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.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease in the central nervous system (CNS), predominantly mediated by autoreactive CD4+ Th1 and Th17 cells
BD750 Treatment Induces Tolerogenic Dendritic cells (DCs) (tolDC) Mature dendritic cells possess numerous dendrites that may be of great advantage to interaction with T cells [21]
Treatment with a low dose of BD750 (1 μM) did not change the morphology of mature DCs (mDCs), and both mDCs that had been treated with low-dose BD750 and vehicle displayed large clusters of adherent cells with sharp cytoplasmic projections
Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease in the central nervous system (CNS), predominantly mediated by autoreactive CD4+ Th1 and Th17 cells. During the pathogenic process of MS, autoreactive CD4+ T cells pass through the bloodbrain barrier and migrate into the brain and spinal cord to cause demyelination in the CNS [1,2]. Together with defects in the function of regulatory T cells (Tregs) in patients with MS, this enhances pathogenic Th1 and Th17 responses within the brain [3]. Mature DCs present peptide of antigens by major histocompatibility complex (MHC) molecules and express high levels of costimulatory molecules, such as CD80, CD83, CD86 and CD40, on their surface to provide two necessary signals for full T cell activation. TolDC from relapsing-remitting MS patients can induce stable antigen-specific hyporesponsiveness in myelin-reactive T cells [13]
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