Immunologic effects of chronic administration of tofacitinib, a Janus kinase inhibitor, in cynomolgus monkeys and rats – Comparison of juvenile and adult responses

Collinge, Mark; Ball, Douglas J.; Bowman, Christopher J.; Nilson, Andrea; Radi, Smaail; Vogel, Werner

doi:10.1016/j.yrtph.2018.02.006

Cited by 10 publications

(2 citation statements)

References 79 publications

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“…Изучение места ингибиторов JAK в педиатрической ревматологии только начинается [39]. Предварительные результаты фармакокинетических исследований и безопасности (РКИ фазы I) [40] и экспериментальных исследований [41], а также предварительные результаты РКИ фазы III свидетельствуют о хороших перспективах применения ТОФА при различных субтипах ювенильного идиопатического артрита (ЮИА). В РКИ фазы III [42] было включено 225 пациентов (возраст от 2 до 18 лет), среди которых 184 страдали полиартикулярным ЮИА, 20 ПсА и 21артритом, связанным с энтезитом.…”

Section: ювенильный идиопатический артритunclassified

Efficacy and Safety of Tofacitinib for Immunemediated Inflammatory Rheumatic Diseases (Part Ii)

Nasonov

Авдеева²,

Лила

2020

Naučno-praktičeskaâ revmatologiâ

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Разработка «таргетных» пероральных противовоспалительных лекарственных препаратов-ингибиторов Янус-киназ (Janus kinase, JAK) [1, 2], первым представителем которых является тофацитиниб (ТОФА), рассматривается как крупное достижение био-П р о г р е с с в р е в м а т о л о г и и в X X I в е к е Насонов Е.Л.научный руководитель ФГБНУ «НИИР им. В.А. Насоновой», академик РАН, профессор, докт. мед. наук 1 ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой»,

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Section: ювенильный идиопатический артритunclassified

Efficacy and Safety of Tofacitinib for Immunemediated Inflammatory Rheumatic Diseases (Part Ii)

Nasonov

Авдеева²,

Лила

2020

Naučno-praktičeskaâ revmatologiâ

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“…JAKs, cytoplasmic tyrosine kinases, are known to play important roles in many cellular processes such as the modulation of the CD80/CD86 expression on LPS-stimulated DCs. Therefore, the chosen compounds will target the effects of the selected stimuli (for example abatacept/belatacept and SEB, rapamycin and PHA, tofacitinib and ConA) ( 24 , 34 – 39 ).…”

Section: Introductionmentioning

confidence: 99%

Species comparison: human and minipig PBMC reactivity under the influence of immunomodulating compounds in vitro

Pernold,

Lagumdzic,

Stadler

et al. 2024

Front. Immunol.

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Considering the similarities between swine and humans, it is a logical consequence to use swine as a translational model in research and drug development, including non-clinical safety. Here, we compared the reactivity of peripheral blood mononuclear cells (PBMCs) from humans and minipigs under the influence of different compounds in vitro. We conducted a flow cytometry-based proliferation assay that focused on the T-cell response to three different stimuli: concanavalin A (ConA), phytohemagglutinin-L (PHA-L), and staphylococcal Enterotoxin B (SEB). Furthermore, four approved immunosuppressive drugs—abatacept, belatacept, rapamycin, and tofacitinib—which are used for the treatment of rheumatoid arthritis or rejection in transplant recipients, were combined with the different stimuli. This allowed us to study the effect of suppressive drugs in comparison with the different stimuli in both species. We examined proliferating T cells (CD3+) and investigated the presence of TCR-αβ+ and TCR-γδ+ T cells. Differences in the response of T cells of the two species under these various conditions were evident. CD4+ T cells were more activated within humans, whereas CD8+ T cells were generally more abundant in swine. The effectiveness of the used humanized antibodies is most likely related to the conserved structure of CTLA-4 as abatacept induced a much stronger reduction in swine compared with belatacept. The reduction of proliferation of rapamycin and tofacitinib was highly dependent on the used stimuli. We further investigated the effect of the immunosuppressive compounds on antigen-specific restimulation of pigs immunized against porcine circovirus 2 (PCV2). Treatment with all four compounds resulted in a clear reduction of the proliferative response, with rapamycin showing the strongest effect. In conclusion, our findings indicate that the effectiveness of suppressive compounds is highly dependent on the stimuli used and must be carefully selected to ensure accurate results. The results highlight the importance of considering the response of T cells in different species when evaluating the potential of an immunomodulatory drug.

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Development of a transcriptome-based determination of innate immune suppressor (TDIS) assay as an in vitro test for immunotoxicity

et al. 2022

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Immunologic effects of chronic administration of tofacitinib, a Janus kinase inhibitor, in cynomolgus monkeys and rats – Comparison of juvenile and adult responses

Cited by 10 publications

References 79 publications

Efficacy and Safety of Tofacitinib for Immunemediated Inflammatory Rheumatic Diseases (Part Ii)

Efficacy and Safety of Tofacitinib for Immunemediated Inflammatory Rheumatic Diseases (Part Ii)

Species comparison: human and minipig PBMC reactivity under the influence of immunomodulating compounds in vitro

Development of a transcriptome-based determination of innate immune suppressor (TDIS) assay as an in vitro test for immunotoxicity

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