Bone Marrow Mesenchymal Stem Cells Suppress Lymphocyte Proliferation In Vitro but Fail to Prevent Graft-versus-Host Disease in Mice

Sudres, Muriel; Norol, Françoise; Trenado, Aurélie; Grégoire, Sylvie; Charlotte, Frédéric; Levacher, Béatrice; Lataillade, Jean‐Jacques; Bourin, Philippe; Holy, Xavier; Vernant, Jean‐Paul; Klatzmann, David; Cohen, José L.

doi:10.4049/jimmunol.176.12.7761

Cited by 354 publications

(291 citation statements)

References 35 publications

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“…This number of MSC exceeds the numbers obtained from the classic method in which MSC are not devoid of myeloid cells until passage six. This technique also avoided long-term exposure of primitive MSC to mature myeloid lineages, which may enable murine MSC to become more immunostimulatory than immunosuppressive in vivo [33]. Using previously reported methods, these cells were observed to be capable of differentiating into adipogenic and osteogenic tissues (data not shown) [27,39].…”

Section: Msc Treatment Of Gvhdmentioning

confidence: 97%

“…Identification and simulation of the events that stimulate MSC to suppress GVHD might aid in the development of a preventive GVHD strategy. Murine experimental models used to dissect the mechanism of MSC effects in the course of GVHD have yielded mixed results, with some studies showing MSC efficacy and others finding no effect [32][33][34][35]. Several factors are likely to contribute to the variable results.…”

Section: Introductionmentioning

confidence: 99%

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IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

et al. 2008

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Graft versus host disease (GVHD), mediated by donor T cells, is a significant source of morbidity and mortality following allogeneic stem cell transplantation. Mesenchymal stem cells (MSC) can successfully treat ongoing graft versus host disease, presumably due to their ability to suppress donor T cell proliferation. Little is known about the potential of MSC to prevent GVHD. Here we show that bone marrow-isolated MSC can suppress the development of GVHD if given after donor T cell recognition of antigen. IFN-c was required to initiate MSC efficacy. Recipients of IFN-c -/-T cells did not respond to MSC treatment and succumbed to GVHD. MSC, pre-treated with IFN-c, became immediately active and could suppress GVHD more efficiently than a fivefold-greater number of MSC that were not activated. When given at the time of bone marrow transplantation, activated MSC could prevent GVHD mortality (100% survival, p=0.006). MSC activation was dependent on the magnitude of IFN-c exposure, with increased IFN-c exposure leading to increased MSC suppression of GVHD. Activated MSC present a new strategy for preventing GVHD using fewer MSC. Key words: Mesenchymal stem cell Á GVH disease Á IFN-c See accompanying commentary by Dazzi and Marelli-Berg IntroductionAllogeneic hematopoietic stem cell transplants have the potential to play a significant curative role in the treatment of malignant and non-malignant hematopoietic disorders, autoimmune diseases, and immunological deficiencies, and in the induction of transplantation tolerance [1][2][3][4][5][6][7][8][9][10]. Widespread application of this therapeutic modality is limited due to the morbidity and mortality of graft versus host disease (GVHD), which affects 50% of stem cell transplant recipients [11][12][13][14][15][16]. While grafts highly matched to the recipient, young donors, donor/recipient sex match, and posttransplant immunosuppression are strategies used to reduce the risk of GVHD [17], thus far, the greatest preventative measure has been intentional underutilization of stem cell transplantation. Theoretically, strategies aimed at preventing GVHD would target early initiating factors either during the inflammatory milieu created in the wake of tissue damage from conditioning regimens [18,19] or during T cell antigen recognition and proliferation [20,21]. Once the efferent effector phase occurs, donor T cell-mediated destruction of host tissues occurs and preventive strategies are replaced with treatment regimens [19].Mesenchymal stem cells (MSC) have been used in the efferent phase of GVHD to successfully treat ongoing, acute, steroidresistant GVHD [22,23]. In contrast, when given at the time of BM transplant, for the prevention of GVHD, the incidence of grade III/ IV GVHD was not significantly improved [24], suggesting the [26,27,29,30]. In addition, MSC do not suppress the modest T cell proliferative response to recall antigens [31]. These findings suggest MSC may exert their optimal effects during the events surrounding larger scale T cell activation and proliferat...

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Section: Msc Treatment Of Gvhdmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

et al. 2008

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“…In particular, while in humans MSC i.v. infusion was found to be therapeutically effective in some patients with GVHD refractory to standard treatments [15], in mice MSC failed to prevent GVHD [69].…”

Section: Msc-mediated Immunological Effects In Vivomentioning

confidence: 99%

Immunoregulatory function of mesenchymal stem cells

2006

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Mesenchymal stem cells (MSC) are a rare subset of stem cells residing in the bone marrow where they closely interact with hematopoietic stem cells and support their growth and differentiation. MSC can differentiate into multiple mesenchymal and non‐mesenchymal lineages, providing a promising tool for tissue repair. In addition, MSC suppress many T cell, B cell and NK cell functions and may affect also dendritic cell activities. Due to their limited immunogenicity, MSC are poorly recognized by HLA‐incompatible hosts. Based on these unique properties, MSC are currently under investigation for their possible use to treat immuno‐mediated diseases. However, both their condition of immunoprivilege and their immunosuppressive function have recently been challenged when analyzed under particular experimental conditions. Thus, it is likely that MSC effects on the immune system may be deeply influenced not only by cell‐to‐cell interactions, but also by environmental factors shaping their phenotype and functions.

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“…Besides tissue repair and regeneration, it has been recently found that MSCs also possess an immunoregulatory property [4][5][6][7][8][9]. MSCs inhibit mitogen-or antigen-stimulated lymphocyte proliferation [10,11]. MSCs have also been successfully used for the treatment of some human cases of graft-versus-host-disease (GVHD) [12][13][14], though different results are reported by other studies [11].…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive properties of cloned bone marrow mesenchymal stem cells

Xu¹,

Zhang²,

Ren³

et al. 2007

Cell Res

135

101

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Mesenchymal stem cells (MSCs), derived from adult tissues, are multipotent progenitor cells, which hold great promise for regenerative medicine. Recent studies have shown that MSCs are immunosuppressive in vivo and in vitro in both animals and humans. However, the mechanisms that govern these immune modulatory functions of MSCs remain largely elusive. Some studies with bulk populations of MSCs indicated that soluble factors such as PGE2 and TGFb are important, while others support a role for cell-cell contact. In this study, we intended to clarify these issues by examining immunosuppressive effects of cloned MSCs. We derived MSC clones from mouse bone marrow and showed that the majority of these clones were able to differentiate into adipocytes and osteoblast-like cells. Importantly, cells from these clones exhibited strong inhibitory effects on TCR activation-induced T cell proliferation in vitro, and injection of a small number of these cells promoted the survival of allogeneic skin grafts in mice. Conditioned medium from MSC cultures showed some inhibitory effect on anti-CD3 induced lymphocyte proliferation independent of PGE2 and TGFb. In comparison, direct co-culture of MSCs with stimulated lymphocytes resulted in much stronger immunosuppressive effect. Interestingly, the suppression was bi-directional, as MSC proliferation was also reduced in the presence of lymphocytes. Taking together, our findings with cloned MSCs demonstrate that these cells exert their immunosuppressive effects through both soluble factor(s) and cell-cell contact, and that lymphocytes and MSCs are mutually inhibitory on their respective proliferation.

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Bone Marrow Mesenchymal Stem Cells Suppress Lymphocyte Proliferation In Vitro but Fail to Prevent Graft-versus-Host Disease in Mice

Cited by 354 publications

References 35 publications

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

Immunoregulatory function of mesenchymal stem cells

Immunosuppressive properties of cloned bone marrow mesenchymal stem cells

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