Janus Kinase Inhibitor Baricitinib Modulates Human Innate and Adaptive Immune System

Abstract

The purpose of this study was to elucidate the mechanism of action of baricitinib on Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, which involves in human innate and adaptive immune system. The effects of baricitinib were evaluated using human monocyte-derived dendritic cells (MoDCs), plasmacytoid dendritic cells (pDCs), B cells, and T cells. Baricitinib concentration-dependently suppressed the expression of CD80/CD86 on MoDCs and the production of type-I interferon (IFN) by pDCs. Baricitinib also suppressed the differentiation of human B cells into plasmablasts by B cell receptor and type-I IFN stimuli and inhibited the production of interleukin (IL)-6 from B cells. Human CD4+ T cells proliferated after T cell receptor stimulation with anti-CD3 and anti-CD28 antibody; however, such proliferation was suppressed by baricitinib in a concentration-dependent manner. In addition, baricitinib inhibited Th1 differentiation after IL-12 stimulation and Th17 differentiation by TGF-β1, IL-6, IL-1β, and IL-23 stimulation. Tofacitinib showed similar effects in these experiments. In naive CD4+ T cells, IFN-α and IFN-γ induced phosphorylation of STAT1, which was inhibited by baricitinib and tofacitinib. Furthermore, IL-6-induced phosphorylation of STAT1 and STAT3 was also inhibited by JAK inhibitors. In conclusion, the results indicated that baricitinib suppresses the differentiation of plasmablasts, Th1 and Th17 cells, as well as innate immunity, such as the T cell stimulatory capacity of dendritic cells. Thus, JAK inhibitors can be potentially clinically effective not only in rheumatoid arthritis but other immune-related diseases.

The Role of B7 Family Molecules in Maternal–Fetal Immunity

“…However, due to a lack of MHC molecules, the capacity of syncytiotrophoblasts to deliver a reverse signal via PD-1 ligation is prohibited; instead, syncytiotrophoblasts transmit signals to inactivate PD-1-expressing immune cells (49). The epidermal growth factor receptor (EGFR) and JAK2/STAT1 pathways might account for the upregulation of B7-H1 in cytotrophoblasts (51). The maternal blood level of soluble PD-L1 (sPD-L1) is elevated in normal pregnant women at the early stage compared with non-pregnant controls (52).…”

Changes in selected haematological parameters associated with JAK1/JAK2 inhibition observed in patients with rheumatoid arthritis treated with baricitinib

“…42 Increases in haemoglobin in patients with RA treated with the anti-IL-6 receptor antibody tocilizumab are associated with the reversal of iron sequestration by hepcidin. 43 By inhibiting IL-6 receptor signalling, 44 baricitinib may also facilitate iron mobilisation. Our observation of increased iron in the JADN study supports the hypothesis that reduction in proinflammatory cytokine receptor signalling through JAK1 inhibition is a possible mechanism for the improvements in haemoglobin concentrations observed with baricitinib treatment.…”

Baricitinib: New Pharmacotherapy Options for Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Rheumatic Diseases

“…Рассмотрим некоторых из них. Была продемонстрирована способность БАРИ (как и ТОФА) дозозависимым образом блокировать экспрессию CD80/CD86 (костимуляторные молекулы, участвующие в регуляции активации Т-клеток) на мембране моноцитарных дендритных клеток (ДК), синтез ИФН типа I плазмоцитоидными ДК, дифференцировку В-клеток в плазмобласты, синтез ИЛ6 В-клетками, ингибировать дифференцировку Th1-клеток (стимулированных ИЛ12) и Th17-клеток (стимулированных ИЛ1β, ИЛ6, ИЛ23 и трансформирующим фактором роста β) [105]. Кроме того, оба препарата подавляли ИЛ6-зависимое фосфорилирование STAT1-и STAT3-компонентов сигнального пути JAK-STAT.…”