Mouse Mesenchymal Stem Cells Suppress Antigen-Specific TH Cell Immunity Independent of Indoleamine 2,3-Dioxygenase 1 (IDO1)

被引:38
作者
Lanz, Tobias V. [1 ,2 ]
Opitz, Christiane A. [1 ]
Ho, Peggy P. [3 ]
Agrawal, Ankur [3 ]
Lutz, Christian [4 ]
Weller, Michael [5 ]
Mellor, Andrew L. [6 ]
Steinman, Lawrence [3 ]
Wick, Wolfgang [1 ]
Platten, Michael [1 ]
机构
[1] Univ Heidelberg Hosp, Dept Neurooncol, German Canc Res Ctr, D-69120 Heidelberg, Germany
[2] Univ Tubingen, Dept Gen Neurol, Hertie Inst Clin Brain Res, Tubingen, Germany
[3] Stanford Univ, Beckman Ctr Mol Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA
[4] Heidelberg Pharma AG, Ladenburg, Germany
[5] Univ Zurich, Dept Neurol, CH-8006 Zurich, Switzerland
[6] Med Coll Georgia, Inst Mol Med & Genet, Augusta, GA 30912 USA
关键词
EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MARROW STROMAL CELLS; DENDRITIC CELLS; TRYPTOPHAN DEGRADATION; INHIBIT; EXPRESSION; DIFFERENTIATION; PROLIFERATION; CATABOLISM; MATURATION;
D O I
10.1089/scd.2009.0385
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Due to their immunosuppressive properties, human mesenchymal stem cells (hMSC) represent a promising tool for cell-based therapies of autoimmune diseases such as multiple sclerosis (MS). Mouse MSC (mMSC) have been used extensively to characterize and optimize route of administration, motility, cellular targets, and immunosuppressive mechanisms in mouse models of autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE). Tryptophan (trp) catabolism by indolamine-2,3-dioxygenase 1 (IDO1) is a chief endogenous metabolic pathway that tightly regulates unwanted immune responses through depletion of trp and generation of immunosuppressive kynurenines (kyn). IDO1 activity contributes to the immunosuppressive phenotype of hMSC. Here, we demonstrate that although IDO1 is inducible in bone marrow-derived mMSC by proinflammatory stimuli such as interferon-g (IFN-g) and ligands of toll-like receptors (TLR), it does not lead to catabolism of trp in vitro. This failure to catabolize trp is not due to defective TLR signaling as demonstrated by induction of interleukin 6 (IL-6) by TLR activation. While mMSC suppressed the activation of antigen-specific myelin oligodendrocyte glycoprotein (MOG)-reactive T-cell receptor (TCR) transgenic T-helper (TH) cells in co-culture, neither pharmacologic inhibition nor genetic ablation of IDO1 reversed this suppressive effect. Finally, systemic administration of both, IDO1-proficient and phenotypically identical IDO1-deficient mMSC, equally resulted in amelioration of EAE. mMSC, unlike hMSC, do not display IDO1-mediated suppression of antigen-specific T-cell responses.
引用
收藏
页码:657 / 668
页数:12
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