Stem cells ameliorate EAE via an indoleamine 2,3-dioxygenase (IDO) mechanism

Background: Stem cells (SC)have been shown to have beneficial effects during autoimmune demyelination but underlying mechanisms remain unknown. In mice, lineage negative cells expressing the Sca1 molecule (Lin-Sca1+) represent a pluripotent population of bone marrow SC (BMSC) depleted of mature hematopoietic precursors and enriched in mesenchymal SC. Objective: In this study we have assessed the immunoregulatory role of pluripotent Lin-Sca1+ bone marrow stem cells (Lin-Sca1+BMSC) in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Methods: Syngeneic pluripotent Lin-Sca1+BMSC were transferred at peak of disease to mice with PLP139-151-induced EAE. At different time points after transplantation proliferation of T cells and IFN-gamma secretion were assessed. Accumulation of PKH26 stained SC in mouse organs was analyzed by flow cytometry. The role of indoleamine 2,3-dioxygenase (IDO) was established using Western blot analysis and specific competitive inhibition with 1-methy1-DL-tryptophan (1-MT). Results: Lin-Sca1+BMSC transfer enhanced recovery (p=0.000950), prevented relapses (p=0.0076), reduced central nervous system damage and enhanced remyelination. T cells from treated mice showed decreased proliferation to PLP139-151 (p=0.0019) and elevated interferon-gamma production. In dendritic cells (DC) increased induction of IDO was observed. Specificity of IDO involvement was confirmed by demonstration that in the presence of CD11c+ DC, with high IDO expression, PLP-induced proliferation was inhibited and the IDO-inhibitor, 1-MT, abrogated the immunoregulatory effect of Lin-Sca1+BMSC (p=0.000912). Relapse prevention correlated with inhibition of antigen spreading, the latter evidenced by loss of T cell responsiveness to PLP178-191 and MBP85-99 during chronic disease. Conclusions: Thus, pluripotent SC induce IDO in DC, leading to inhibition of antigen reactivity and spreading in EAE.