Susceptibility of Human Mesenchymal Stem Cells to Tacrolimus, Mycophenolic Acid, and Rapamycin

Hoogduijn, Martin J.; Crop, Meindert J.; Korevaar, Sander S.; Peeters, Annemiek M.A.; Eijken, Marco; Maat, Lex P.W.M.; Balk, A. H. M. M.; Weimar, Willem; Baan, Carla C.

doi:10.1097/tp.0b013e31818aa536

Cited by 97 publications

(75 citation statements)

References 32 publications

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“…However, little understanding exists about how these drugs interact with MSCs. Some studies have demonstrated that therapeutic concentrations of some immunosuppressive drugs affect MSC proliferation and survival [31][32][33]. This study adds new insight to this complex picture.…”

Section: Discussionmentioning

confidence: 90%

Human mesenchymal stromal cells modulate T‐cell responses through TNF‐α‐mediated activation of NF‐κB

Dorronsoro¹,

Ferrin²,

Salcedo³

et al. 2013

Eur J Immunol

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Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF-κB) in human MSCs. This pathway is activated by TNF-α that is generated following TCR stimulation of T cells. Inhibition of NF-κB through silencing of IκB kinase β or the TNF-α receptor abolishes the immunosuppressive capacity of MSCs. Our data also indicate that MSC-associated NF-κB activation primarily leads to inhibition of T-cell proliferation with little effect on expression of the activation markers CD69 and CD25. Thus, our data support the hypothesis that the TNF-α/NF-κB signalling pathway is required for the initial priming of immunosuppressive function in human MSCs. Interestingly, drugs that interfere with NF-κB activation significantly antagonise the immunoregulatory effect of MSCs, which could have important implications for immunosuppression regimens in the clinic. Keywords:Immunoregulation r MSC r NF-κB r TNF-α See accompanying Commentary by Pistoia and RaffaghelloAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMesenchymal stromal cells (MSCs) are multipotent progenitor cells that have the capacity to differentiate into multiple lineages. These cells are found in a variety of tissues during development, of which BM represents the most common source for research purposes. From a clinical perspective, MSCs are considered to Correspondence: Dr. César Trigueros e-mail: ctrigueros@inbiomed.org have a potential use in tissue repair for bone, cartilage and tendon. However, due to their immunomodulatory properties and their inclusion as a stromal component of the marrow microenvironment, MSCs are currently utilised in other therapeutic scenarios, such as those encountered in hematopoietic stem cell transplantation, GVH disease or chronic inflammatory diseases [1,2]. These characteristics, together with their low immunogenicity [1,2], have opened up promising new avenues of research for the use of MSCs not only in autologous but also in allogeneic settings.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 480-488 Immunomodulation 481 The immunomodulatory activity of MSCs, directed against a wide range of effector cells of both the innate and adaptive immune system, has been described. Communication between MSCs and immune cells, through cell-to-cell contact-dependent and/or contact-independent mechanisms, has been shown to lead to increased production of soluble immunomodulatory factors such as indoleamine 2,3-deoxigenase [3,4], prostaglandin E2 [5][6][7], iNOS [8], transforming growth factor β (TGF-β), hepatocyte growth factor [9], human lymphocytes Ag molecule 5 and IL-10 [10]. Thus, the picture is complex, as it is likely that multiple regulatory mechanisms exist without an obvious hierarchy of importance.The inflammatory e...

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Section: Discussionmentioning

confidence: 90%

Human mesenchymal stromal cells modulate T‐cell responses through TNF‐α‐mediated activation of NF‐κB

Dorronsoro¹,

Ferrin²,

Salcedo³

et al. 2013

Eur J Immunol

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show abstract

“…Moreover, a high dose of tacrolimus seems to be toxic for MSCs, while MPA and rapamycin at a therapeutic dose just inhibit MSC proliferation [32]. Furthermore, it has been demonstrated that MPA and MSCs have a synergistic immunosuppressive effect [32]. In vivo, MPA and MSCs also synergize to promote long-term allograft tolerance in rat heart transplantation [33].…”

Section: Discussionmentioning

confidence: 99%

“…No difference could be detected between the MSC and control groups on graft rejection episodes, opportunistic infection rates, graft histology Such an effect has not been found with mycophenolic acid (MPA), an MMF metabolite. Moreover, a high dose of tacrolimus seems to be toxic for MSCs, while MPA and rapamycin at a therapeutic dose just inhibit MSC proliferation [32]. Furthermore, it has been demonstrated that MPA and MSCs have a synergistic immunosuppressive effect [32].…”

Section: Discussionmentioning

confidence: 99%

Infusion of mesenchymal stromal cells after deceased liver transplantation: A phase I–II, open-label, clinical study

Detry

Vandermeulen

Delbouille

et al. 2017

Journal of Hepatology

113

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“…At same time, MSC are able to reduce the efficacy of tacrolimus and rapamycin [59,60]. As MSC lack expression of the CTLA-4 ligands CD80 and CD86, it was not surprising that belatacept did not diminish MSC function [62].…”

Section: Cd28mentioning

confidence: 99%

“…Co-administration of MSC with other immunosuppressive drugs is not always encouraged; agents such as tacrolimus, mammalian target of rapamycin (mTor) inhibitor rapamycin and rabbit anti-thymocyte globulin (rATG) negatively affect the suppressive capacity of MSC in vitro [59][60][61]. At same time, MSC are able to reduce the efficacy of tacrolimus and rapamycin [59,60].…”

Section: Cd28mentioning

confidence: 99%

Mesenchymal stem cells control alloreactive CD8+CD28− T cells

Engela

Baan

Litjens

et al. 2013

Clinical and Experimental Immunology

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Susceptibility of Human Mesenchymal Stem Cells to Tacrolimus, Mycophenolic Acid, and Rapamycin

Abstract: This study demonstrates that therapeutic concentrations of immunosuppressive drugs affect MSC function. MSC affect the efficacy of immunosuppressive medication. These findings are important for potential clinical use of MSC in combination with immunosuppressants.

Cited by 97 publications

References 32 publications

Human mesenchymal stromal cells modulate T‐cell responses through TNF‐α‐mediated activation of NF‐κB

Human mesenchymal stromal cells modulate T‐cell responses through TNF‐α‐mediated activation of NF‐κB

Infusion of mesenchymal stromal cells after deceased liver transplantation: A phase I–II, open-label, clinical study

Mesenchymal stem cells control alloreactive CD8+CD28− T cells

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