The impact of inflammatory licensing on heme oxygenase-1–mediated induction of regulatory T cells by human mesenchymal stem cells

Mougiakakos, Dimitrios; Jitschin, Regina; Johansson, C. Christian; Okita, Riki; Kiessling, Rolf; Blanc, Katarina Le

doi:10.1182/blood-2010-12-324038

Cited by 189 publications

(149 citation statements)

References 49 publications

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“…These variations resulted in a modification of TH1/Treg and TH17/Treg ratios, in particular, Th1/Treg ratio decreased up to 4.2 times and Th17/Treg ratio decreased up to 6 times (see Supplementary Information). This observation is in accordance with recent reports from in vitro studies describing the ability of MSCs to induce Tregs in vitro 10,11 and in vivo after infusion in patients with severe and treatment-refractory systemic lupus erythematosus.…”

supporting

confidence: 82%

Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune monitoring

et al. 2012

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supporting

confidence: 82%

Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune monitoring

et al. 2012

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“…Here, we found that the exposure to inflammatory milieu leads to IDO activation that becomes the central immunosuppressive enzyme affecting T cell proliferation in all SC types, as shown previously also by other authors [36,38], even if some other molecules may be involved. The discrepancies among different published data could be related to different experimental approaches; thus, method and assay standardization is required to obtain comparable results, as suggested by ISCT MSC Committee [78].…”

supporting

confidence: 64%

“…predominant therapeutic efficacy of MSCs and MSC-like SCs is mediated via a paracrine mechanism associated with the release of several cytokines that profoundly influence the response of IECs [22,31,34,[36][37][38]40,43]. This principle applies to all SCs that modulate inflammation and have a limited capacity to generate a specialized progeny.…”

mentioning

confidence: 99%

“…In response to these stimuli, MSCs migrate to the site of injury, and become immune modulatory by affecting inflammation and tissue repair in a positive manner. The paracrine mechanisms underlying the impact of MSCs on the local immune adaptation include a broad panel of molecular pathways, such as IFN-g, IL-1b, transforming growth factorb, indoleamine-2,3-dioxygenase (IDO), IL-6, IL-10, prostaglandin-E2 (PGE2), hepatocyte growth factor, TNF-a, nitric oxide (NO), heme oxygenase-1 (HO-1), HLA-G5 [21,22,[31][32][33][34][35][36][37][38][39][40][41][42][43], and others, some of which are still unknown.…”

Section: Introductionmentioning

confidence: 99%

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Comparative study of immune regulatory properties of stem cells derived from different tissues

et al. 2014

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“…The original HO-1 KO mouse showed a progressive chronic inflammatory and proinflammatory state as demonstrated by enlarged lymph nodes, high white blood cell counts, hepatic inflammatory cell infiltrates, and a shift in T-helper (Th)-2 to Th1 cytokine response (17,18). Several authors have reported that HO-1 confers immune suppression by affecting Tregs (19,20), but these data are controversial, as others have shown that HO-1 does not affect the development and/or suppressive function of Tregs (21,22). Overall, the importance of HO-1 for Treg-mediated immune regulation has not been clearly characterized.…”

Section: Protection Of Nec By Ho-1mentioning

confidence: 99%

Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

et al. 2015

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Background: Necrotizing enterocolitis (NEC), an intestinal inflammatory disease affecting premature infants, is associated with low regulatory T (Treg) to effector T (Teff ) cell ratios. We recently demonstrated that heme oxygenase-1 (HO-1) deficiency leads to increased NEC development. Here, we investigated the effects of HO-1 on T-cell proportions in a murine NEC-like injury model. Methods: Intestinal injury was induced in 7-d-old wildtype (WT) or HO-1 heterozygous (HO-1 Het) pups by formulafeeding every 4 h for 24-78 h by oral gavage and exposures to 5%O 2 . Controls remained breastfed. HO-1 was induced in WT pups by administering heme preinjury induction. Lamina propria T cells were identified by flow cytometry. For adoptive transfer studies, WT splenic/thymic Tregs were injected intraperitoneally into HO-1 Het pups 12-24 h preinduction. results: Het mice showed increased intestinal injury and decreased Treg/Teff ratios. Genes for pattern recognition (Toll-like receptor-4, C-reactive protein, MyD88) and neutrophil recruitment increased in Het pups after NEC induction. Inducing intestinal HO-1 decreased NEC scores and incidence, and increased Treg/Teff ratios. Moreover, adoptive transfer of Tregs from WT to HO-1 Het pups decreased NEC scores and incidence and restored Treg/Teff ratios. conclusion: HO-1 can change Treg proportions in the lamina propria of young mice under inflammatory conditions, which might, in part, confer intestinal protection.n EC is a devastating disease of premature infants.Characterized by intestinal inflammation, it can progress rapidly to intestinal necrosis. Its incidence correlates inversely with low birth weight and gestational age, reaching ~7% in infants weighing 500-1,500 g. Unfortunately, 20-40% of NEC patients need to undergo surgery, which increases mortality up to 50% and places these infants at higher risk for developing long-term sequelae, such as short bowel syndrome and neurodevelopmental impairments (1).Although advances in the understanding of its pathophysiology have been made in the last decades, the pathogenesis of NEC remains incompletely understood. Thus, current prevention and treatment strategies are limited. Three factors are generally present when NEC occurs: (i) an immature intestinal barrier and immune system; (ii) enteral feedings; and (iii) a putative bacterial component. A genetic predisposition, an in utero maternal or fetal insult (hypoxia), and/or a highly immune-reactive intestinal mucosa may then cause the initial inflammation that precedes NEC (2).Several studies have demonstrated the importance of the innate immune system in the pathophysiology of NEC. For example, a significant component is the pattern recognition of pathogens through Toll-like receptor (TLR)-4 (3,4). Also, a reduction in Paneth and in mucin-producing goblet cells (5,6) and an increase in proinflammatory mediators (i.e., TNF-α, IL-1, -6, -8, and platelet-activating factor) are associated with NEC (7).However, less attention has been given to the adaptive immune system. The fact th...

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The impact of inflammatory licensing on heme oxygenase-1–mediated induction of regulatory T cells by human mesenchymal stem cells

Cited by 189 publications

References 49 publications

Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune monitoring

Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune monitoring

Comparative study of immune regulatory properties of stem cells derived from different tissues

Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

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