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Article ; Online: Erratum to "Hydroxychloroquine Effects on TLR Signalling: Underexposed but Unneglectable in COVID-19".

In 't Veld, Aliede E / Jansen, Manon A A / Ciere, Luuk C A / Moerland, Matthijs

2021 Volume 2021, Page(s) 9789246

Abstract: This corrects the article DOI: 10.1155/2021/6659410.]. ...

Abstract	[This corrects the article DOI: 10.1155/2021/6659410.].
Language	English
Publishing date	2021-05-08
Publishing country	Egypt
Document type	Published Erratum
ZDB-ID	2817541-4
ISSN	2314-7156 ; 2314-8861
ISSN (online)	2314-7156
ISSN	2314-8861
DOI	10.1155/2021/9789246
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Article ; Online: Hydroxychloroquine Effects on TLR Signalling: Underexposed but Unneglectable in COVID-19.

In 't Veld, Aliede E / Jansen, Manon A A / Ciere, Luuk C A / Moerland, Matthijs

Journal of immunology research

2021 Volume 2021, Page(s) 6659410

Abstract: The main basis for hydroxychloroquine (HCQ) treatment in COVID-19 is the compound's ability to inhibit viral ... ...

Abstract	The main basis for hydroxychloroquine (HCQ) treatment in COVID-19 is the compound's ability to inhibit viral replication
MeSH term(s)	Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; Humans ; Hydroxychloroquine/therapeutic use ; Immunosuppression/methods ; SARS-CoV-2/drug effects ; SARS-CoV-2/immunology ; Severity of Illness Index ; Signal Transduction/drug effects ; Treatment Outcome ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Hydroxychloroquine (4QWG6N8QKH)
Language	English
Publishing date	2021-03-09
Publishing country	Egypt
Document type	Journal Article ; Review
ZDB-ID	2817541-4
ISSN	2314-7156 ; 2314-8861
ISSN (online)	2314-7156
ISSN	2314-8861
DOI	10.1155/2021/6659410
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Article: Immune Monitoring of Mycophenolate Mofetil Activity in Healthy Volunteers Using

In 't Veld, Aliede E / Jansen, Manon A A / de Kam, Marieke L / Yavuz, Yalҫin / Moes, Dirk Jan A R / Oudhoff, Kathalijne A / van Poelgeest, Mariette I E / Burggraaf, Jacobus / Moerland, Matthijs

Pharmaceutics

2023 Volume 15, Issue 6

Abstract: ... T cell proliferation, and cytokine production were measured and compared to MPA (MMF's ... T cells). MPA concentrations in T cells exceeded those in PBMCs, but all intracellular concentrations ... production was mildly suppressed, while MPA T cell proliferation was strongly inhibited. Based on these data ...

Abstract	Mycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as "one-dose-fits-all" together with a calcineurin inhibitor (CNI). Although drug concentrations are frequently monitored, there is still a group of patients who experience side effects related to excessive or insufficient immune suppression. We therefore aimed to identify biomarkers that reflect the overall immune status of the patient and might support individualized dosing. We previously studied immune biomarkers for CNIs and aimed to investigate whether these are also suitable to monitor MMF activity. Healthy volunteers received a single dose of MMF or placebo, after which IMPDH enzymatic activity, T cell proliferation, and cytokine production were measured and compared to MPA (MMF's active metabolite) concentration in three different matrices (plasma, peripheral blood mononuclear cells, and T cells). MPA concentrations in T cells exceeded those in PBMCs, but all intracellular concentrations correlated strongly with plasma concentrations. At clinically relevant MPA concentrations, IL-2 and IFN-γ production was mildly suppressed, while MPA T cell proliferation was strongly inhibited. Based on these data, it is expected that monitoring of T cell proliferation in MMF-treated transplantation patients may be a valid strategy to avoid excessive immune suppression.
Language	English
Publishing date	2023-05-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15061635
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Article ; Online: Immunosuppression by hydroxychloroquine: mechanistic proof in in vitro experiments but limited systemic activity in a randomized placebo-controlled clinical pharmacology study.

In 't Veld, Aliede E / Grievink, Hendrika W / van der Plas, Johan L / Eveleens Maarse, Boukje C / van Kraaij, Sebastiaan J W / Woutman, Tess D / Schoonakker, Mascha / Klarenbeek, Naomi B / de Kam, Marieke L / Kamerling, Ingrid M C / Jansen, Manon A A / Moerland, Matthijs

Immunologic research

2023 Volume 71, Issue 4, Page(s) 617–627

Abstract: ... experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor ...

Abstract	Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To gain insight in this relationship, we performed in vitro experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor (TLR)3/TLR7/TLR9/RIG-I-induced cytokine production. In a placebo-controlled clinical study, these same endpoints were evaluated in healthy volunteers that were treated with a cumulative dose of 2400 mg HCQ over 5 days. In vitro, HCQ inhibited TLR responses with IC
MeSH term(s)	Humans ; Hydroxychloroquine/pharmacology ; Hydroxychloroquine/therapeutic use ; Pharmacology, Clinical ; Toll-Like Receptor 7 ; Toll-Like Receptor 9 ; Immunosuppression Therapy ; Cytokines
Chemical Substances	Hydroxychloroquine (4QWG6N8QKH) ; Toll-Like Receptor 7 ; Toll-Like Receptor 9 ; Cytokines
Language	English
Publishing date	2023-02-22
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	632857-x
ISSN	1559-0755 ; 0257-277X
ISSN (online)	1559-0755
ISSN	0257-277X
DOI	10.1007/s12026-023-09367-3
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Article: Monitoring of Ex Vivo Cyclosporin a Activity in Healthy Volunteers Using T Cell Function Assays in Relation to Whole Blood and Cellular Pharmacokinetics.

In 't Veld, Aliede E / Jansen, Manon A A / Huisman, Bertine W / Schoonakker, Mascha / de Kam, Marieke L / Moes, Dirk Jan A R / van Poelgeest, Mariëtte I E / Burggraaf, Jacobus / Moerland, Matthijs

Pharmaceutics

2022 Volume 14, Issue 9

Abstract: Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is ... blood samples were stimulated to measure ex vivo T cell functionality, including proliferation, cytokine ... production and expression of CD154 and CD71 on T cells. Moreover, the in vitro effect of CsA was studied ...

Abstract	Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has strongly decreased, there are still many patients who experience severe side effects or rejection after long-term treatment. In this healthy volunteer study we therefore aimed to identify biomarkers to move from a pharmacokinetic-based towards a pharmacodynamic-based monitoring approach for calcineurin inhibitor treatment. Healthy volunteers received a single dose of cyclosporine A (CsA) or placebo, after which whole blood samples were stimulated to measure ex vivo T cell functionality, including proliferation, cytokine production, and activation marker expression. The highest whole blood concentration of CsA was found at 2 h post-dose, which resulted in a strong inhibition of interferon gamma (IFNy) and interleukin-2 (IL-2) production and expression of CD154 and CD71 on T cells. Moreover, the in vitro effect of CsA was studied by incubation of pre-dose whole blood samples with a concentration range of CsA. The average in vitro and ex vivo CsA activity overlapped, making the in vitro dose-effect relationship an interesting method for prediction of post-dose drug effect. The clinical relevance of the results is to be explored in transplantation patients on calcineurin inhibitor treatment.
Language	English
Publishing date	2022-09-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14091958
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Article ; Online: Disruption of Cxcr3 chemotactic signaling alters lysosomal function and renders macrophages more microbicidal.

Sommer, Frida / Torraca, Vincenzo / Xie, Yufei / In 't Veld, Aliede E / Willemse, Joost / Meijer, Annemarie H

Cell reports

2021 Volume 35, Issue 2, Page(s) 109000

Abstract: Chemotaxis and lysosomal function are closely intertwined processes essential for the inflammatory response and clearance of intracellular bacteria. We used the zebrafish model to examine the link between chemotactic signaling and lysosome physiology in ... ...

Abstract	Chemotaxis and lysosomal function are closely intertwined processes essential for the inflammatory response and clearance of intracellular bacteria. We used the zebrafish model to examine the link between chemotactic signaling and lysosome physiology in macrophages during mycobacterial infection and wound-induced inflammation in vivo. Macrophages from zebrafish larvae carrying a mutation in a chemokine receptor of the Cxcr3 family display upregulated expression of vesicle trafficking and lysosomal genes and possess enlarged lysosomes that enhance intracellular bacterial clearance. This increased microbicidal capacity is phenocopied by inhibiting the lysosomal transcription factor EC, while its overexpression counteracts the protective effect of chemokine receptor mutation. Tracking macrophage migration in zebrafish revealed that lysosomes of chemokine receptor mutants accumulate in the front half of cells, preventing macrophage polarization during chemotaxis and reaching sites of inflammation. Our work shows that chemotactic signaling affects the bactericidal properties and localization during chemotaxis, key aspects of the inflammatory response.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/immunology ; Cell Tracking ; Chemotaxis/genetics ; Chemotaxis/immunology ; Embryo, Nonmammalian ; Gene Expression Profiling ; Gene Expression Regulation ; Genes, Reporter ; Larva/immunology ; Larva/microbiology ; Luminescent Proteins/genetics ; Luminescent Proteins/immunology ; Lysosomes/immunology ; Lysosomes/metabolism ; Lysosomes/microbiology ; Lysosomes/ultrastructure ; Macrophage Activation ; Macrophages/immunology ; Macrophages/microbiology ; Macrophages/ultrastructure ; Mutation ; Mycobacterium Infections/genetics ; Mycobacterium Infections/immunology ; Mycobacterium Infections/microbiology ; Mycobacterium marinum/immunology ; Mycobacterium marinum/pathogenicity ; Receptors, CXCR3/genetics ; Receptors, CXCR3/immunology ; Sequence Analysis, RNA ; Signal Transduction/genetics ; Signal Transduction/immunology ; Zebrafish/genetics ; Zebrafish/immunology ; Zebrafish/microbiology ; Zebrafish Proteins/genetics ; Zebrafish Proteins/immunology ; Red Fluorescent Protein
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Luminescent Proteins ; Receptors, CXCR3 ; Tfec protein, zebrafish ; Zebrafish Proteins
Language	English
Publishing date	2021-04-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.109000
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Article ; Online: Disruption of Cxcr3 chemotactic signaling alters lysosomal function and renders macrophages more microbicidal

Frida Sommer / Vincenzo Torraca / Yufei Xie / Aliede E. in ‘t Veld / Joost Willemse / Annemarie H. Meijer

Cell Reports, Vol 35, Iss 2, Pp 109000- (2021)

2021

Abstract: Summary: Chemotaxis and lysosomal function are closely intertwined processes essential for the inflammatory response and clearance of intracellular bacteria. We used the zebrafish model to examine the link between chemotactic signaling and lysosome ... ...

Abstract	Summary: Chemotaxis and lysosomal function are closely intertwined processes essential for the inflammatory response and clearance of intracellular bacteria. We used the zebrafish model to examine the link between chemotactic signaling and lysosome physiology in macrophages during mycobacterial infection and wound-induced inflammation in vivo. Macrophages from zebrafish larvae carrying a mutation in a chemokine receptor of the Cxcr3 family display upregulated expression of vesicle trafficking and lysosomal genes and possess enlarged lysosomes that enhance intracellular bacterial clearance. This increased microbicidal capacity is phenocopied by inhibiting the lysosomal transcription factor EC, while its overexpression counteracts the protective effect of chemokine receptor mutation. Tracking macrophage migration in zebrafish revealed that lysosomes of chemokine receptor mutants accumulate in the front half of cells, preventing macrophage polarization during chemotaxis and reaching sites of inflammation. Our work shows that chemotactic signaling affects the bactericidal properties and localization during chemotaxis, key aspects of the inflammatory response.
Keywords	macrophage ; chemotaxis ; lysosome ; vesicle ; zebrafish ; mycobacteria ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Effect of hydroxychloroquine on the cardiac ventricular repolarization: A randomized clinical trial.

Eveleens Maarse, Boukje C / Graff, Claus / Kanters, Jørgen K / van Esdonk, Michiel J / Kemme, Michiel J B / In 't Veld, Aliede E / Jansen, Manon A A / Moerland, Matthijs / Gal, Pim

British journal of clinical pharmacology

2021 Volume 88, Issue 3, Page(s) 1054–1062

Abstract: ... on the ventricular repolarization, including QTcF-duration and T-wave morphology.: Methods: Twenty young (≤30 y ... Tpc, Tp-Te) and T-wave morphology, measured with the morphology combination score, were analysed ... There were no associations between hydroxychloroquine concentration and the T-wave morphology (P = .34 ...

Abstract	Aims: Hydroxychloroquine has been suggested as possible treatment for severe acute respiratory syndrome-coronavirus-2. Studies reported an increased risk of QTcF-prolongation after treatment with hydroxychloroquine. The aim of this study was to analyse the concentration-dependent effects of hydroxychloroquine on the ventricular repolarization, including QTcF-duration and T-wave morphology. Methods: Twenty young (≤30 y) and 20 elderly (65-75 y) healthy male subjects were included. Subjects were randomized to receive either a total dose of 2400 mg hydroxychloroquine over 5 days, or placebo (ratio 1:1). Follow-up duration was 28 days. Electrocardiograms (ECGs) were recorded as triplicate at baseline and 4 postdose single recordings, followed by hydroxychloroquine concentration measurements. ECG intervals (RR, QRS, PR, QTcF, J-Tpc, Tp-Te) and T-wave morphology, measured with the morphology combination score, were analysed with a prespecified linear mixed effects concentration-effect model. Results: There were no significant associations between hydroxychloroquine concentrations and ECG characteristics, including RR-, QRS- and QTcF-interval (P = .09, .34, .25). Mean ΔΔQTcF-interval prolongation did not exceed 5 ms and the upper limit of the 90% confidence interval did not exceed 10 ms at the highest measured concentrations (200 ng/mL). There were no associations between hydroxychloroquine concentration and the T-wave morphology (P = .34 for morphology combination score). There was no significant effect of age group on ECG characteristics. Conclusion: In this study, hydroxychloroquine did not affect ventricular repolarization, including the QTcF-interval and T-wave morphology, at plasma concentrations up to 200 ng/mL. Based on this analysis, hydroxychloroquine does not appear to increase the risk of QTcF-induced arrhythmias.
MeSH term(s)	Aged ; Electrocardiography ; Heart Rate ; Humans ; Hydroxychloroquine/adverse effects ; Long QT Syndrome/chemically induced ; Male ; SARS-CoV-2 ; COVID-19 Drug Treatment
Chemical Substances	Hydroxychloroquine (4QWG6N8QKH)
Language	English
Publishing date	2021-08-24
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.15013
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Article ; Online: Immunomonitoring of Tacrolimus in Healthy Volunteers: The First Step from PK- to PD-Based Therapeutic Drug Monitoring?

In 't Veld, Aliede E / Grievink, Hendrika W / Saghari, Mahdi / Stuurman, Frederik E / de Kam, Marieke L / de Vries, Aiko P J / de Winter, Brenda C M / Burggraaf, Jacobus / Cohen, Adam F / Moerland, Matthijs

International journal of molecular sciences

2019 Volume 20, Issue 19

Abstract	Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71,
MeSH term(s)	Adolescent ; Adult ; Antigens, CD/immunology ; CD40 Ligand/immunology ; Drug Monitoring ; Female ; Humans ; Interferon-gamma/immunology ; Interleukin-2/immunology ; Leukocytes, Mononuclear/immunology ; Male ; Maximum Tolerated Dose ; Middle Aged ; Phytohemagglutinins/pharmacology ; Receptors, Transferrin/immunology ; Tacrolimus/administration & dosage ; Tacrolimus/pharmacokinetics
Chemical Substances	Antigens, CD ; CD71 antigen ; IFNG protein, human ; IL2 protein, human ; Interleukin-2 ; Phytohemagglutinins ; Receptors, Transferrin ; CD40 Ligand (147205-72-9) ; Interferon-gamma (82115-62-6) ; Tacrolimus (WM0HAQ4WNM)
Language	English
Publishing date	2019-09-23
Publishing country	Switzerland
Document type	Clinical Trial ; Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20194710
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Article ; Online: Immunomonitoring of Tacrolimus in Healthy Volunteers

Aliede E. in ‘t Veld / Hendrika W. Grievink / Mahdi Saghari / Frederik E. Stuurman / Marieke L. de Kam / Aiko P. J. de Vries / Brenda C. M. de Winter / Jacobus Burggraaf / Adam F. Cohen / Matthijs Moerland

International Journal of Molecular Sciences, Vol 20, Iss 19, p

The First Step from PK- to PD-Based Therapeutic Drug Monitoring?

2019 Volume 4710

Abstract: ... and whole blood tacrolimus concentrations were measured and were related to T cell functionality ... A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations ... the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post ...

Abstract	Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFNγ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell.
Keywords	immunosuppressive drugs ; transplantation ; pharmacodynamics ; pharmacokinetics ; tacrolimus ; therapeutic drug monitoring ; immunomonitoring ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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