T Cell Response to Infliximab in Exposed Patients: A Longitudinal Analysis

ABIRISK Consortium

Research output: Contribution to journalArticle

Abstract

This study aimed to evaluate the proportion of infliximab (IFX)-exposed patients exhibiting cellular response to the drug in a longitudinal way and to establish whether it is predictive for anti-drug antibodies (ADA) development. Seventeen patients suffering from immuno-mediated disorders were enrolled. Blood was sampled at baseline and before each of the first eight infusions of IFX. The proliferation of PBMCs to 15-mer peptides covering VH/VL frames of IFX was assessed as well as transcription factors and cytokines mRNA expression of memory T cells in IFX-stimulated PBMCs. The number of peptides recognized by T cells after four infusions was higher than those recognized by the same patients before treatment. IFX-stimulated PBMCs from more than 90% of patients were able to express the main regulators and adaptive cytokines of memory T cells. While IFN-γ mRNAs increased after the first infusion and declined during the subsequent ones, IL-10 mRNA was upregulated throughout the treatment. IL-10 was functionally active because its neutralization improved IFN-γ and IL-13 mRNA expression in vitro. The IL-10/IFN-γ ratio was shown to be lower in patients who developed ADAs solely at the early infusions. IL-10 production consistently preceded or paralleled the IFN-γ onset in ADA- patients, while it was not produced or followed IFN-γ onset in ADA+ patients. In conclusion, this study provides evidence that the majority of exposed patients undergo a cellular response to IFX with the upregulation of IL-10. The development of ADA is associated with the early impairment of IL-10 and low levels of the IL-10/IFN-γ ratio.

Original languageEnglish
Pages (from-to)3113
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - 2018

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Interleukin-10
T-Lymphocytes
Anti-Idiotypic Antibodies
Messenger RNA
Pharmaceutical Preparations
Cytokines
Peptide T
Interleukin-13
Infliximab
Transcription Factors
Up-Regulation
Peptides
Therapeutics

Cite this

T Cell Response to Infliximab in Exposed Patients : A Longitudinal Analysis. / ABIRISK Consortium.

In: Frontiers in Immunology, Vol. 9, 2018, p. 3113.

Research output: Contribution to journalArticle

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abstract = "This study aimed to evaluate the proportion of infliximab (IFX)-exposed patients exhibiting cellular response to the drug in a longitudinal way and to establish whether it is predictive for anti-drug antibodies (ADA) development. Seventeen patients suffering from immuno-mediated disorders were enrolled. Blood was sampled at baseline and before each of the first eight infusions of IFX. The proliferation of PBMCs to 15-mer peptides covering VH/VL frames of IFX was assessed as well as transcription factors and cytokines mRNA expression of memory T cells in IFX-stimulated PBMCs. The number of peptides recognized by T cells after four infusions was higher than those recognized by the same patients before treatment. IFX-stimulated PBMCs from more than 90{\%} of patients were able to express the main regulators and adaptive cytokines of memory T cells. While IFN-γ mRNAs increased after the first infusion and declined during the subsequent ones, IL-10 mRNA was upregulated throughout the treatment. IL-10 was functionally active because its neutralization improved IFN-γ and IL-13 mRNA expression in vitro. The IL-10/IFN-γ ratio was shown to be lower in patients who developed ADAs solely at the early infusions. IL-10 production consistently preceded or paralleled the IFN-γ onset in ADA- patients, while it was not produced or followed IFN-γ onset in ADA+ patients. In conclusion, this study provides evidence that the majority of exposed patients undergo a cellular response to IFX with the upregulation of IL-10. The development of ADA is associated with the early impairment of IL-10 and low levels of the IL-10/IFN-γ ratio.",
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AU - ABIRISK Consortium

AU - Pratesi, Sara

AU - Nencini, Francesca

AU - Grosso, Francesca

AU - Dies, Laura

AU - Bormioli, Susanna

AU - Cammelli, Daniele

AU - Maggi, Enrico

AU - Matucci, Andrea

AU - Vultaggio, Alessandra

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AB - This study aimed to evaluate the proportion of infliximab (IFX)-exposed patients exhibiting cellular response to the drug in a longitudinal way and to establish whether it is predictive for anti-drug antibodies (ADA) development. Seventeen patients suffering from immuno-mediated disorders were enrolled. Blood was sampled at baseline and before each of the first eight infusions of IFX. The proliferation of PBMCs to 15-mer peptides covering VH/VL frames of IFX was assessed as well as transcription factors and cytokines mRNA expression of memory T cells in IFX-stimulated PBMCs. The number of peptides recognized by T cells after four infusions was higher than those recognized by the same patients before treatment. IFX-stimulated PBMCs from more than 90% of patients were able to express the main regulators and adaptive cytokines of memory T cells. While IFN-γ mRNAs increased after the first infusion and declined during the subsequent ones, IL-10 mRNA was upregulated throughout the treatment. IL-10 was functionally active because its neutralization improved IFN-γ and IL-13 mRNA expression in vitro. The IL-10/IFN-γ ratio was shown to be lower in patients who developed ADAs solely at the early infusions. IL-10 production consistently preceded or paralleled the IFN-γ onset in ADA- patients, while it was not produced or followed IFN-γ onset in ADA+ patients. In conclusion, this study provides evidence that the majority of exposed patients undergo a cellular response to IFX with the upregulation of IL-10. The development of ADA is associated with the early impairment of IL-10 and low levels of the IL-10/IFN-γ ratio.

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