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J Leukoc Biol. 2016 Aug;100(2):403-11. doi: 10.1189/jlb.3A1215-540R. Epub 2016 Apr 22.

Systemic delivery of IL-27 by an adeno-associated viral vector inhibits T cell-mediated colitis and induces multiple inhibitory pathways in T cells.

Author information

1
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;
2
Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA; Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China;
3
Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA;
4
Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China;
5
Department of Physiology, Ohio State University, Columbus, Ohio, USA; and.
6
Division of Hematology, Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA.
7
Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China;
8
Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; lims@smu.edu.cn.
9
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.

Abstract

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.

KEYWORDS:

IL-30; PD-L1; Th1/17; Tregs; autoimmune colitis

PMID:
27106672
PMCID:
PMC4945352
DOI:
10.1189/jlb.3A1215-540R
[Indexed for MEDLINE]
Free PMC Article

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