Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550)
This study investigated the effects of the novel Janus kinase (JAK) inhibitor CP-690,550 (now known as tofacitinib) on adaptive and innate immune responses, in order to establish the mode of action of JAK inhibitors in the setting of inflammatory diseases. The inhibition of specific JAK/STAT-dependent pathways by CP-690,550 was determined through analysis of cytokine stimulation of mouse and human T cells in vitro.The effects of CP-690,550 on Th-cell differentiation of naive murine CD4+ T cells and its effects in a model of established arthritis were also investigated. CP-690,550 was found to interfere with Th1 and Th2 differentiation, impair production of inflammatory Th17 cells generated in response to interleukin (IL)-1ß, IL-6 and IL-23, and enhance production of IL-17A in cells cultured with IL-6 and TGF-ß1. It was associated with amelioration of murine arthritis by inhibiting production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. CP-690,550 also suppressed cytokine production in a sepsis model, suggesting it blocks the action of cytokines during innate and adaptive responses. The study findings showed that CP-690,550 may reduce the activity of autoimmune diseases and prevent transplant rejection through suppression of differentiation of Th1 and Th17 cells and innate immune cell signalling.