Application of IOX1 in prevention and/or treatment of autoimmune diseases

[0118] Example 1: CD4 in vitro + Screening of an epigenetic compound library for IFN-γ and IL-17A inhibitors in T cells

[0119] The inventors have found in previous studies that epigenetic regulation occurs in CD4 + Plays a key role in T cell differentiation. To systematically assess which molecular components of the epigenetic machinery can be directly manipulated to achieve optimal control of inflammatory cytokine expression in helper T cells, the inventors screened a commercially available "epigenetic compound library" ( Purchased from Selleck in 2015) and its potential role in the proliferation and differentiation of Th1, Th17 and Treg cells was studied. The compound library is a collection of 128 inhibitors of epigenetic enzymes and signaling molecules, including histone deacetylases (HDACs), JAKs, histone demethylases, histone acetyltransferases (HATs), DNA and methyl Transferase (Dnmts) (such as figure 1 shown in A). These 128 compounds were first screened for the...

[0125] Example 2: IOX1 inhibits CD4 + In vitro expression of IL-17 in T cells

[0126] Due to the limited in vivo anti-inflammatory effect of OTX015 (data not shown), the inventors focused further studies on IOX1, a potent broad-spectrum inhibitor of 2OG oxygenases, including JmjC demethylase and DNA demethylase base enzyme. In addition to the screening test, the inventors further examined the inhibitory effect of two different doses of IOX1 on the expression of IFN-γ and IL-17 in Th1 and Th17 cells after 48 hours, 72 hours and 96 hours of culture (eg image 3 B-D and Figure 4 shown in A-E). The results demonstrate that IOX1 preferentially controls Th17 differentiation without altering CD4 in vitro + Viability and proliferation of T cells in total T cell cultures. These results were further confirmed using naive T cell-derived Th1 and Th17 cultures (e.g. Figure 5 shown in A-D). Furthermore, when using the OVA-stimulated OT-II cell system, the inventors found that IOX1...

[0127] Example 3: IOX1 inhibits Il17a expression by targeting TET2 protein

[0128] To explore the overall effect of IOX1 on Th17 cells, the inventors performed RNA-seq analysis to dissect the genome-wide expression changes induced by IOX1 in Th17 cells. Such as volcano map (such as Figure 6 As shown in A), in Th17 cells, IOX1 significantly down-regulated the expression of 36 genes (P2), while only up-regulated the expression of 7 genes (as shown in Table 2). The expressions of Th17 marker cytokines Il17a and Ccl20 were significantly inhibited by IOX1 (such as Figure 6 shown in A). However, under the action of IOX1, no changes were found in transcription factors promoting Th17 differentiation (such as Rorc, Rora, Stat3 or Irf4). Further Gene Ontology analysis using the Ingenuity Pathway Analysis program showed that 43 IOX1-responsive genes were significantly enriched in pathways such as IL-17A signaling and inflammasome (e.g. Figure 6 B), while various upstream regulato...