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

Abstract

Syngeneic, pluripotent Lin − Sca1 + bone marrow stem cells (SC), transferred to mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis, enhanced recovery, prevented relapses and promoted myelin repair. SC-treated mice showed elevated interferon-γ production and induction of indoleamine 2,3-dioxygenase (IDO) in CD11c + dendritic cells (DC). IDO induction was specific since in the presence of IDO-producing CD11c + DC, PLP stimulated Tcell proliferation was inhibited and the IDO-inhibitor, 1-MT, abrogated the SC effect. Relapse prevention during chronic disease correlated with decreased responsiveness to PLP [178][179][180][181][182][183][184][185][186][187][188][189][190][191] and MBP [85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] . Thus, pluripotent SC induce IDO in DC leading to inhibition of antigen reactivity and spreading in EAE.

How stem cells speak with host immune cells in inflammatory brain diseases

“…In vivo in mice with EAE, transplanted syngeneic MSCs prevent relapses and promote myelin repair via an IFN-γ-dependent mechanism that induces IDO in CD11c + DCs and leads to the inhibition of antigen reactivity and disease spread (Matysiak et al, 2008(Matysiak et al, , 2011.…”

“…Data in Table 1 are in part summarized in (Chamberlain et al, 2008;Hall et al, 2006;Martino and Pluchino 2006;Pluchino et al, 2009b;Rojewski et al, 2008;Uccelli et al, 2008;Yuan et al, 2011). (Cusimano et al, 2012;Jaderstad et al, 2010) aracrine IDO-kynurenine MSCs (h) T cells, DCs T cell apoptosis, inhibition of antigen presentation (Lanz et al, 2010;Matysiak et al, 2008Matysiak et al, , 2011Meisel et al, 2004;Plumas et al, 2005 Bonnamain et al, 2012;Chabannes et al, 2007;Moll et al, 2011) Paracrine VEGF NPCs Microglia/macrophages Inhibition of microglial activation, proliferation and phagocytosis (Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine LIF NPCs Th17 cells Inhibition of Th17 cell differentiation (Cao et al, 2011;Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine Galectins MSCs/NPCs T cells Inhibition of T cell proliferation (Gieseke et al, 2010;Sioud 2011;Yamane et al, 2010Yamane et al, , 2011 Endocrine/Paracrine TSG-6 MSCs Macrophages Inhibition of macrophage activation, proliferation and phagocytosis (Fisher-Shoval et al, 2012;Lee et al, 2009;Roddy et al, 2011) EVs miR transfer MSCs/NPCs Multiple Post-transcriptional regulation (Bruno et al, 2009;Chen et al, 2010;…”

Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration

“…Recently, reports have appeared suggesting that bone marrow-derived cells can ameliorate toxic and inflammatory experimental demyelinating disease following intravenous delivery [1,3,5,7,[13][14][15][16]. However, whether this effect is achieved through cell replacement and…”

“…Others have previously reported the amelioration of EAE using bone marrow derived cells [1,3,5,7,[13][14][15][16]. Some studies propose and indeed help define systemic immune effects [3,5,7,13,14]; some find there to be CNS infiltration (following intravenous delivery of cells) [1,3,5,16] with certain groups proposing not immune 'therapeutic' activity but rather differentiation into microglia and/or oligodendrocyte lineage cells [1,5,16].…”

“…Some studies propose and indeed help define systemic immune effects [3,5,7,13,14]; some find there to be CNS infiltration (following intravenous delivery of cells) [1,3,5,16] with certain groups proposing not immune 'therapeutic' activity but rather differentiation into microglia and/or oligodendrocyte lineage cells [1,5,16]. Alternatively, local neuroprotective effects dependent on local infiltration also have been suggested as the therapeutic mechanism [5,16].…”