Clinical-Grade Human Multipotent Adult Progenitor Cells Block CD8+ Cytotoxic T Lymphocytes

Plessers, Jeroen; Dekimpe, Emily; Woensel, Matthias Van; Roobrouck, Valerie D.; Bullens, Dominique; Pinxteren, Jef; Verfaillie, Catherine M.; Gool, Stefaan Van

doi:10.5966/sctm.2016-0030

Cited by 15 publications

(17 citation statements)

References 45 publications

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“…Stem cell‐based therapy and research have made exceptional progress in the last decade. Apart from their capacity to regenerate damaged tissues, mesenchymal stem cells (MSCs) possess unique immunomodulatory capabilities and have improved the outcome of clinical diseases with aberrant immune responses . We recently published on the safety and efficacy of autologous adipose‐derived mesenchymal stem cells (ASCs) to treat naturally occurring feline chronic gingivostomatitis (FCGS).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis

Arzi

Clark

Sundaram

et al. 2017

Stem Cells Translational Medicine

115

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Mesenchymal stem cells (MSCs) have potent immunomodulatory functions and are a promising therapy for immune‐mediated inflammatory disorders. We previously demonstrated the efficacy of fresh, autologous, adipose‐derived MSCs (ASCs) to treat feline chronic gingivostomatitis (FCGS), a chronic oral mucosal inflammatory disease similar to human oral lichen planus. Here, we investigate the use of fresh allogeneic ASCs for treatment of FCGS in seven cats. Radiolabeled ASCs were also tracked systemically. Each cat received two intravenous injections of 20 million ASCs, 1 month apart. Oral inflammation, blood lymphocyte subsets, anti‐fetal bovine serum antibody levels, ASC crossmatching and serum proteins and cytokine concentrations were determined. Four of the 7 cats (57%) responded to treatment [complete clinical remission (n = 2) or substantial clinical improvement (n = 2)]. Three cats were nonresponders. Prior to therapy, most cats had increased circulating CD8+ T cells, decreased CD8lo cells, and a decreased CD4/CD8 ratio, however clinical resolution was not associated with normalization of these parameters. Nonresponders showed more severe systemic inflammation (neutrophilia, hyperglobulinemia and increased interferon gamma and tumor necrosis factor alpha concentration) prior to ASC therapy. Clinical remission took up to 20 months and no clinical relapse has occurred. A higher fraction of radiolabeled ASCs were identified in the oral cavity of FCGS affected cats than the control cat. The administration of fresh, allogenic ASCs appeared to have lower clinical efficacy with a delayed response as compared to the fresh, autologous ASCs. In addition, the mechanism(s) of action for autologous and allogenic ASCs may differ in this model of oral inflammation. Stem Cells Translational Medicine 2017;6:1710–1722

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Section: Introductionmentioning

confidence: 99%

Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis

Arzi

Clark

Sundaram

et al. 2017

Stem Cells Translational Medicine

115

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“…MAPCs promote angiogenesis and improve cardiac and limb function when injected into the peri‐infarct areas in ischaemic mice . These cells have extensive replication potential, are commercially available at clinical grade (Athersys Inc, Cleveland, Ohio) and are non‐immunogenic for alloreactive cytotoxic T lymphocyte induction, thus without potential adverse immune reactions . MAPCs have been approved for clinical studies in human patients with multiple disease indications including neurological, cardiovascular and inflammatory and immune diseases in the United States and Europe .…”

Section: Discussionmentioning

confidence: 99%

“…[31][32][33][34][35][36][37][38][39][40] These cells have extensive replication potential, are commercially available at clinical grade (Athersys Inc, Cleveland, Ohio) and are non-immunogenic for alloreactive cytotoxic T lymphocyte induction, thus without potential adverse immune reactions. 41,42 MAPCs have been approved for clinical studies in human patients with multiple disease indications including neurological, cardiovascular and inflammatory and immune diseases in the United States and Europe. 43,44 Clinical-grade human MAPCs are safe in human patients and effective on controlling human autoimmune disease and allograft rejection.…”

Section: Discussionmentioning

confidence: 99%

N‐acetylcysteine prevents oxidized low‐density lipoprotein‐induced reduction of MG53 and enhances MG53 protective effect on bone marrow stem cells

Jiang

Tan

et al. 2019

J Cellular Molecular Medi

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MG53 is an important membrane repair protein and partially protects bone marrow multipotent adult progenitor cells (MAPCs) against oxidized low‐density lipoprotein (ox‐LDL). The present study was to test the hypothesis that the limited protective effect of MG53 on MAPCs was due to ox‐LDL‐induced reduction of MG53. MAPCs were cultured with and without ox‐LDL (0‐20 μg/mL) for up to 48 hours with or without MG53 and antioxidant N‐acetylcysteine (NAC). Serum MG53 level was measured in ox‐LDL‐treated mice with or without NAC treatment. Ox‐LDL induced significant membrane damage and substantially impaired MAPC survival with selective inhibition of Akt phosphorylation. NAC treatment effectively prevented ox‐LDL‐induced reduction of Akt phosphorylation without protecting MAPCs against ox‐LDL. While having no effect on Akt phosphorylation, MG53 significantly decreased ox‐LDL‐induced membrane damage and partially improved the survival, proliferation and apoptosis of MAPCs in vitro. Ox‐LDL significantly decreased MG53 level in vitro and serum MG53 level in vivo without changing MG53 clearance. NAC treatment prevented ox‐LDL‐induced MG53 reduction both in vitro and in vivo. Combined NAC and MG53 treatment significantly improved MAPC survival against ox‐LDL. These data suggested that NAC enhanced the protective effect of MG53 on MAPCs against ox‐LDL through preventing ox‐LDL‐induced reduction of MG53.

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“…MAPC cells are adult bone marrow derived adherent cells with immunomodulatory properties that reduce in ammation by regulation of immune system functions (11). MAPC cells inhibit allogeneic T-cells in a mixed lymphocyte reaction (MLR) and suppress an allogeneic reaction between two mismatched lymphocyte populations (12,13). MAPC cells inhibit allogeneic cell and memory response mediated T-cell proliferation in vitro in a dose-dependent manner (14).…”

Section: Introductionmentioning

confidence: 99%

Multipotent Adult Progenitor Cells induce Regulatory T cells and promote their Suppressive Phenotype via TGFβ and Monocyte-dependent Mechanisms

Valentin-Torres

Day

Taggart

et al. 2020

Preprint

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Background: Dysregulation of the immune system can initiate chronic inflammatory responses that exacerbate disease pathology. Multipotent adult progenitor cells (MAPC® cells), an adult, adherent bone-marrow derived stromal cell, have been observed to promote the resolution of uncontrolled inflammatory responses in a variety of clinical conditions including: acute ischemic stroke, acute myocardial infarction (AMI), graft vs host disease (GvHD), and acute respiratory distress syndrome (ARDS). One of the proposed mechanisms by which MAPC cells modulate immune responses is via the induction of regulatory T cells (Tregs), however, the mechanism(s) involved remains to be fully elucidated. Methods: To examine MAPC cell mediated Treg induction, peripheral mononuclear cells (PBMCs) were co-cultured with MAPC cells at various PBMC: MAPC cell ratios. Treg frequencies and phenotype was determined by flow cytometry. The mechanisms involved in MAPC cell induction of Tregs were assessed using transforming growth factor β (TGF) and indoleamine 2, 3 dioxygenase (IDO) inhibitors. Monocyte involvement in MAPC cell induction of Tregs was also explored.Results: Herein, we demonstrate that, in an in vitro setting, MAPC cells increase Treg frequencies by promoting Treg proliferation and CD4+ T cell differentiation into Tregs. Moreover, MAPC cell-induced Tregs (miTregs) have a more suppressive phenotype characterized by increased expression of CTLA-4, HLA-DR, and PD-L1 and T cell suppression capacity. MAPC cells also promoted Treg activation by inducing CD45RA+ CD45RO+ transitional Tregs. Additionally, we identify TGFβ as an essential factor for Treg induction secreted by MAPC cells. Furthermore, IDO resulted in decreased Treg induction by MAPC cells demonstrating IDO involvement. Our studies also show that CD14+ monocytes play a critical role in Treg induction by MAPC cells. Conclusions Our study describes MAPC cell dependent Treg phenotypic changes and provides evidence of potential mechanisms by which MAPC cells promote Treg differentiation.

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Clinical-Grade Human Multipotent Adult Progenitor Cells Block CD8+ Cytotoxic T Lymphocytes

Cited by 15 publications

References 45 publications

Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis

Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis

N‐acetylcysteine prevents oxidized low‐density lipoprotein‐induced reduction of MG53 and enhances MG53 protective effect on bone marrow stem cells

Multipotent Adult Progenitor Cells induce Regulatory T cells and promote their Suppressive Phenotype via TGFβ and Monocyte-dependent Mechanisms

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