Glatiramer acetate ameliorates inflammatory bowel disease in mice through the induction of Qa‐1‐restricted CD8⁺ regulatory cells

Abstract

Inflammatory bowel diseases (IBDs) are complex multifactorial immunological disorders characterized by dysregulated immune reactivity in the intestine. Here, we investigated the contribution of Qa-1-restricted CD8 + Treg cells in regulating experimental IBD in mice. We found that CD8 + T cells induced by T-cell vaccination ameliorated the pathological manifestations of dextran sulfate sodium induced IBD when adoptively transferred into IBD mice. In addition, CD8 + cell suppressive activity was induced by vaccination with glatiramer acetate (GA), an FDA-approved drug for multiple sclerosis (MS). We next showed that GA-induced CD8 + Treg cells worked in a Qa-1-dependent manner and their suppressive activity depends on perforin-mediated cytotoxicity. Finally, we confirmed the role of CD4 + T cells in dextran sulfate sodium induced colitis progression, and clarified that GA-induced CD8 + T cells exerted their therapeutic effects on colitis by targeting pathogenic CD4 + T cells. Our results reveal a new regulatory role of Qa-1-restricted CD8 + Treg cells in IBD and suggest their induction by GA vaccination as a potential therapeutic approach to IBD.Keywords: CD8 + Treg r Colitis r Inflammation r Qa-1 Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionInflammatory bowel diseases (IBDs) are severe gastrointestinal disorders that include ulcerative colitis and Crohn's disease. Both Crohn's disease and ulcerative colitis patients have activated innate (macrophage, neutrophil) and acquired (T and B cell) immune responses and loss of tolerance to enteric commensal bacteria [1]. Histologically, mucosal accumulation of leukocytes is * These authors contributed equally to this work.www.eji-journal.eu 126Yunliang Yao et al. Eur. J. Immunol. 2013. 43: 125-136 also a characteristic feature of IBD, and the activation of T cells and monocyte macrophages has been regarded as a crucial factor in its pathogenesis [2,3]. Although the specific enterobacterial antigens have not yet been characterized, it is generally acknowledged that CD4 + T cells play important roles in experimental mucosal inflammation as effector cells, not only because these cells make up the main cell populations that infiltrate mucosal tissues in all IBD models studied thus far [1,4], but also because in instances in which they are deleted in vivo, inflammation is ameliorated [5]. Although significant progress has been made on the pathogenesis of IBD in recent years, the immunological treatment of this disease still relies largely on the use of anti-inflammatory drugs and immunosuppressants. The use of immunomodulation carries the risk of promoting cancer and/or infection [6,7]. Treg cells, which are already used in clinical trials in the transplantation setting, represent a promising strategy for engineering tolerance to self and nonself antigens in inflammatory diseases. Numerous studies have already demonstrated that IBDs can be suppressed by CD4 + Foxp3 + Treg cells in different a...

Glatiramer acetate ameliorates experimental autoimmune neuritis

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Gut Microbiota in Multiple Sclerosis: Possible Influence of Immunomodulators

“…Glatiramer acetate has also been shown to improve a mouse model of inflammatory bowel disease by inducing CD8 + T regulatory cells. 9 Regardless of the putative mechanism or direction of the relationship, the finding that the gut microbial profile may differ in treated versus untreated MS patients has immediate implications for design of studies of the gut microbiota in MS; investigators should carefully consider whether patients are treated or not and may even consider that different MS therapies could differentially impact gut microflora, in order to avoid heterogeneity and confounding.…”

CD11chighCD8+ Regulatory T Cell Feedback Inhibits CD4 T Cell Immune Response via Fas Ligand–Fas Pathway

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