Prevention of Experimental Autoimmune Encephalomyelitis by Transfer of Embryonic Stem Cell-Derived Dendritic Cells Expressing Myelin Oligodendrocyte Glycoprotein Peptide along with TRAIL or Programmed Death-1 Ligand

Abstract

Experimental autoimmune encephalomyelitis (EAE) is caused by activation of myelin Ag-reactive CD4+ T cells. In the current study, we tested a strategy to prevent EAE by pretreatment of mice with genetically modified dendritic cells (DC) presenting myelin oligodendrocyte glycoprotein (MOG) peptide in the context of MHC class II molecules and simultaneously expressing TRAIL or Programmed Death-1 ligand (PD-L1). For genetic modification of DC, we used a recently established method to generate DC from mouse embryonic stem cells (ES cells) in vitro (ES-DC). ES cells were sequentially transfected with an expression vector for TRAIL or PD-L1 and an MHC class II-associated invariant chain-based MOG epitope-presenting vector. Subsequently, double-transfectant ES cell clones were induced to differentiate to ES-DC, which expressed the products of introduced genes. Treatment of mice with either of the double-transfectant ES-DC significantly reduced T cell response to MOG, cell infiltration into spinal cord, and the severity of MOG peptide-induced EAE. In contrast, treatment with ES-DC expressing MOG alone, irrelevant Ag (OVA) plus TRAIL, or OVA plus PD-L1, or coinjection with ES-DC expressing MOG plus ES-DC-expressing TRAIL or PD-L1 had no effect in reducing the disease severity. In contrast, immune response to irrelevant exogenous Ag (keyhole limpet hemocyanin) was not impaired by treatment with any of the genetically modified ES-DC. The double-transfectant ES-DC presenting Ag and simultaneously expressing immune-suppressive molecules may well prove to be an effective therapy for autoimmune diseases without inhibition of the immune response to irrelevant Ag.

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

“…7 The impact of the TRAIL:TRAIL-R signaling axis on inflammatory events is primarily via inhibition of a range of immune functions-T-cell cycle progression, autoreactive T-cell proliferation, pro-inflammatory cytokine production, Ab production, and inflammatory reactions. [27][28][29][30][57][58][59] This range of immunoinhibitory effects clearly extends beyond CD4 ϩ T cells per se, encompassing CD8 ϩ T cells, B cells, monocytes, and dendritic cells. 8,60 -63 The precise nature of TRAIL's effects on these various cell types in not fully resolved.…”

“…29 As alternatives, however, surrogates for soluble TRAIL have been invoked, namely, agonistic anti-DR5 Ab 27,73 and dendritic cells with enforced TRAIL expression. 30 In each of these latter cases, the TRAIL receptor trigger may be achieving a higher effective valency. This, along with dosing factors, could explain why soluble TRAIL in our hands, expressed by in vivo gene transfer, displayed no therapeutic benefit when administered as a control alongside Fn14-TRAIL.…”

“…In a sense, this is replicating the situation with dendritic cell neo-expressing surface TRAIL, which have been shown to be effective in suppressing EAE. 30 3) There is evidence that TRAIL-mediated inhibition may function primarily at the EAE priming phase (during T-cell triggering and expansion), 29 whereas TWEAKblockade's benefit may be more focused on downstream pro-inflammatory events (including preventing breakdown of the BBB). 55 Thus, by combining the two, one has a single agent that could in principle impact both priming and later phases of the disease.…”

“…[27][28][29] Moreover, embryonic stem cell-derived dendritic cells with enforced co-expression of TRAIL and pathogenic myelin oligodendrocyte glycoprotein (MOG) protein suppress EAE induction. 30 Interestingly, soluble TRAIL has emerged as a response marker in MS patients undergoing interferon (IFN)-␤ therapy, 31 with those most likely to respond to treatment showing early and sustained soluble TRAIL induction after therapeutic cytokine administration.…”

Characterization of Dendritic Cells and Macrophages Generated by Directed Differentiation from Mouse Induced Pluripotent Stem Cells

“…By genetic engineering, we can generate ES-DCs capable of modulating immune response in an antigen-specific manner. Mouse systems have demonstrated the induction of anti-cancer immunity [6][7][8][9][10] and the prevention of autoimmune disease [11,12] by in vivo administration of genetically engineered ES-DCs.…”