Effect of IL-6R Inhibition with Tocilizumab on the Proteome of Peripheral Blood Mononuclear Cells from a Rheumatoid Arthritis Patient

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Abstract

Abstract Objective: The availability of biological disease-modifying anti-rheumatic drugs (bDMARDs) has increased during the last decade, and while focus has been on treating clinical symptoms, the associated changes in the immune system remains poorly understood. Several key immunological regulators, including Interleukin (IL)-6 are intimately associated with rheumatoid arthritis disease progression. In this proof-of-concept case study we assess the immunological changes in multiple important immune cell populations to treatment with the commonly applied bDMARD tocilizumab, a humanized monoclonal antibody against the IL-6 receptor. Methods: Peripheral blood was obtained from one rheumatoid arthritis patient with poor response to conventional DMARD, before biological treatment and 4 months after. Peripheral blood mononuclear cells were extracted and separated into CD14+, CD4+, CD8+, CD19+, and CD56+ immune cells. Each cell-type was prepared through a discovery proteomics pipeline, and analyzed on a Q Exactive Plus mass spectrometer by gel-free shotgun proteomics. Results: The patient responded well to tocilizumab monotherapy, and reached clinical remission without any observed side effects. A combined total of 4,343 proteins were identified at <1% false discovery rate, hereof 3,242 proteins qualified for label free quantification. We systematically evaluated the metabolic, inflammatory and signaling pathways of each immune cell type as a result of the IL-6R inhibition. The CD14+ cells were the most responsive to therapy, and proteins involved in the JAK/STAT and MAPK signaling pathways were less abundant. Conclusion: Our data support that effective treatment of rheumatoid arthritis with tocilizumab causes decrease in the JAK/STAT and modulation of the MAPK signaling pathways, increases glucose metabolism, and reduces stress responses.
Original languageEnglish
JournalJournal of Proteomics & Bioinformatics
Volume8
Issue number12
Pages (from-to)274-282
ISSN0974-276X
DOIs
Publication statusPublished - 2015

Cite this

@article{a00306377bae481093cbeccca081e162,
title = "Effect of IL-6R Inhibition with Tocilizumab on the Proteome of Peripheral Blood Mononuclear Cells from a Rheumatoid Arthritis Patient",
abstract = "Abstract Objective: The availability of biological disease-modifying anti-rheumatic drugs (bDMARDs) has increased during the last decade, and while focus has been on treating clinical symptoms, the associated changes in the immune system remains poorly understood. Several key immunological regulators, including Interleukin (IL)-6 are intimately associated with rheumatoid arthritis disease progression. In this proof-of-concept case study we assess the immunological changes in multiple important immune cell populations to treatment with the commonly applied bDMARD tocilizumab, a humanized monoclonal antibody against the IL-6 receptor. Methods: Peripheral blood was obtained from one rheumatoid arthritis patient with poor response to conventional DMARD, before biological treatment and 4 months after. Peripheral blood mononuclear cells were extracted and separated into CD14+, CD4+, CD8+, CD19+, and CD56+ immune cells. Each cell-type was prepared through a discovery proteomics pipeline, and analyzed on a Q Exactive Plus mass spectrometer by gel-free shotgun proteomics. Results: The patient responded well to tocilizumab monotherapy, and reached clinical remission without any observed side effects. A combined total of 4,343 proteins were identified at <1{\%} false discovery rate, hereof 3,242 proteins qualified for label free quantification. We systematically evaluated the metabolic, inflammatory and signaling pathways of each immune cell type as a result of the IL-6R inhibition. The CD14+ cells were the most responsive to therapy, and proteins involved in the JAK/STAT and MAPK signaling pathways were less abundant. Conclusion: Our data support that effective treatment of rheumatoid arthritis with tocilizumab causes decrease in the JAK/STAT and modulation of the MAPK signaling pathways, increases glucose metabolism, and reduces stress responses.",
author = "Meyer, {Michael Kruse} and Marlene Andersen and Bennike, {Tue Bjerg} and Svend Birkelund and Andersen, {Grethe Neumann} and Allan Stensballe",
year = "2015",
doi = "10.4172/jpb.1000380",
language = "English",
volume = "8",
pages = "274--282",
journal = "Journal of Proteomics & Bioinformatics",
issn = "0974-276X",
publisher = "OMICS Publishing Group",
number = "12",

}

Effect of IL-6R Inhibition with Tocilizumab on the Proteome of Peripheral Blood Mononuclear Cells from a Rheumatoid Arthritis Patient. / Meyer, Michael Kruse; Andersen, Marlene; Bennike, Tue Bjerg; Birkelund, Svend; Andersen, Grethe Neumann; Stensballe, Allan.

In: Journal of Proteomics & Bioinformatics, Vol. 8, No. 12, 2015, p. 274-282.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Effect of IL-6R Inhibition with Tocilizumab on the Proteome of Peripheral Blood Mononuclear Cells from a Rheumatoid Arthritis Patient

AU - Meyer, Michael Kruse

AU - Andersen, Marlene

AU - Bennike, Tue Bjerg

AU - Birkelund, Svend

AU - Andersen, Grethe Neumann

AU - Stensballe, Allan

PY - 2015

Y1 - 2015

N2 - Abstract Objective: The availability of biological disease-modifying anti-rheumatic drugs (bDMARDs) has increased during the last decade, and while focus has been on treating clinical symptoms, the associated changes in the immune system remains poorly understood. Several key immunological regulators, including Interleukin (IL)-6 are intimately associated with rheumatoid arthritis disease progression. In this proof-of-concept case study we assess the immunological changes in multiple important immune cell populations to treatment with the commonly applied bDMARD tocilizumab, a humanized monoclonal antibody against the IL-6 receptor. Methods: Peripheral blood was obtained from one rheumatoid arthritis patient with poor response to conventional DMARD, before biological treatment and 4 months after. Peripheral blood mononuclear cells were extracted and separated into CD14+, CD4+, CD8+, CD19+, and CD56+ immune cells. Each cell-type was prepared through a discovery proteomics pipeline, and analyzed on a Q Exactive Plus mass spectrometer by gel-free shotgun proteomics. Results: The patient responded well to tocilizumab monotherapy, and reached clinical remission without any observed side effects. A combined total of 4,343 proteins were identified at <1% false discovery rate, hereof 3,242 proteins qualified for label free quantification. We systematically evaluated the metabolic, inflammatory and signaling pathways of each immune cell type as a result of the IL-6R inhibition. The CD14+ cells were the most responsive to therapy, and proteins involved in the JAK/STAT and MAPK signaling pathways were less abundant. Conclusion: Our data support that effective treatment of rheumatoid arthritis with tocilizumab causes decrease in the JAK/STAT and modulation of the MAPK signaling pathways, increases glucose metabolism, and reduces stress responses.

AB - Abstract Objective: The availability of biological disease-modifying anti-rheumatic drugs (bDMARDs) has increased during the last decade, and while focus has been on treating clinical symptoms, the associated changes in the immune system remains poorly understood. Several key immunological regulators, including Interleukin (IL)-6 are intimately associated with rheumatoid arthritis disease progression. In this proof-of-concept case study we assess the immunological changes in multiple important immune cell populations to treatment with the commonly applied bDMARD tocilizumab, a humanized monoclonal antibody against the IL-6 receptor. Methods: Peripheral blood was obtained from one rheumatoid arthritis patient with poor response to conventional DMARD, before biological treatment and 4 months after. Peripheral blood mononuclear cells were extracted and separated into CD14+, CD4+, CD8+, CD19+, and CD56+ immune cells. Each cell-type was prepared through a discovery proteomics pipeline, and analyzed on a Q Exactive Plus mass spectrometer by gel-free shotgun proteomics. Results: The patient responded well to tocilizumab monotherapy, and reached clinical remission without any observed side effects. A combined total of 4,343 proteins were identified at <1% false discovery rate, hereof 3,242 proteins qualified for label free quantification. We systematically evaluated the metabolic, inflammatory and signaling pathways of each immune cell type as a result of the IL-6R inhibition. The CD14+ cells were the most responsive to therapy, and proteins involved in the JAK/STAT and MAPK signaling pathways were less abundant. Conclusion: Our data support that effective treatment of rheumatoid arthritis with tocilizumab causes decrease in the JAK/STAT and modulation of the MAPK signaling pathways, increases glucose metabolism, and reduces stress responses.

U2 - 10.4172/jpb.1000380

DO - 10.4172/jpb.1000380

M3 - Journal article

VL - 8

SP - 274

EP - 282

JO - Journal of Proteomics & Bioinformatics

JF - Journal of Proteomics & Bioinformatics

SN - 0974-276X

IS - 12

ER -