Naive human T-cells become non-responsive towards anti-TNFalpha (infliximab) treatment in vitro if co-stimulated through CD28

2.50
Hdl Handle:
http://hdl.handle.net/2336/46775
Title:
Naive human T-cells become non-responsive towards anti-TNFalpha (infliximab) treatment in vitro if co-stimulated through CD28
Authors:
Gunnlaugsdottir, B; Skaftadottir, I; Ludviksson, B R
Citation:
Scand. J. Immunol. 2008, 68(6):624-34
Issue Date:
1-Dec-2008
Abstract:
Tumour necrosis factor alpha (TNFalpha) inhibitors are widely used successfully as immunomodulatory agents in various autoimmune diseases. They primarily target the direct pro-inflammatory effect of TNFalpha. They have also been found to be critical for T-cell viability and activation. In this study we evaluated the effect of infliximab treatment under different in vitro stimulatory conditions of naive human cord blood T-cells and adult peripheral blood mononuclear cells (PBMC). PBMC and negatively selected cord blood naive human T-cells were stimulated with alphaCD3 with or without alphaCD28 co-stimulation. The role of in vitro infliximab treatment was evaluated in relation to transforming growth factor-beta1 (TGF-beta1) under the above different stimulatory conditions. Anti-TNFalpha treatment with infliximab significantly suppressed proliferation of adult and cord blood T-cells (P < 0.013) during suboptimal stimulatory conditions. Infliximab prevented division of naive CD4+ and CD8+ T-cells and consequently also activation induced cell death, which was induced after three cell divisions. Interleukin (IL)-2 secretion was significantly decreased during infliximab treatment of suboptimally stimulated T-cells (P < 0.05) while TGF-beta1 levels were unchanged. Strikingly, the anti-proliferative effect of infliximab was overcome by the administration of anti-TGF-beta1 or by the addition of exogenous IL-2. Interestingly, CD28 mediated co-stimulation restored the proliferative response in a dose-responsive manner during infliximab treatment. Finally, exogenous TNFalpha administration during suboptimal stimulation reduced the inhibitory effect of TGF-beta1 upon proliferation (P < 0.03). These results demonstrate that anti-TNFalpha treatment is primarily working upon T cells under low stimulatory conditions and probably through TGF-beta1.
Description:
Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/Open
Additional Links:
http://www3.interscience.wiley.com/journal/121495296/abstract

Full metadata record

DC FieldValue Language
dc.contributor.authorGunnlaugsdottir, B-
dc.contributor.authorSkaftadottir, I-
dc.contributor.authorLudviksson, B R-
dc.date.accessioned2008-12-19T15:21:34Z-
dc.date.available2008-12-19T15:21:34Z-
dc.date.issued2008-12-01-
dc.date.submitted2008-12-19-
dc.identifier.citationScand. J. Immunol. 2008, 68(6):624-34en
dc.identifier.issn0300-9475-
dc.identifier.pmid19000096-
dc.identifier.doi10.1111/j.1365-3083.2008.02181.x-
dc.identifier.urihttp://hdl.handle.net/2336/46775-
dc.descriptionNeðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/Openen
dc.description.abstractTumour necrosis factor alpha (TNFalpha) inhibitors are widely used successfully as immunomodulatory agents in various autoimmune diseases. They primarily target the direct pro-inflammatory effect of TNFalpha. They have also been found to be critical for T-cell viability and activation. In this study we evaluated the effect of infliximab treatment under different in vitro stimulatory conditions of naive human cord blood T-cells and adult peripheral blood mononuclear cells (PBMC). PBMC and negatively selected cord blood naive human T-cells were stimulated with alphaCD3 with or without alphaCD28 co-stimulation. The role of in vitro infliximab treatment was evaluated in relation to transforming growth factor-beta1 (TGF-beta1) under the above different stimulatory conditions. Anti-TNFalpha treatment with infliximab significantly suppressed proliferation of adult and cord blood T-cells (P < 0.013) during suboptimal stimulatory conditions. Infliximab prevented division of naive CD4+ and CD8+ T-cells and consequently also activation induced cell death, which was induced after three cell divisions. Interleukin (IL)-2 secretion was significantly decreased during infliximab treatment of suboptimally stimulated T-cells (P < 0.05) while TGF-beta1 levels were unchanged. Strikingly, the anti-proliferative effect of infliximab was overcome by the administration of anti-TGF-beta1 or by the addition of exogenous IL-2. Interestingly, CD28 mediated co-stimulation restored the proliferative response in a dose-responsive manner during infliximab treatment. Finally, exogenous TNFalpha administration during suboptimal stimulation reduced the inhibitory effect of TGF-beta1 upon proliferation (P < 0.03). These results demonstrate that anti-TNFalpha treatment is primarily working upon T cells under low stimulatory conditions and probably through TGF-beta1.en
dc.language.isoenen
dc.publisherBlackwell Scientific Publicationsen
dc.relation.urlhttp://www3.interscience.wiley.com/journal/121495296/abstracten
dc.subject.meshInterleukin-2en
dc.subject.meshAntibodies, Monoclonalen
dc.subject.meshTransforming Growth Factor beta1en
dc.subject.meshTumor Necrosis Factor-alphaen
dc.titleNaive human T-cells become non-responsive towards anti-TNFalpha (infliximab) treatment in vitro if co-stimulated through CD28en
dc.typeArticleen
dc.identifier.eissn1365-3083-
dc.contributor.departmentDepartment of Immunology, Landspitali-University Hospital, Reykjavik, Iceland.en
dc.identifier.journalScandinavian journal of immunologyen
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