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

Authors
Yan Zhou, Xiao Leng, Hua Li, Shuxia Yang, Tai Yang, Limei Li, Ying Xiong, Qiang Zou, Yang Liu, and Yantang Wang
Abstract
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.
Volume
2017
Page Range
204-214
DOI
10.2119/molmed.2016.00110
Date Published
September 27, 2017
Article PDF
16_110_Zhou.pdf14100 KB
Supplemental Data
16_110_Zhou_Suppl.pdf300 KB
Keywords
Zhou, Leng, Yang, Li, Xiong, Zou, Liu, Wang, multiple sclerosis, MS, tolerogenic dendritic cells, tolDC, BD750, autoimmune encephalitis, inflammation, autoimmune diseases
Article Type
Research Article