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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Texler, B; Zollner, A; Reinstadler, V; Reider, SJ; Macheiner, S; Jelusic, B; Pfister, A; Watschinger, C; Przysiecki, N; Tilg, H; Oberacher, H; Moschen, AR.
Tofacitinib-Induced Modulation of Intestinal Adaptive and Innate Immunity and Factors Driving Cellular and Systemic Pharmacokinetics.
Cell Mol Gastroenterol Hepatol. 2021; 13(2):383-404
Doi: 10.1016/j.jcmgh.2021.09.004
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- Co-authors Med Uni Graz
- Kapo Barbara
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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.
- Find related publications in this database (Keywords)
- pharmacokinetics
- inflammatory bowel disease
- mucosal inflammation
- JAK inhibitor
- tofacitinib