Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner

Joo, Sunyoung; Cho, Kyung‑Ah; Jung, YunJae; Kim, Han-Seong; Park, Seong-Yeol; Choi, Yong-Bock; Hong, Kyeong-Man; Woo, So Youn; Seoh, Ju Young; Cho, Su Jin; Ryu, Kyung Ha

doi:10.3109/14653240903502712

Cited by 68 publications

(47 citation statements)

References 32 publications

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“…We observed a significantly increased survival rate in the high-dose PD-MSC group but not in the low-dose PD-MSC group when compared to the control GVHD group. Our results are consistent with those of a recent study of optimal MSC dose in a mouse model; Joo et al [30 ]reported that mice infused with an intermediate-dose (1 × 10 6 cells) and a high-dose (2 × 10 6 cells) of MSCs showed significantly higher survival rates than the control GVHD group, in a dose-dependent manner. These results were also supported by the histologic GVHD score.…”

Section: Discussionsupporting

confidence: 82%

Placenta-Derived Mesenchymal Stem Cells Have an Immunomodulatory Effect That Can Control Acute Graft-Versus-Host Disease in Mice

Jang¹,

Kim

Lee

et al. 2012

Acta Haematol

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Background and Aims: Immunomodulatory properties of mesenchymal stem cells (MSCs) have been applied to reduce the incidence of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). Among the various sources of MSCs that have immunomodulatory effects in vitro, only placenta-derived MSCs (PD-MSCs) have not been evaluated in an in vivo model of GVHD. In this study, we investigated the immunomodulatory properties of PD-MSCs in vitro and evaluated their clinical potential for controlling GVHD in an animal model. Methods: A GVHD animal model was established by transplanting C57BL/6 donor bone marrow cells and spleen cells into lethally irradiated BALB/c recipient mice. To control GVHD, human PD-MSCs were transplanted into recipient mice (5 × 10⁵ or 1 × 10⁶ cells). Results: PD-MSCs suppressed mitogen-stimulated T cell proliferation in vitro in a dose-dependent manner. Moreover, PD-MSCs inhibited cytokine secretion (interleukin-12, tumor necrosis factor-α and interferon-γ) of activated T cells. In vivo, the survival rate in the PD-MSC group (transplanted with 1 × 10⁶ cells) was higher than that in the control group and histological scores were low in the PD-MSC group. Conclusion: We present the first evidence that human PD-MSCs can efficiently control GVHD in an HSCT in vivo model.

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Section: Discussionsupporting

confidence: 82%

Placenta-Derived Mesenchymal Stem Cells Have an Immunomodulatory Effect That Can Control Acute Graft-Versus-Host Disease in Mice

Jang¹,

Kim

Lee

et al. 2012

Acta Haematol

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“…31 These data are in contrast with those of several other preclinical and clinical studies. The significant differences between our study and those which showed a prolonged survival benefit from MSC in pre-clinical models 12,22,23,26,28 may result from variations in MSC isolation and culture methods, the degree of H-2 disparity between the donor and host and our use of a clinically relevant conditioning regimen. The lack of congruity between our results and the majority of clinical studies 5,7,29,30 may be due to the fact that MSC are administered to highly immunosuppressed patients and the use of combination therapy may mask the effect of MSC on GVHD suppression and resolution, a variable not taken into consideration in pre-clinical transplant models.…”

Section: Discussionmentioning

confidence: 57%

“…12,[22][23][24][25][26][27][28] Figure 6A). In contrast, conditioned BALB.B mice that received UBI-GFP/BL6 BM and splenocytes on day 0 and 1¥10 6 MSC 24 h post-HSCT survived a significantly shorter time (21.67±1.2 days) compared to controls ( Figure 6A, P<0.01).…”

Section: Effect Of Mesenchymal Stromal Cells After Major Histocompatimentioning

confidence: 99%

Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease

Christensen¹,

Turner²,

Sinfield³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundMultipotent mesenchymal stromal cells suppress T-cell function in vitro, a property that has underpinned their use in treating clinical steroid-refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. However the potential of mesenchymal stromal cells to resolve graft-versus-host disease is confounded by a paucity of pre-clinical data delineating their immunomodulatory effects in vivo. Design and MethodsWe examined the influence of timing and dose of donor-derived mesenchymal stromal cells on the kinetics of graft-versus-host disease in two murine models of graft-versus-host disease (major ]) using clinically relevant conditioning regimens. We also examined the effect of mesenchymal stromal cell infusion on bone marrow and spleen cellular composition and cytokine secretion in transplant recipients. ResultsDespite T-cell suppression in vitro, mesenchymal stromal cells delayed but did not prevent graftversus-host disease in the major histocompatibility complex-mismatched model. In the sibling transplant model, however, 30% of mesenchymal stromal cell-treated mice did not develop graft-versus-host disease. The timing of administration and dose of the mesenchymal stromal cells influenced their effectiveness in attenuating graft-versus-host disease, such that a low dose of mesenchymal stromal cells administered early was more effective than a high dose of mesenchymal stromal cells given late. Compared to control-treated mice, mesenchymal stromal cell-treated mice had significant reductions in serum and splenic interferon-g, an important mediator of graft-versus-host disease. ConclusionsMesenchymal stromal cells appear to delay death from graft-versus-host disease by transiently altering the inflammatory milieu and reducing levels of interferon-g. Our data suggest that both the timing of infusion and the dose of mesenchymal stromal cells likely influence these cells' effectiveness in attenuating graft-versus-host disease.Key words: stem cell transplantation, graft-versus-host disease, mesenchymal stromal cells, IFNg.Citation: Christensen ME, Turner BE, Sinfield LL, Kollar K, Cullup H, Waterhouse NJ, Hart DNJ, Atkinson K, and Rice AM. Mesenchymal stromal cells transiently alter the inflammatory milieu posttransplant to delay graft-versus-host disease. Haematologica 2010;95(12):2102-2110. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease

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“…Removal of T cells before transplantation and the application of immunosuppressants are the primary strategies in the prevention and treatment of GVHD, yet the former increases the incidence of graft rejection and leukemia relapse, while the latter has severe toxic side effects that often lead to lethal infections. Studies have demonstrated that an immune tolerance of the graft by the host induced by adoptive immunotherapy of mesenchymal stem cells, (Edinger et al, 2009;Huang et al, 2010;Alpdogan and van den Brink, 2012), regulatory T cells, natural killer cells, dendritic cells, etc., has shown favorable results in the prevention and treatment of GVHD (Cools et al, 2007;Joo et al, 2010;Morales-Tirado et al, 2011). Dendritic cells (DCs) comprise heterogeneous cell populations with different subsets and various functions.…”

Section: Introductionmentioning

confidence: 99%

Suppression of lentivirus-mediated transgenic dendritic cells in graft-versus-host disease after allogeneic bone marrow transplantation in mice

Xu¹,

Chen²,

Li³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We determined whether genetically engineered immature dendritic cells (imDCs) mediated by lentiviral vectors alleviate acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) in mice. We introduced the mouse chemokine receptor 7 (Ccr7) gene into the bone marrowderived imDCs of C57BL/6 mice to construct genetically engineered imDCs. A 1:1 mixture of bone marrow and spleen cells from the donors was injected into the recipients, which were divided into four groups: radiation, transplantation, empty vector, and transgenic imDC groups. Symptoms, clinical scores, GVHD pathological changes, and survival times and rates of recipients were recorded; secretion of IFN-γ and IL- 11444-11455 (2015) 4, and allogeneic chimerism rates were detected. The survival time of the transgenic imDC group (27.5 ± 7.55 days) was significantly longer than in the other three groups (P < 0.01). The GVHD score of the imDC group mice was significantly lower than in the transplantation and empty vector groups (P < 0.05), which meant that mice in the transgenic imDC group had the lightest pathology damage in the target organs. In the transplantation group, IFN-γ increased while IL-4 decreased. In contrast, IFN-γ decreased and IL-4 increased in both empty vector and trans-imDC groups, and the difference was significant in the latter (P < 0.01). Thirty days or more following transplantation, the allogeneic chimerism rate was still 95-100%, suggesting complete donor type implantation. Ccr7 transfection into imDCs suppressed occurrence and severity of acute GVHD after allo-BMT in mice; the mechanism might be associated with IFN-γ decrease and IL-4 increase.

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Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner

Cited by 68 publications

References 32 publications

Placenta-Derived Mesenchymal Stem Cells Have an Immunomodulatory Effect That Can Control Acute Graft-Versus-Host Disease in Mice

Placenta-Derived Mesenchymal Stem Cells Have an Immunomodulatory Effect That Can Control Acute Graft-Versus-Host Disease in Mice

Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease

Suppression of lentivirus-mediated transgenic dendritic cells in graft-versus-host disease after allogeneic bone marrow transplantation in mice

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