Pharmacodynamic Analysis of Tofacitinib and Basiliximab in Kidney Allograft Recipients

Vafadari, Ramin; Quaedackers, Monique E.; Kho, Marcia M. L.; Mol, Wendy M.; Weimar, Willem; Baan, Carla C.

doi:10.1097/tp.0b013e3182626b5a

Cited by 16 publications

(8 citation statements)

References 21 publications

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“…Although it has been shown that Celastrol not only inhibits NOX5, but can also inhibit NOX2 ( 8 , 49 ), the fact that we show a lack of effect of the specific NOX2 inhibitor (TAT) on Tofacitinib mechanisms, suggests that the effect observed in this study is solely due to NOX5 inhibition and not NOX2. We have previously shown in Mo-DC that NOX5 inhibition, both pharmacologically and with siRNA technology, significantly decrease STAT5 phosphorylation ( 8 ), in addition it has been shown that STAT5 phosphorylation is inhibited by Tofacitinib in T cells ( 68 ) and lymphocytes from RA patients ( 69 ). We can, therefore, speculate, that STAT5 might be involved in the Tofacitinib/NOX5 pathway in Mo-DC from RA and PsA patients.…”

Section: Discussionmentioning

confidence: 99%

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation

et al. 2020

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Monocyte-derived Dendritic cells (Mo-DC) are a distinct DC subset, involved in inflammation and infection, they originate from monocytes upon stimulation in the circulation and their activation and function may vary in autoimmune diseases. In this study we investigate the differences in Mo-DC differentiation and function in patients with Rheumatoid (RA) compared to Psoriatic arthritis (PsA). A significant increase in the Mo-DC differentiation marker CD209, paralleled by a corresponding decrease in the monocytic marker CD14, was demonstrated in RA compared to PsA, as early as 1 day post Mo-DC differentiation. RA monocytes ex-vivo were phenotypically different to PsA, displaying a more mature phenotype associated with altered cellular-morphology, early dendrite formation, and a significant increase in the CD40 marker. In addition, SPICE algorithm flow cytometric analysis showed distinct differences in chemokine receptors distribution in HC compared to PsA and RA CD14 + cells in the blood, with increased expression of the chemokine receptors CCR7 and CXCR4 observed in PsA and RA. In addition CD14 + cells at the site of inflammation showed a different chemokine receptor pattern between PsA and RA patients, with higher expression of CXCR3 and CXCR5 in RA when compared to PsA. The early priming observed in RA resulted in monocyte-endocytosis and antigen-uptake mechanisms to be impaired, effects that were not observed in PsA where phagocytosis capacity remained highly functional. Tofacitinib inhibited early Mo-DC differentiation, decreasing both CD209 and CD40 activation markers in RA. Inhibition of Mo-DC differentiation in response to Tofacitinib was mediated via an imbalance in the activation of NADPH-oxidases NOX5 and NOX2. This effect was reversed by NOX5 inhibition, but not NOX2, resulting in suppression of NOX5-dependent ROS production. In conclusion, RA monocytes are already primed ex vivo to become DC, evident by increased expression of activation markers, morphological appearance and impaired endocytosis capacity. Furthermore, we demonstrated for the first time that NOX5 mediates Mo-DC differentiation and function in response to Tofacitinib, which may alter DC functions.

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Section: Discussionmentioning

confidence: 99%

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation

et al. 2020

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“…However, the drug induces a redistribution of lymphocyte subsets by increasing the death of B cells and NK cells and by a stronger inhibition of CD8 compared to CD4 T cells. In other studies, anti-T cell receptor antibody-induced proliferation of naïve CD4 cells was not affected by the addition of Tofa at doses between 10 and 100 ng/ml, which are in the range of the pre-dose levels of the drug in peripheral blood of treated patients [18], [20], [21]. In contrast, we showed that a near complete block in proliferation can be obtained by using much higher doses of Tofa (100 µM), still without appreciable cytotoxicity.…”

Section: Discussionmentioning

confidence: 81%

“…In other studies, responsiveness of lymphocytes to cytokines stimulation was shown to be restored after Tofa withdrawal, however the drug was used at lower dosages and the residual lymphocyte proliferation was not investigated [18].…”

Section: Discussionmentioning

confidence: 98%

“…Other authors evaluated the response to cytokine stimulation in the presence of Tofa, showing a variable impact on JAK signalling, as confirmed by changes in STAT proteins phosphorylation, accounting for a preferential action on Th1 and Th17 lineages [18], [19]. On the contrary, low dose Tofa led to the worsening of experimental encephalomyelitis in vivo and resulted in increased Th17 differentiation in vitro [20].…”

Section: Discussionmentioning

confidence: 99%

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Fate of Lymphocytes after Withdrawal of Tofacitinib Treatment

et al. 2014

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Tofacitinib (Tofa) is an inhibitor of Janus Kinase 3, developed for the treatment of autoimmune diseases and for the prevention of transplant rejection. Due to its selective action on proliferating cells, Tofa can offer a way to block T cell activation, without toxic effects on resting cells. However, few studies have investigated the effects of Tofa on lymphocyte activation in vitro. Our aim was to study the action of Tofa on different lymphocyte subsets after in vitro stimulation and to track the behaviour of treated cells after interruption of the treatment. Peripheral blood lymphocytes were stimulated in vitro with mitogen and treated with two concentrations of Tofa. After a first period in culture, cells were washed and further incubated for an additional time. Lymphocyte subsets, activation phenotype and proliferation were assessed at the different time frames. As expected, Tofa was able to reduce the activation and proliferation of lymphocytes in the first four days of treatment. In addition the drug led to a relative decrease of Natural Killer, B cells and CD8 T cells compared to CD4 T cells. However, treated cells were still viable after the first period in culture and begun to proliferate, strikingly, in a dose dependent manner when the drug was removed from the environment by replacing the culture medium. This novel data does not necessarily predict a similar behaviour in vivo, but can warn about the clinical use of this drug when a discontinuation of treatment with Tofa is considered for any reason.

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“…Phosphospecific flow cytometry panels allow monitoring the activation of STAT3 and STAT5 by ex vivo whole blood analysis but require an in vitro stimulation of cells. [7][8][9] The technical difficulty of carrying out this type of assay makes its use in everyday practice complicated for therapeutic drug monitoring.…”

Section: The Nightmare Monitoring Of Jakinhibsmentioning

confidence: 99%

The Nightmare Monitoring of JAKinhibs

Paul¹,

Roblin

2020

Gastroenterology

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Pharmacodynamic Analysis of Tofacitinib and Basiliximab in Kidney Allograft Recipients

Abstract: Tofacitinib therapy strongly inhibits γ(c) cytokine-induced JAK/STAT5 activation, whereas basiliximab suppresses IL-2-stimulated activation only. Pharmacodynamic monitoring offers a unique tool to evaluate the biologic effects of immunosuppressive drugs.

Cited by 16 publications

References 21 publications

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation

Fate of Lymphocytes after Withdrawal of Tofacitinib Treatment

The Nightmare Monitoring of JAKinhibs

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