The Synergistic Local Immunosuppressive Effects of Neural Stem Cells Expressing Indoleamine 2,3-Dioxygenase (IDO) in an Experimental Autoimmune Encephalomyelitis (EAE) Animal Model

Abstract

Neurodegenerative diseases provoke robust immunological reactions in the central nervous system (CNS), which further deteriorate the neural tissue damage. We hypothesized that the expression levels of indoleamine 2,3-dioxygenase (IDO), an enzyme that has potent immune suppressive activities, in neural stem cells (NSCs) would have synergistic therapeutic effects against neurodegenerative diseases, since NSCs themselves have low IDO expression. In this study, the synergistic immune suppressive effects of rat fetal NSCs expressing IDO (rfNSCs-IDO) were validated by mixed leukocyte reaction (MLR) in vitro and an experimental autoimmune encephalomyelitis (EAE) animal model in vivo. rfNSCs-IDO showed significantly more suppressive effects on T cell proliferation in the MLR compared to control rfNSCs (rfNSCs-Cont). Importantly, IDO inhibition using 1-methyl-DL-tryptophan (1-MT), an IDO inhibitor, reversed the synergistic effects, confirming IDO-specific effects in rfNSCs-IDO. In the EAE animal model, systemic rfNSCs-IDO injections resulted in significant local immune suppression in the cervical lymph nodes and CNS, evidenced by a reduction in the number of activated T lymphocytes and an increase in regulatory T cell numbers, which induced significantly fewer clinical symptoms and faster recovery. In contrast, rfNSCs-Cont failed to reduce symptoms in the EAE animal models, although they showed local immune suppression, which was significantly less than that in rfNSCs-IDO. Taken together, IDO expression in NSCs synergistically potentiates the immune suppression activities of NSCs and could be applicable for the development of therapeutic modalities against various neurodegenerative diseases.

Adult Human Multipotent Neural Cells Could Be Distinguished from Other Cell Types by Proangiogenic Paracrine Effects via MCP-1 and GRO

“…Matrigel that was in semiliquid solution at 4°C solidified after in vivo transplantation, which could affect the morphologies of Matrigel. To prepare green fluorescent protein- (GFP-) expressing cells, a lentiviral system (Life Technologies; Carlsbad, CA, USA) was utilized according to previous studies [ 37 , 38 ]. These cell-Matrigel mixtures were transplanted subcutaneously into the dorsal surface of immune-deficient Balb-c/nu mice (6-week-old, male) (Orient Bio; Seongnam, South Korea) under isoflurane (Ifran™, Hana Pharm, Seoul, South Korea) anesthesia.…”

A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease

“… 2 Interestingly, this study observed no significant impact of IFN-γ exposure on initial KP rate-limiting enzymes, IDO-1/2 or TDO-2. However, our understanding of IDO expression in NSCs remains inconclusive, with alternative studies showing no IDO transcripts or protein in rat foetal NSCs, 306 while the conditionally immortalized CTX0E03 human NSC cell line 307 shows basal IDO-1 expression, which is potently induced by IFN-γ, and IDO-2 and TDO-2 are absent or present in very low abundance in unstimulated and IFN-γ-treated cells. 308 Variation between these studies may be associated with factors including innate differences between primary NSCs and the CTX0E03 cell line, the developmental stage of NSCs (embryonic/foetal versus adult), interspecies variability, or the exposure time and/or concentration of IFN-γ.…”

“…Immune suppression is relevant in inflammatory diseases of the CNS such as MS. A study utilising NSCs genetically modified to express high levels of IDO protein, showed IDO-associated inhibition of T cell proliferation in vitro, immune suppression and reduced symptoms when transplanted in EAE-induced mice. 306 An alternative study found that while intravenous injection of IL-10 over-expressing NSCs into EAE mice had an immunosuppressive effect by inhibiting T cell activation; this effect was independent of IDO. 318 The discrepancy in findings may be due to cytokine-specific effects on IDO-linked pathway regulation.…”