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

Objective: 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 mo...

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Published inCellular and molecular gastroenterology and hepatology Vol. 13; no. 2; pp. 383 - 404
Main Authors Bernhard Texler, Andreas Zollner, Vera Reinstadler, Simon J. Reider, Sophie Macheiner, Barbara Jelusic, Alexandra Pfister, Christina Watschinger, Nicole Przysiecki, Herbert Tilg, Herbert Oberacher, Alexander R. Moschen
Format Journal Article
LanguageEnglish
Published Elsevier 01.01.2022
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Abstract Objective: 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. Design: 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. Results: 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. Conclusions: 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.
AbstractList Objective: 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. Design: 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. Results: 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. Conclusions: 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.
Author Alexandra Pfister
Sophie Macheiner
Nicole Przysiecki
Herbert Tilg
Bernhard Texler
Vera Reinstadler
Christina Watschinger
Alexander R. Moschen
Andreas Zollner
Herbert Oberacher
Barbara Jelusic
Simon J. Reider
Author_xml – sequence: 1
  fullname: Bernhard Texler
  organization: Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Daniel Swarovski Laboratory, Medical University Innsbruck, Innsbruck, Austria
– sequence: 2
  fullname: Andreas Zollner
  organization: Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Division of Internal Medicine I (Gastroenterology, Hepatology, Endocrinology, and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck, Austria
– sequence: 3
  fullname: Vera Reinstadler
  organization: Institute of Legal Medicine and Core Facility Metabolomics, Medical University Innsbruck, Innsbruck, Austria
– sequence: 4
  fullname: Simon J. Reider
  organization: Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Internal Medicine 2 (Gastroenterology and Hepatology), Kepler University Hospital, Faculty of Medicine, Johannes Kepler University Linz, Linz, Austria
– sequence: 5
  fullname: Sophie Macheiner
  organization: Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Division of Internal Medicine I (Gastroenterology, Hepatology, Endocrinology, and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck, Austria
– sequence: 6
  fullname: Barbara Jelusic
  organization: Institute of Pathology, Medical University of Graz, Graz, Austria
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  fullname: Alexandra Pfister
  organization: Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Division of Internal Medicine I (Gastroenterology, Hepatology, Endocrinology, and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck, Austria
– sequence: 8
  fullname: Christina Watschinger
  organization: Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Internal Medicine 2 (Gastroenterology and Hepatology), Kepler University Hospital, Faculty of Medicine, Johannes Kepler University Linz, Linz, Austria
– sequence: 9
  fullname: Nicole Przysiecki
  organization: Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Division of Internal Medicine I (Gastroenterology, Hepatology, Endocrinology, and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck, Austria
– sequence: 10
  fullname: Herbert Tilg
  organization: Division of Internal Medicine I (Gastroenterology, Hepatology, Endocrinology, and Metabolism), Department of Medicine, Medical University Innsbruck, Innsbruck, Austria
– sequence: 11
  fullname: Herbert Oberacher
  organization: Institute of Legal Medicine and Core Facility Metabolomics, Medical University Innsbruck, Innsbruck, Austria
– sequence: 12
  fullname: Alexander R. Moschen
  organization: Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, Linz, Austria; Internal Medicine 2 (Gastroenterology and Hepatology), Kepler University Hospital, Faculty of Medicine, Johannes Kepler University Linz, Linz, Austria; Correspondence Address correspondence to: Alexander R. Moschen, MD, PhD, Christian Doppler Laboratory for Mucosal Immunology, Internal Medicine (Gastroenterology and Hepatology), Faculty of Medicine, Johannes Kepler University Linz, Altenberger Strasse 69, A-4040 Linz, Austria
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Snippet Objective: By interfering with multiple cytokines, human Janus kinase inhibitors (JAKis) are of growing importance in the treatment of malignant and...
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StartPage 383
SubjectTerms inflammatory bowel disease
JAK inhibitor
mucosal inflammation
pharmacokinetics
tofacitinib
Title Tofacitinib-Induced Modulation of Intestinal Adaptive and Innate Immunity and Factors Driving Cellular and Systemic PharmacokineticsSummary
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