Tolerogenic Dendritic Cells Induced by BD750 Ameliorate Proinflammatory T cell Responses and Experimental Autoimmune Encephalitis in Mice

Yan Zhou, Xiao Leng, Hua Li, Shuxia Yang, Tai Yang, Limei Li, Ying Xiong, Qiang Zou, Yang Liu, Yantang Wang

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, LPS-induced maturation of DC, allogeneic T cell proliferation, Th1 and Th17 cell functional differentiation, the STAT5 and AKT activation were determined. The effect of tolDC loaded with antigen peptide on the development and severity of EAE and their splenic Th1 and Th17 cell responses were determined. In comparison with LPS-induced mature DC (mDC), BD750 treatment induced tolDC with lower expression levels of costimulatory molecules and pro-inflammatory 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 MOG35-55 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 of mice. 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 the JAK/STAT inhibitor, CP690550-treated DC. In conclusion, treatment with BD750 induced tolDC that inhibited pro-inflammatory 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.