Background: We have reported that cyclosporin A (CsA) therapy may be a promising and safe option for patients with Kawasaki disease (KD) resistant to initial and additional intravenous immunoglobulin (IVIG). Up to now, it has been considered that CsA exerts effects on the intracellular phosphatase calcineurin, and subsequently inhibits activation of nuclear factor of activated T cells (NFAT). However, the functional mechanism of CsA therapy in KD patients has remained unclear.
Methods: The KD patients enrolled in this study were treated with CsA between April 2012 and December 2013. In accordance with our treatment protocol, KD patients are initially treated with IVIG and aspirin. If there is no response, a further course of IVIG is given, and if there is no response to this additional IVIG, the patients are treated with CsA. Peripheral blood samples were obtained just before and after the initial course of IVIG, additional IVIG, and CsA therapy. To evaluate the NFAT pathway and activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, we examined the gene expression of cytokines and intracellular signal transducers using real-time RT-PCR and phospho-STAT3 (pSTAT3) and STAT5 (pSTAT5) using flow cytometry.
Results: Thirty-six KD patients were divided into three groups: responsive to initial IVIG (n=19), responsive to additional IVIG (n=7), and treated with CsA group (n=10). In the CsA group, expression of mRNAs for interleukin (IL)-2, NFATc1 and NFATc2 was significantly increased, whereas the mean fluorescence intensity (MFI) of pSTAT3 (CD3+ T cell) and pSTAT3 (CD16b+ granulocyte) was decreased after CsA treatment. In the group responsive to initial IVIG, the expression of mRNAs for IL-2, IL-6, NFATc1 and NFATc2 was significantly increased, whereas that for STAT3, 5A, 5B was decreased after IVIG treatment; on the other hand, the MFI of pSTAT3 (CD3+ T cell) and pSTAT3 (CD16b+ granulocyte) was decreased, and that of pSTAT5 (CD16b+ granulocyte) was increased, after IVIG.
Conclusion: In patients with refractory KD, CsA exerts effects on the activity of the NFAT and JAK-STAT pathways. However, our results suggest that in patients with immunoglobulin-resistant KD, CsA may act through a mechanism other than the NFAT pathway.