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Enhanced Immunosuppressive Properties of Human Mesenchymal Stem Cells Primed by Interferon-?.

ABSTRACT: Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases owing to their immunosuppressive properties. In this study, we aimed to identify the effect of interferon (IFN)-? priming on immunomodulation by MSCs and elucidate the possible mechanism underlying their properties for the clinical treatment of allogeneic conflicts. Infusion of MSCs primed with IFN-? significantly reduced the symptoms of graft-versus-host disease (GVHD) in NOD-SCID mice, thereby increasing survival rate when compared with naïve MSC-infused mice. However, infusion of IFN-?-primed MSCs in which indoleamine 2,3-dioxygenase (IDO) was downregulated did not elicit this effect. The IDO gene was expressed in MSCs via the IFN-?-Janus kinase (JAK)-signal transducer and activator of transcription 1 (STAT1) pathway, and the infusion of IDO-over-expressing MSCs increased survival rate in an in vivo GVHD model, similar to infusion of IFN-?-primed MSCs. These data indicate that IFN-? production by activated T-cells is correlated with the induction of IDO expression in MSCs via the IFN-?-JAK-STAT1 pathway, which in turn results in the suppression of T-cell proliferation. Our findings also suggest that cell therapy based on MSCs primed with IFN-? can be used for the clinical treatment of allogeneic conflicts, including GVHD.

SUBMITTER: Kim DS

PROVIDER: S-EPMC5898027 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Enhanced Immunosuppressive Properties of Human Mesenchymal Stem Cells Primed by Interferon-γ.

Kim Dae Seong DS Jang In Keun IK Lee Myoung Woo MW Ko Young Jong YJ Lee Doo-Hoon DH Lee Ji Won JW Sung Ki Woong KW Koo Hong Hoe HH Yoo Keon Hee KH

EBioMedicine 20180109

Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases owing to their immunosuppressive properties. In this study, we aimed to identify the effect of interferon (IFN)-γ priming on immunomodulation by MSCs and elucidate the possible mechanism underlying their properties for the clinical treatment of allogeneic conflicts. Infusion of MSCs primed with IFN-γ significantly reduced the symptoms of graft-versus-host disease (GVHD) in NOD-SCID mice, thereby ...[more]

PMID: 29366627

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Project description:The immunomodulatory activity of mesenchymal stem/stromal cells (MSCs) to suppress innate and adaptive immune responses offers a potent cell therapy for modulating inflammation and promoting tissue regeneration. However, the inflammatory cytokine milieu plays a critical role in stimulating MSC immunomodulatory activity. In particular, interferon-γ (IFN-γ)-induced expression of indoleamine 2,3-dioxygenase (IDO) is primarily responsible for MSC suppression of T-cell proliferation and activation. Although pretreatment with IFN-γ is commonly used to prime MSCs for immunomodulatory activity prior to transplantation, the transient effects of pretreatment may limit the potential of MSCs to potently modulate immune responses. Therefore, the objective of this study was to investigate whether microparticle-mediated presentation of bioactive IFN-γ within three-dimensional spheroidal MSC aggregates could precisely regulate and induce sustained immunomodulatory activity. Delivery of IFN-γ via heparin-microparticles within MSC aggregates induced sustained IDO expression during 1 week of culture, whereas IDO expression by IFN-γ-pretreated MSC spheroids rapidly decreased during 2 days. Furthermore, sustained IDO expression induced by IFN-γ-loaded microparticles resulted in an increased and sustained suppression of T-cell activation and proliferation in MSC cocultures with CD3/CD28-activated peripheral blood mononuclear cells. The increased suppression of T cells by MSC spheroids containing IFN-γ-loaded microparticles was dependent on induction of IDO and supported by affecting monocyte secretion from pro- to anti-inflammatory cytokines. Altogether, microparticle delivery of IFN-γ within MSC spheroids provides a potent means of enhancing and sustaining immunomodulatory activity to control MSC immunomodulation after transplantation and thereby improve the efficacy of MSC-based therapies aimed at treating inflammatory and immune diseases. Stem Cells Translational Medicine 2017;6:223-237.

Dataset Information

Enhanced Immunosuppressive Properties of Human Mesenchymal Stem Cells Primed by Interferon-?.

Publications

Enhanced Immunosuppressive Properties of Human Mesenchymal Stem Cells Primed by Interferon-γ.

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