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Naive Human T‐Cells become Non‐Responsive towards Anti‐TNFα (Infliximab) Treatment In vitro if Co‐Stimulated through CD28
Author(s) -
Gunnlaugsdottir B.,
Skaftadottir I.,
Ludviksson B. R.
Publication year - 2008
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/j.1365-3083.2008.02181.x
Subject(s) - infliximab , cd28 , peripheral blood mononuclear cell , tumor necrosis factor alpha , t cell , medicine , cytokine , cd8 , immunology , stimulation , pharmacology , in vitro , immune system , biology , biochemistry
Tumour necrosis factor α (TNFα) inhibitors are widely used successfully as immunomodulatory agents in various autoimmune diseases. They primarily target the direct pro‐inflammatory effect of TNFα. 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 αCD3 with or without αCD28 co‐stimulation. The role of in vitro infliximab treatment was evaluated in relation to transforming growth factor‐β1 (TGF‐β1) under the above different stimulatory conditions. Anti‐TNFα 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‐β1 levels were unchanged. Strikingly, the anti‐proliferative effect of infliximab was overcome by the administration of anti‐TGF‐β1 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 TNFα administration during suboptimal stimulation reduced the inhibitory effect of TGF‐β1 upon proliferation ( P < 0.03). These results demonstrate that anti‐TNFα treatment is primarily working upon T cells under low stimulatory conditions and probably through TGF‐β1.