Background/Purpose: We previously reported that Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway-mediated regulation of interferon (IFN) regulatory factor (IRF)-related genes may have an important role in the disease activity of systemic lupus erythematosus (SLE) through analyzing the difference of gene expression in peripheral blood CD3+ T cells obtained from active and inactive phases of SLE patients. Recently pan JAK inhibitor tofacitinib (TOFA) were developed and successfully applied to patients with rheumatoid arthritis. Therefore, the application possibility of TOFA was investigated for the new therapeutic strategy of SLE.

Methods: Monotherapy with TOFA or dual therapy with TOFA and 0.5mg/kg dexamethasone (DEXA) had been administered to two-lupus model mice with different genetic background, MRL/lpr for ten weeks and (NZB/NZW) F1 for eleven weeks, respectively. We evaluated and analyzed the disease, pathological and immunological condition of these mice. In addition, the gene expression obtained from SLE mouse CD4+ and patients CD3+ T cells were analyzed by DNA microarray and real-time PCR. 

Results: Anti-DNA antibody titers and proteinuria were decreased in any TOFA administered groups. Both glomerular and interstitial nephritis were ameliorated in pathological kidney image analysis. Deposition of immunoglobulin and complements in the kidney were also significantly diminished. In CD4+ T cell analysis, CD44^lowCD62L^high naïve cells increased and CD44^highCD62L^loweffector/memory cells significantly decreased in TOFA administered groups. Dual therapy with DEXA showed tendency to indicate stronger inhibitory effect comparing with monotherapy through any analysis. After TOFA administration, the gene expression of IFN induced protein with tetratricopeptide repeats 3 (IFIT3) that is related with IFN signaling pathway and contribute to anti-viral mechanism was significantly suppressed in both CD4+ from lupus prone mice and CD3+ T cells from SLE patients.

Conclusion: Both TOFA monotherapy and dual therapy with DEXA could suppress nephritis and modify immunological function in SLE mice with different genetic background. IFN signaling pathway was supposed to be important for the functional mechanism of TOFA to improve the disease condition. TOFA may contribute to the development of a new therapeutic strategy for SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pan-jak-inhibitor-tofacitinib-ameliorate-autoimmunity-and-nephritis-in-lupus-prone-mice-via-inhibition-of-interferon-signaling-pathway/