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.

1.
Rager A, Frey N, Goldstein SC, Reshef R, Hexner EO, Loren A, Luger SM, Perl A, Tsai D, Davis J, Vozniak M, Smith J, Stadtmauer EA, Porter DL: Inflammatory cytokine inhibition with combination daclizumab and infliximab for steroid-refractory acute GVHD. Bone Marrow Transplant 2011;46:430–435.
2.
Schmitt T, Luft T, Hegenbart U, Tran TH, Ho AD, Dreger P: Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis. Bone Marrow Transplant 2011;46:580–585.
3.
Schub N, Gunther A, Schrauder A, Claviez A, Ehlert C, Gramatzki M, Repp R: Therapy of steroid-refractory acute GVHD with CD52 antibody alemtuzumab is effective. Bone Marrow Transplant 2011;46:143–147.
4.
Arai S, Margolis J, Zahurak M, Anders V, Vogelsang GB: Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment. Biol Blood Marrow Transplant 2002;8:155–160.
5.
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM: Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99:3838–3843.
6.
Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O: Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003;57:11–20.
7.
Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC: Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003;75:389–397.
8.
Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F: Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 2005;105:2821–2827.
9.
Aggarwal S, Pittenger MF: Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815–1822.
10.
Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A: Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005;106:1755–1761.
11.
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O: Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008;371:1579–1586.
12.
Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F: Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003;101:3722–3729.
13.
Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, Taureau C, Cousin B, Abbal M, Laharrague P, Penicaud L, Casteilla L, Blancher A: Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005;129:118–129.
14.
Tolar J, Hippen KL, Blazar BR: Immune regulatory cells in umbilical cord blood: T regulatory cells and mesenchymal stromal cells. Br J Haematol 2009;147:200–206.
15.
Wolbank S, Peterbauer A, Fahrner M, Hennerbichler S, van Griensven M, Stadler G, Redl H, Gabriel C: Dose-dependent immunomodulatory effect of human stem cells from amniotic membrane: a comparison with human mesenchymal stem cells from adipose tissue. Tissue Eng 2007;13:1173–1183.
16.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147.
17.
Rao MS, Mattson MP: Stem cells and aging: expanding the possibilities. Mech Ageing Dev 2001;122:713–734.
18.
Li C, Zhang W, Jiang X, Mao N: Human-placenta-derived mesenchymal stem cells inhibit proliferation and function of allogeneic immune cells. Cell Tissue Res 2007;330:437–446.
19.
Li CD, Zhang WY, Li HL, Jiang XX, Zhang Y, Tang PH, Mao N: Mesenchymal stem cells derived from human placenta suppress allogeneic umbilical cord blood lymphocyte proliferation. Cell Res 2005;15:539–547.
20.
Lee MJ, Jung J, Na KH, Moon JS, Lee HJ, Kim JH, Kim GI, Kwon SW, Hwang SG, Kim GJ: Anti-fibrotic effect of chorionic plate-derived mesenchymal stem cells isolated from human placenta in a rat model of CCI(4)-injured liver: potential application to the treatment of hepatic diseases. J Cell Biochem 2010;111:1453–1463.
21.
Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, Lerner KG, Glucksberg H, Buckner CD: Bone-marrow transplantation (second of two parts). N Engl J Med 1975;292:895–902.
22.
Tabera S, Perez-Simon JA, Diez-Campelo M, Sanchez-Abarca LI, Blanco B, Lopez A, Benito A, Ocio E, Sanchez-Guijo FM, Canizo C, San Miguel JF: The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica 2008;93:1301–1309.
23.
Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R: Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002;30:42–48.
24.
Lu X, Liu T, Gu L, Huang C, Zhu H, Meng W, Xi Y, Li S, Liu Y: Immunomodulatory effects of mesenchymal stem cells involved in favoring type 2 T cell subsets. Transpl Immunol 2009;22:55–61.
25.
Almeida-Porada G, Porada CD, Tran N, Zanjani ED: Cotransplantation of human stromal cell progenitors into preimmune fetal sheep results in early appearance of human donor cells in circulation and boosts cell levels in bone marrow at later time points after transplantation. Blood 2000;95:3620–3627.
26.
Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, Pennesi G: Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 2005;35:1482–1490.
27.
Tisato V, Naresh K, Girdlestone J, Navarrete C, Dazzi F: Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. Leukemia 2007;21:1992–1999.
28.
Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA: Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 2006;24:2582–2591.
29.
Miao Z, Jin J, Chen L, Zhu J, Huang W, Zhao J, Qian H, Zhang X: Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. Cell Biol Int 2006;30:681–687.
30.
Joo SY, Cho KA, Jung YJ, Kim HS, Park SY, Choi YB, Hong KM, Woo SY, Seoh JY, Cho SJ, Ryu KH: Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner. Cytotherapy 2010;12:361–370.
31.
Sudres M, Norol F, Trenado A, Gregoire S, Charlotte F, Levacher B, Lataillade JJ, Bourin P, Holy X, Vernant JP, Klatzmann D, Cohen JL: Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 2006;176:7761–7767.
32.
Badillo AT, Peranteau WH, Heaton TE, Quinn C, Flake AW: Murine bone marrow derived stromal progenitor cells fail to prevent or treat acute graft-versus-host disease. Br J Haematol 2008;141:224–234.
33.
Martin PJ, Uberti, JP, Soiffer RJ, Klingemann H, Waller EK, Daly AS, Herrmann RP, Kebriaei P: Prochymal improves response rates in patients with steroid refractory acute graft versus host disease (SR-GVHD) involving the liver and gut: results of a randomized, placebo-controlled multicenter phase III trial in GVHD. Abstract 41 BMT Tandem Meetings, Orlando, February 2010.
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