Adoptive Cell Therapy of Induced Regulatory T Cells Expanded by Tolerogenic Dendritic Cells on Murine Autoimmune Arthritis.

Jie Yang,Yiming Yang,Ning Kong,Xueyu Jiang,Juan Sun,Rufeng Xie,Lidong Liu

doi:10.1155/2017/7573154

Abstract

Objective Tolerogenic dendritic cells (tDCs) can expand TGF-β-induced regulatory T cells (iTregs); however, the therapeutic utility of these expanded iTregs in autoimmune diseases remains unknown. We sought to determine the properties of iTregs expanded by mature tolerogenic dendritic cells (iTregmtDC) in vitro and explore their potential to ameliorate collagen-induced arthritis (CIA) in a mouse model. Methods After induction by TGF-β and expansion by mature tDCs (mtDCs), the phenotype and proliferation of iTregmtDC were assessed by flow cytometry. The ability of iTregs and iTregmtDC to inhibit CD4+ T cell proliferation and suppress Th17 cell differentiation was compared. Following adoptive transfer of iTregs and iTregmtDC to mice with CIA, the clinical and histopathologic scores, serum levels of IFN-γ, TNF-α, IL-17, IL-6, IL-10, TGF-β and anti-CII antibodies, and the distribution of the CD4+ Th subset were assessed. Results Compared with iTregs, iTregmtDC expressed higher levels of Foxp3 and suppressed CD4+ T cell proliferation and Th17 cell differentiation to a greater extent. In vivo, iTregmtDC reduced the severity and progression of CIA more significantly than iTregs, which was associated with a modulated inflammatory cytokine profile, reduced anti-CII IgG levels, and polarized Treg/Th17 balance. Conclusion This study highlights the potential therapeutic utility of iTregmtDC in autoimmune arthritis and should facilitate the future design of iTreg immunotherapeutic strategies.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease causing chronic inflammation of the synovial joints
Our findings suggest the potential use of iTregmtDC as a therapy for autoimmune arthritis
Following stimulation with LPS for 48 h, the mean fluorescence intensity (MFI) of each of these molecules was consistently lower on the mature Tolerogenic dendritic cells (tDCs) than on the mature dendritic cells (DCs) (Figure 1(a))

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease causing chronic inflammation of the synovial joints. The inflammatory processes occurring in RA result in hyperplasia of the synovial membrane and infiltration of monocytes, macrophages, T and B cells, mast cells, and dendritic cells (DCs) [1]. Pharmacological therapies for RA include analgesics and anti-inflammatory steroids, which halt the progression of RA but do not cure it. A curative treatment has yet to be found. The development of novel antirheumatic therapies that target aberrant immune processes, dampen inflammation, and promote tolerance is needed. Cellular therapy for autoimmune diseases has attracted much attention, and as the master regulators of all immune responses, regulatory T cells (Tregs) are the most promising candidates for cell therapy. Natural Tregs (nTregs) are primarily derived from the thymus, and induced

Methods

Results

Conclusion