JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation

Keigo Ikeda, Kunihiro Hayakawa, Maki Fujishiro, Mikiko Kawasaki, Takuya Hirai, Hiroshi Tsushima, Tomoko Miyashita, Satoshi Suzuki, Shinji Morimoto, Naoto Tamura, Kenji Takamori, Hideoki Ogawa, Iwao Sekigawa

We previously reported that JAK-STAT-pathway mediated regulation of IFN-regulatory factor genes could play an important role in SLE pathogenesis. Here, we evaluated the efficacy of the JAK inhibitor tofacitinib (TOFA) for controlling IFN signalling via the JAK-STAT pathway and as a therapeutic for SLE. We treated NZB/NZW F1 mice with TOFA and assessed alterations in their disease, pathological, and immunological conditions. Gene-expression results obtained from CD4(+) T cells (SLE mice) and CD3(+) T cells (human SLE patients) were measured by DNA microarray and qRT-PCR. TOFA treatment resulted in reduced levels of anti-dsDNA antibodies, decreased proteinuria, and amelioration of nephritis as compared with those observed in control animals. Moreover, we observed the rebalance in the populations of naïve CD4(+) T cells and effector/memory cells in TOFA-treated mice; however, treatment with a combination of TOFA and dexamethasone (DEXA) elicited a stronger inhibitory effect toward the effector/memory cells than did TOFA or DEXA monotherapy. We also detected decreased expression of several IFN-signature genes Ifit3 and Isg15 in CD4(+) from SLE-prone mice following TOFA and DEXA treatment, and IFIT3 in CD3(+) T cells from human patients following immunosuppressant therapy including steroid, respectively. Modulation of type I IFN signalling via JAK-STAT inhibition may exert a beneficial effect in SLE patients, and our results suggest that TOFA could be utilised for the development of new SLE-specific therapeutic strategies.