Tofacitinib-Induced Modulation of Intestinal Adaptive and Innate Immunity and Factors Driving Cellular and Systemic Pharmacokinetics

By interfering with multiple cytokines, human Janus kinase inhibitors (JAKis) are of growing importance in the treatment of malignant and inflammatory conditions. Although tofacitinib has demonstrated efficacy as the first-in-class JAKi in ulcerative colitis many aspects concerning its mode of actio...

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Published inCellular and molecular gastroenterology and hepatology Vol. 13; no. 2; pp. 383 - 404
Main Authors Texler, Bernhard, Zollner, Andreas, Reinstadler, Vera, Reider, Simon J., Macheiner, Sophie, Jelusic, Barbara, Pfister, Alexandra, Watschinger, Christina, Przysiecki, Nicole, Tilg, Herbert, Oberacher, Herbert, Moschen, Alexander R.
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Published United States Elsevier Inc 01.01.2022
Elsevier
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Abstract By interfering with multiple cytokines, human Janus kinase inhibitors (JAKis) are of growing importance in the treatment of malignant and inflammatory conditions. Although tofacitinib has demonstrated efficacy as the first-in-class JAKi in ulcerative colitis many aspects concerning its mode of action and pharmacokinetics remain unresolved. We studied tofacitinib’s impact on various primary human innate and adaptive immune cells. In-depth in vivo studies were performed in dextran sodium sulfate–induced colitis in mice. Immune populations were characterized by flow cytometry and critical transcription factors and effector cytokines were analyzed. Pharmacokinetics of tofacitinib was studied by liquid chromatography–tandem mass spectrometry. Tofacitinib inhibited proliferation in CD4+ and CD8+ T cells along with Th1 and Th17 differentiation, while Th2 and regulatory T cell lineages were largely unaffected. Monocytes and macrophages were directed toward an anti-inflammatory phenotype and cytokine production was suppressed in intestinal epithelial cells. These findings were largely reproducible in murine cells of the inflamed mucosa in dextran sulfate sodium colitis. Short-term treatment with tofacitinib had little impact on the mouse microbiota. Strikingly, the degree of inflammation and circulating tofacitinib levels showed a strong positive correlation. Finally, we identified inflammation-induced equilibrative nucleoside transporters as regulators of tofacitinib uptake into leukocytes. We provide a detailed analysis of the cell-specific immune-suppressive effects of the JAKis tofacitinib on innate and adaptive immunity and reveal that intestinal inflammation critically impacts tofacitinib’s pharmacokinetics in mice. Furthermore, we describe an unappreciated mechanism—namely induction of equilibrative nucleoside transporters—enhancing baseline cellular uptake that can be inhibited pharmaceutically. [Display omitted]
AbstractList By interfering with multiple cytokines, human Janus kinase inhibitors (JAKis) are of growing importance in the treatment of malignant and inflammatory conditions. Although tofacitinib has demonstrated efficacy as the first-in-class JAKi in ulcerative colitis many aspects concerning its mode of action and pharmacokinetics remain unresolved. We studied tofacitinib's impact on various primary human innate and adaptive immune cells. In-depth in vivo studies were performed in dextran sodium sulfate-induced colitis in mice. Immune populations were characterized by flow cytometry and critical transcription factors and effector cytokines were analyzed. Pharmacokinetics of tofacitinib was studied by liquid chromatography-tandem mass spectrometry. Tofacitinib inhibited proliferation in CD4 and CD8 T cells along with Th1 and Th17 differentiation, while Th2 and regulatory T cell lineages were largely unaffected. Monocytes and macrophages were directed toward an anti-inflammatory phenotype and cytokine production was suppressed in intestinal epithelial cells. These findings were largely reproducible in murine cells of the inflamed mucosa in dextran sulfate sodium colitis. Short-term treatment with tofacitinib had little impact on the mouse microbiota. Strikingly, the degree of inflammation and circulating tofacitinib levels showed a strong positive correlation. Finally, we identified inflammation-induced equilibrative nucleoside transporters as regulators of tofacitinib uptake into leukocytes. We provide a detailed analysis of the cell-specific immune-suppressive effects of the JAKis tofacitinib on innate and adaptive immunity and reveal that intestinal inflammation critically impacts tofacitinib's pharmacokinetics in mice. Furthermore, we describe an unappreciated mechanism-namely induction of equilibrative nucleoside transporters-enhancing baseline cellular uptake that can be inhibited pharmaceutically.
By interfering with multiple cytokines, human Janus kinase inhibitors (JAKis) are of growing importance in the treatment of malignant and inflammatory conditions. Although tofacitinib has demonstrated efficacy as the first-in-class JAKi in ulcerative colitis many aspects concerning its mode of action and pharmacokinetics remain unresolved. We studied tofacitinib’s impact on various primary human innate and adaptive immune cells. In-depth in vivo studies were performed in dextran sodium sulfate–induced colitis in mice. Immune populations were characterized by flow cytometry and critical transcription factors and effector cytokines were analyzed. Pharmacokinetics of tofacitinib was studied by liquid chromatography–tandem mass spectrometry. Tofacitinib inhibited proliferation in CD4+ and CD8+ T cells along with Th1 and Th17 differentiation, while Th2 and regulatory T cell lineages were largely unaffected. Monocytes and macrophages were directed toward an anti-inflammatory phenotype and cytokine production was suppressed in intestinal epithelial cells. These findings were largely reproducible in murine cells of the inflamed mucosa in dextran sulfate sodium colitis. Short-term treatment with tofacitinib had little impact on the mouse microbiota. Strikingly, the degree of inflammation and circulating tofacitinib levels showed a strong positive correlation. Finally, we identified inflammation-induced equilibrative nucleoside transporters as regulators of tofacitinib uptake into leukocytes. We provide a detailed analysis of the cell-specific immune-suppressive effects of the JAKis tofacitinib on innate and adaptive immunity and reveal that intestinal inflammation critically impacts tofacitinib’s pharmacokinetics in mice. Furthermore, we describe an unappreciated mechanism—namely induction of equilibrative nucleoside transporters—enhancing baseline cellular uptake that can be inhibited pharmaceutically. [Display omitted]
Author Texler, Bernhard
Oberacher, Herbert
Zollner, Andreas
Pfister, Alexandra
Reider, Simon J.
Macheiner, Sophie
Jelusic, Barbara
Moschen, Alexander R.
Watschinger, Christina
Tilg, Herbert
Przysiecki, Nicole
Reinstadler, Vera
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Issue 2
Keywords M-CSF
DI
IHC
PHA
ENT
IBD
mRNA
mucosal inflammation
LPS
UC
tofacitinib
LC-MS/MS
Th
FSC
JAKi
pharmacokinetics
JAK inhibitor
IFNγ
PBS
CD
IL
ASV
DSS
IEC
CFSE
PBMC
inflammatory bowel disease
3D
STAT
TNF-α
JAK
PI
ATP
ELISA
Language English
License This is an open access article under the CC BY-NC-ND license.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Notes Authors share co-first authorship.
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Snippet By interfering with multiple cytokines, human Janus kinase inhibitors (JAKis) are of growing importance in the treatment of malignant and inflammatory...
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SubjectTerms inflammatory bowel disease
JAK inhibitor
mucosal inflammation
Original Research
pharmacokinetics
tofacitinib
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Title Tofacitinib-Induced Modulation of Intestinal Adaptive and Innate Immunity and Factors Driving Cellular and Systemic Pharmacokinetics
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https://www.ncbi.nlm.nih.gov/pubmed/34624526
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Volume 13
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