Tolerogenic Dendritic Cells Induced by BD750 Ameliorate Proinflammatory T cell Responses and Experimental Autoimmune Encephalitis in Mice
BD750, a novel JAK3/STAT5 inhibitor, can inhibit T cell proliferation. This study aims to evaluate whether BD750 can induce tolerogenic dendritic cells (tolDC) and their function in experimental autoimmune encephalitis (EAE) in mice. Following BD750 treatment, lipopolysaccharide (LPS)-induced maturation of DCs, allogeneic T cell proliferation, Th1 and Th17 cell functional differentiation, and STAT5 and AKT activation were determined. The effect of tolDC loaded with antigen peptide on the development and severity of EAE and splenic Th1 and Th17 cell responses was determined. In comparison with LPS-induced mature DCs (mDCs), BD750 treatment induced tolDC with lower expression levels of costimulatory molecules and proinflammatory cytokines and lower levels of STAT5 phosphorylation. TolDC inhibited allogeneic T cell proliferation and reduced Th1 and Th17 responses. Adoptive transfer of tolDC loaded with myelin oligodendrocyte glycoprotein35-55 inhibited the development and severity of EAE in mice, accompanied by reduced numbers of inflammatory infiltrates and decreased levels of demyelination in the spinal cord tissues. In addition, treatment with tolDC loaded with antigen peptide also significantly reduced the frequency of splenic Th1 and Th17 cells in EAE mice. The effects of tolDC were similar to that of JAK/STAT inhibitor CP690550-treated DCs. In conclusion, treatment with BD750 induced tolDC that inhibited proinflammatory T cell immunity in vitro and in vivo. BD750 and tolDC may be valuable for development of new therapies for EAE and other autoimmune diseases.
We thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript. This work was supported by grants from the National Natural Science Foundation of China (nos. 81202363, 81302786, 81273530), the Research Fund of Development and Regeneration Key Laboratory of Sichuan Province (no. SYS16-002), the Program for Provincial Universities Innovative Research Team in Sichuan Province (no. 13TD0028), the Innovative Research Team Fund of Chengdu Medical College (no. CYTD15-01), the Scientific Research Fund of Sichuan Provincial Education Department (no. 16ZB0271) and the National Undergraduates Innovating Experimentation Project (no. 201513705005).
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