Systemic delivery of IL-27 by an adeno-associated viral vector inhibits T cell-mediated colitis and induces multiple inhibitory pathways in T cells.
IL-27 is a heterodimeric cytokine that is composed of two subunits, i.e., EBV-induced gene 3 and IL-27p28 (also known as IL-30). Although the role of endogenous IL-27 in the pathogenesis of autoimmune colitis, an experimental model of human inflammatory bowel disease, remains controversial, IL-27 local delivery has been shown to inhibit autoimmune colitis. IL-30 has been shown to inhibit Th1 and Th17 responses and is considered a potential therapeutic for certain autoimmune diseases. In this study, we have compared the therapeutic efficacy of adeno-associated viral vector-delivered IL-27 and IL-30 in a murine model of autoimmune colitis. We found that 1 single administration of adeno-associated viral vector-delivered IL-27, but not adeno-associated viral vector-delivered IL-30, nearly completely inhibited autoimmune colitis. Adeno-associated viral vector-delivered IL-27 administration inhibited Th17 responses and induced T cell expression of IL-10, programmed death ligand 1, and stem cell antigen 1. Intriguingly, adeno-associated viral vector-delivered IL-27 treatment enhanced Th1 responses and inhibited regulatory T cell responses. Experiments involving the adoptive transfer of IL-10-deficient T cells revealed that adeno-associated viral vector-delivered IL-27-induced IL-10 production was insufficient to mediate inhibition of autoimmune colitis, whereas anti-programmed death 1 antibody treatment resulted in the breaking of adeno-associated viral vector-delivered IL-27-induced T cell tolerance. Thus, systemic delivery of IL-27 inhibits Th17 responses and induces multiple inhibitory pathways, including programmed death ligand 1 in T cells, and adeno-associated viral vector-delivered IL-27, but not IL-30, may have a therapeutic potential for the treatment of human inflammatory bowel disease.
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA;
Xiaotong
X
Zhu
Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA; Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China;
Zhihao
Z
Liu
Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA;
Jin-Qing
JQ
Liu
Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China;
Jianmin
J
Zhu
Department of Physiology, Ohio State University, Columbus, Ohio, USA; and.
Jianchao
J
Zhang
Department of Physiology, Ohio State University, Columbus, Ohio, USA; and.
Jonathan P
JP
Davis
Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA.
Jianhong
J
Chu
Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA.
Jianhua
J
Yu
Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China;
Jie
J
Zhou
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; lims@smu.edu.cn.
Ming-Song
MS
Li
Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA; Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; Xue-feng.bai@osumc.edu.
Xue-Feng
XF
Bai
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D016207:Cytokines / Q000276:immunology; D000229:Dependovirus / Q000235:genetics*; D005822:Genetic Vectors / Q000008:administration & dosage*; D016753:Interleukin-10 / Q000502:physiology; D064094:Interleukin-27 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D016207:Cytokines; C556062:IL10 protein, mouse; D064094:Interleukin-27; D016753:Interleukin-10
IL-30; PD-L1; Th1/17; Tregs; autoimmune colitis