A novel human truncated IL12rβ1-Fc fusion protein ameliorates experimental autoimmune encephalomyelitis via specific binding of p40 to inhibit Th1 and Th17 cell differentiation

// Wei Guo 1, * , Chen Wang 1, * , Xin Wang 1 , Cheng Luo 1 , Dongmei Yu 1 , Yuheng Wang 1 , Yucong Chen 1 , Wen Lei 1 , Xiangdong Gao 1 , Wenbing Yao 1 1 State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China * These authors have contributed equally to this work Correspondence to: Xiangdong Gao, e-mail: xdgao@cpu.edu.cn Wenbing Yao, e-mail: wbyao@cpu.edu.cn Keywords: Immunology and Microbiology Section, Immune response, Immunity, cytokine-blocking, binding specificity, molecular mechanism, central nervous system, autoimmune disease Received: May 24, 2015 Accepted: August 22, 2015 Published: September 04, 2015 ABSTRACT Interleukin (IL)-12 and IL-23 respectively driving polarization of T helper (Th) 1 and Th17 cells has been strongly implicated in the pathogenesis of both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In this study, we first constructed, expressed and purified a novel human truncated IL12rβ1-Fc fusion protein (tIL12rβ1/Fc) binding multiple forms of the p40 subunit of human IL-12 and IL-23. tIL12rβ1/Fc was found to effectively ameliorate MOG 35–55 -induced EAE through reducing the production of Th1- and Th17-polarized pro-inflammatory cytokines and suppressing inflammation and demyelination in the focused parts. Moreover, tIL12rβ1/Fc suppressed Th1 (IFN-γ + alone) and IFN-γ + IL-17 + as well as the population of classic Th17 (IL-17 + alone) cells in vivo . Furthermore, tIL12rβ1/Fc ameliorated EAE at the peak of disease via the inhibition of STAT pathway, thereby causing a prominent reduction of RORγt (Th17) and T-bet (Th1) expression. Notably, tIL12rβ1/Fc could increase the relative number of CD4 + Foxp3 + regulatory T cells. These findings indicates that tIL12rβ1/Fc is a novel fusion protein for specific binding multiple forms of p40 subunit to exert potent anti-inflammatory effects and provides a valuable approach for the treatment of MS and other autoimmune diseases.