Interleukin-10 promotor polymorphism in patients. The distribution of Interleukin-10.G and Interleukin10.R microsatellite alleles did not vary between patients (n = 78) and healthy controls (n = 80). In addition, when the psoriasis patients were stratified according to age of onset (younger than 40 y of age, or age 40 and older), no difference in allele distribution was observed; however, a clear differential distribution was revealed at the Interleukin10.G locus when patients were stratified according to whether they had a positive family history of psoriasis (p = 0.04). This difference was due to an over-representation of the Interleukin10.G13 allele in those patients with familial disease (40.4% vs 19.6%, Chi-square = 7.292, p = 0.007). The positive association of allele Interleukin10.G13 with familial psoriasis was especially true when patients with an early onset (< 40 y of age) of the disease were compared with those patients with early onset against a nonfamilial background (39.6% vs 14.5%, Chi-square = 8.959, p = 0.003). Patients with age-of-onset of less than 40 were 4-fold [odds ratio = 3.85 (1.55--9.62)] more likely to have a psoriatic family background if they carried this Interleukin10.G13 allele. These data suggest that the Interleukin-10 locus contributes to the heritability of psoriasis susceptibility.
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Effects of systemic Interleukin-10 therapy on psoriatic skin lesions: histologic, immunohistologic, and molecular biology findings.
The Journal of investigative dermatology, 2001Co-Authors: Khusru Asadullah, Markus Friedrich, Hans-dieter Volk, Sandra Hanneken, Christoph Rohrbach, Heike Audring, Athanasios Vergopoulos, Merle Ebeling, Wolf-dietrich Döcke, Wolfram SterryAbstract:Interleukin-10 is an important anti-inflammatory and immunosuppressive cytokine with major impact on several immune reactions, including regulatory mechanisms in the skin. Recently, we performed a phase II trial in psoriatic patients receiving subcutaneously Interleukin-10 over 7 wk. The clinical response suggested that Interleukin-10 might represent a novel anti-psoriatic drug. In order to understand better the mode of action and to elucidate the effects of systemic Interleukin-10 treatment on the skin immune system, skin punch biopsies from sites different from Interleukin-10 injection were analyzed. Biopsies were obtained from the patients before, at the end, and 3 wk after Interleukin-10 therapy. The results are reported here. Histologic examination showed a decrease of several parameters reflecting the psoriatic disease activity as acanthosis and extension of the horny layer. Immunohistologic examination demonstrated decreasing numbers of infiltrating T cells, dermal CD1a + cells, and a diminished proliferation of epidermal cells. Using a novel, quantitative reverse transcriptase–polymerase chain reaction approach a significant shift within the cytokine pattern was found. Interleukin-10 therapy led to a decrease of cutaneous Interleukin-8 and Interleukin-10 mRNA expression. Whereas no significant changes of Interleukin-6, tumor necrosis factor-α, and interferon-γ expression were found, Interleukin-4 was strongly upregulated suggesting a shift from a type 1 towards a type 2 cytokine pattern. The changes within the local cytokine pattern seem to be disease-related, as an inverse course was found in a single Interleukin-10 nonresponding patient. Our findings demonstrate considerable effects of systemic Interleukin-10 application on the skin immune systems, which might contribute to the anti-psoriatic activity of Interleukin-10.
P Ghezzi - One of the best experts on this subject based on the ideXlab platform.
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Systemic Interleukin 10 administration inhibits brain tumor necrosis factor production in mice.
European journal of pharmacology, 1997Co-Authors: E Di Santo, M Adami, R Bertorelli, P GhezziAbstract:Interleukin 10 is an antiinflammatory cytokine and inhibits the production of tumor necrosis factor. We have previously found that intracerebroventricular (i.c.v.) administration of recombinant human Interleukin 10 inhibits brain tumor necrosis factor production induced by an i.c.v. injection of lipopolysaccharide in mice. In view of its possible pharmacological use, we have now studied whether Interleukin 10 administered peripherally could inhibit brain tumor necrosis factor production. Mice were injected with recombinant human Interleukin 10 (20 microg/mouse, i.v.) 10 min-24 h before lipopolysaccharide (2.5 microg, i.c.v.). Tumor necrosis factor was measured, using a bioassay, in brain homogenates 90 min after lipopolysaccharide. Recombinant human Interleukin 10 administered i.v. between 10 min and 6 h before lipopolysaccharide markedly inhibited brain tumor necrosis factor production. We also measured the production of tumor necrosis factor by whole blood of these mice, and it was also markedly inhibited by recombinant human Interleukin 10 treatment. In conclusion, systemic recombinant human Interleukin 10 administration inhibits brain tumor necrosis factor production. suggesting its usefulness in tumor necrosis factor-mediated pathologies of the central nervous system.