Abstract
Acute graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. About 35%–50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute GVHD. It is associated with considerable morbidity and mortality, particularly in patients who do not respond to primary therapy, which usually consists of glucocorticoids(steroids). Most of the available second-line and third-line treatments for steroid-refractory acute GVHD induce severe immunodeficiency, which is commonly accompanied by lethal infectious complications. Mesenchymal stem cells (MSCs) have been shown to mediate immunomodulatory effects. The recently elucidated immunosuppressive potential of mesenchymal stem cells has set the stage for their clinical testing as cellular immunosuppressants, MSCs have been used in patients with steroid-refractory acute GVHD, and encouraging responses have been obtained in many studies. The utility of MSCs for the treatment of GVHD is becoming clear.
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References
Lorenz E, Uphoff D, Reid T R, et al. Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J Natl Cancer Inst, 1951, 12: 197–201, 14874130, 1:STN:280:DyaG38%2FgsVansg%3D%3D
van Bekkum D W, de Vries M J. The production of radiation chimaeras. In: Radiation Chimaeras. London, United Kingdom: Logos Press Limited, 1967. 20–78
Billingham R E. The biology of graft-versus-host reactions. In: The Harvey Lectures. New York: Academic Press, 1966. 21–78
Deeg H J. How I treat refractory acute GVHD. Blood, 2007, 109: 4119–4126, 17234737, 10.1182/blood-2006-12-041889, 1:CAS:528:DC%2BD2sXls1anurg%3D
Larghero J, Vija L, Lecourt S, et al. Mesenchymal stem cells and immunomodulation: toward new immunosuppressive strategies for the treatment of autoimmune diseases? Rev Med Interne, 2009, 30: 287–299, 18930338, 10.1016/j.revmed.2008.08.019, 1:STN:280:DC%2BD1M7mslyhsA%3D%3D
Aggarwal S, Pittenger M F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 2005, 105: 1815–1822, 15494428, 10.1182/blood-2004-04-1559, 1:CAS:528:DC%2BD2MXhsVGjt7Y%3D
Le Blanc K, Ringdén O. Immunomodulation by mesenchymal stem cells and clinical experience. J InternMed, 2007, 262: 509–525, 10.1111/j.1365-2796.2007.01844.x, 1:CAS:528:DC%2BD2sXhtlOhtLrI
Müller I, Kordowich S, Holzwarth C, et al. Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation. Blood Cells Mol Dis, 2008, 40: 25–32, 17869550, 10.1016/j.bcmd.2007.06.021
Hill G R, Ferrara J L M. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: Rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 2000, 95: 2754–2759, 10779417, 1:CAS:528:DC%2BD3cXivVarurw%3D
Ball L M, Egeler R M. EBMT Paediatric Working Party. Acute GvHD: pathogenesis and classification. Bone Marrow Transplant, 2008, 41: S58–64, 18545246, 10.1038/bmt.2008.56, 1:CAS:528:DC%2BD1cXntVCnu7s%3D
David A Jacobsohn, Georgia B Vogelsang. Acute graft versus host disease. Orphanet J Rare Dis, 2007, 2: 35, 17784964, 10.1186/1750-1172-2-35
Messina C, Faraci M, de Fazio V, et al. Prevention and treatment of acute GvHD. Bone Marrow Transplant, 2008, 41: S65–70, 18545247, 10.1038/bmt.2008.57, 1:CAS:528:DC%2BD1cXntVCnu7k%3D
MacMillan M L, Weisdorf D J, Wagner J E. Response of 443 patients to steroids as primary therapy for acute GvHD: Comparison of grading system. Biol Blood Marrow Transplant, 2002, 47: 387–394, 10.1053/bbmt.2002.v8.pm12171485
van Lint M T, Uderzo C, Locasciulli A, et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylpredniso-lone: A multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood, 1998, 92: 2288–2293, 9746766
Cragg L, Blazar B R, Defor T, et al. A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease. Biol Blood Marrow Transplant, 2000, 6: 441–447, 10975513, 10.1016/S1083-8791(00)70036-X, 1:CAS:528:DC%2BD3cXmsFajs70%3D
van Lint M T, Milone G, Leotta S, et al. Treatment of acute graft-versus-host disease with prednisolone: Significant survival advantage for day +5 responders and no advantage for nonresponders receiving anti-thymocyte globulin. Blood, 2006, 107: 4177–4181, 16449522, 10.1182/blood-2005-12-4851, 1:CAS:528:DC%2BD28XkvFWgsL8%3D
Antin J H, Chen A R, Couriel D R, et al. Novel approaches to the therapy of steroid resistant acute graft versus host disease. Biol Blood Marrow Transplant, 2004, 10: 655–668, 15389432, 10.1016/j.bbmt.2004.07.007, 1:CAS:528:DC%2BD2cXpsl2gtbs%3D
Antin J H. Approaches to graft-vs-host disease. Paediatr Transplant, 2005, 9: 71–75, 10.1111/j.1399-3046.2005.00441.x, 1:CAS:528:DC%2BD2MXhtlGitb7E
Doney K, Martin P, Storb R, et al. A randomized trial of antihuman thymocyte globulin versus murine monoclonal antihuman T-cell antibodies as immunosuppressive therapy for aplastic anemia. Exp Hematol, 1985, 13: 520–524, 3873345, 1:STN:280:DyaL2M3gsVWntw%3D%3D
Curtis R E, Travis L B, Rowlings P A, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: A multi-institutional study. Blood, 1999, 94: 2208–2216, 10498590, 1:CAS:528:DyaK1MXmsVCis7Y%3D
Deeg H J, Blazar B R, Bolwell B J, et al. Treatment of steroid-refractory acute graft-verus-host-disease with anti-CD147 monoclonal antibody ABX-CBL. Blood, 2001, 98: 2052–2058, 11567989, 10.1182/blood.V98.7.2052, 1:CAS:528:DC%2BD3MXnsVChsb8%3D
Carpenter P A, Appelbaum F R, Corey L, et al. A humanized non-FcR-bindinganti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. Blood, 2002, 99: 2712–2719, 11929757, 10.1182/blood.V99.8.2712, 1:CAS:528:DC%2BD38XivVyqur0%3D
Jacobsohn D A, Vogelsang G B. Novel pharmacotherapeutic approaches to prevention and treatment of GvHD. Drugs, 2001, 62: 879–889, 10.2165/00003495-200262060-00002
Benito A I, Furlong T, Martin P J, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation, 2001, 72: 1924–1929, 11773890, 10.1097/00007890-200112270-00010, 1:CAS:528:DC%2BD38XnsV2nug%3D%3D
Bolanos-Meade J, Jacobsohn D A, Margolis J, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol, 2005, 20: 2661–2668
Tyndall A, Uccelli A. Multipotent mesenchymal stromal cells for autoimmune diseases: Teaching new dogs old tricks. Bone Marrow Transplant, 2009, 43: 821–828, 19308035, 10.1038/bmt.2009.63, 1:CAS:528:DC%2BD1MXntF2iu7s%3D
Nauta A J, Fibbe W E. Immunomodulatory properties of mesenchymal stromal cells. Blood, 2007, 110: 3499–506, 17664353, 10.1182/blood-2007-02-069716, 1:CAS:528:DC%2BD2sXhtlarurzE
Gonzalo-Daganzo R, Regidor C, Martín-Donaire T, et al. Results of a pilot study on the use of third-party donor mesenchymal stromal cells in cord blood transplantation in adults. Cytotherapy, 2009, 11: 278–288, 19308773, 10.1080/14653240902807018, 1:CAS:528:DC%2BD1MXlt1Kms7o%3D
Noort W A, Kruisselbrink A B, in’t Anker P S, et al. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol, 2002, 30: 870–878, 12160838, 10.1016/S0301-472X(02)00820-2
Klyushnenkova E, Mosca J D, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: Immunogenicity, tolerance, and suppression. J Biomed Sci, 2005, 12: 47–57, 15864738, 10.1007/s11373-004-8183-7, 1:CAS:528:DC%2BD2MXhtlWkur3F
Selmani Z, Naji A, Zidi I, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25 high FOXP3+ regulatory T cells. Stem Cells, 2008, 26: 212–222, 17932417, 10.1634/stemcells.2007-0554, 1:CAS:528:DC%2BD1cXhvVCktb0%3D
Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med, 2003, 9: 1144–1150, 12925844, 10.1038/nm915, 1:CAS:528:DC%2BD3sXmvVWnsrs%3D
Wolf D, Wolf A M, Fong D, et al. Regulatory T-cells in the graft and the risk of acute graft-versus-host disease after allogeneic stem cell transplantation. Transplantation, 2007, 83: 1107–1113, 17452902, 10.1097/01.tp.0000260140.04815.77
Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol, 2003, 31: 890–896, 14550804, 10.1016/S0301-472X(03)00110-3, 1:CAS:528:DC%2BD3sXnvVOlsrk%3D
Le Blanc K, Tammik L, Sundberg B, et al. 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, 12542793, 10.1046/j.1365-3083.2003.01176.x
Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol, 2002, 30: 42–48, 11823036, 10.1016/S0301-472X(01)00769-X
von Bonin M, Stölzel F, Goedecke A, et al. Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium. Bone Marrow Transplant, 2009, 43: 245–251, 10.1038/bmt.2008.316, 1:CAS:528:DC%2BD1MXhslSgtLk%3D
Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood, 2005, 106: 1755–1761, 15905186, 10.1182/blood-2005-04-1496, 1:CAS:528:DC%2BD2MXps1Ogtrk%3D
Glennie S, Soeiro I, Dyson P J, et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood, 2005, 105: 2821–2827, 15591115, 10.1182/blood-2004-09-3696, 1:CAS:528:DC%2BD2MXivFGmt7k%3D
Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol, 2004, 60: 307–315, 15320889, 10.1111/j.0300-9475.2004.01483.x
Bacigalupo A, Valle M, Podesta M, et al. T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia. Exp Hematol, 2005, 33: 819–827, 15963858, 10.1016/j.exphem.2005.05.006, 1:CAS:528:DC%2BD2MXlt1Kis7w%3D
Han Q, Sun Z, Liu L, et al. Impairment in immuno-modulatory function of Flk1(+)CD31(−)CD34(−) MSCss from MDS-RA patients. Leuk Res, 2007, 31: 1469–1478, 17360037, 10.1016/j.leukres.2006.12.016, 1:CAS:528:DC%2BD2sXht1amsrrE
English K, Barry F P, Mahon B P. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation. Immunol Lett, 2008, 115: 50–58, 18022251, 10.1016/j.imlet.2007.10.002, 1:CAS:528:DC%2BD1cXhtlejsQ%3D%3D
Zhang W, Ge W, Li C H, et al. Inhibition effect of bone marrow mesenchymal stem cells on T-lymphocyte proliferation through up-regulation of CD8+CD28− T cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2004, 12: 666–669, 15498131
Jiang X X, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood, 2005, 105: 4120–4126, 15692068, 10.1182/blood-2004-02-0586, 1:CAS:528:DC%2BD2MXktlSrt7k%3D
Nauta A J, Kruisselbrink A B, Lurvink E, et al. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol, 2006, 177: 2080–2087, 16887966, 1:CAS:528:DC%2BD28Xns1Kht7o%3D
Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2 dependent regulatory dendritic cell population. Blood, 2009, 113: 46–57, 18832657, 10.1182/blood-2008-04-154138, 1:CAS:528:DC%2BD1MXmtFSktw%3D%3D
Chen L, Zhang W, Yue H, et al. Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells. Stem Cells Dev, 2007, 16: 719–731, 17999594, 10.1089/scd.2007.0065, 1:CAS:528:DC%2BD2sXht1ykurjP
Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood, 2006, 107: 367–372, 16141348, 10.1182/blood-2005-07-2657, 1:CAS:528:DC%2BD28XhsVGksQ%3D%3D
Sotiropoulou P A, Perez S A, Gritzapis A D, et al. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells, 2006, 24: 74–85, 16099998, 10.1634/stemcells.2004-0359
Spaggiari G M, Capobianco A, Becchetti S, et al. Mesenchymal stem cell-natural killer cell interactions: Evidence that activated NK cells are capable of killing MSCss, whereas MSCss can inhibit IL-2-induced NK-cell proliferation. Blood, 2006, 107: 1484–1490, 16239427, 10.1182/blood-2005-07-2775, 1:CAS:528:DC%2BD28XhsFemtrg%3D
Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet, 2008, 371: 1579–1586, 18468541, 10.1016/S0140-6736(08)60690-X, 1:CAS:528:DC%2BD1cXlslWhsbk%3D
von Bonin M, Stölzel F, Goedecke A, et al. Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium. Biol Bone Marrow Transplant, 2008, 43: 1–7
Fang B, Song Y, Liao L, et al. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc, 2007, 39: 3358–3362, 18089385, 10.1016/j.transproceed.2007.08.103, 1:STN:280:DC%2BD2sjlt1Sitw%3D%3D
Graul A I. Promoting, improving and accelerating the drug development and approval processes. Drug News Perspect, 2008, 22: 30–38, 10.1358/dnp.2009.22.1.1303816, 1:CAS:528:DC%2BD1MXktFGmtLY%3D
Osiris Therapeutics, Inc. Osiris therapeutics reports positive Phase II results using PROCHYMAL(TM) for the treatment of acute graft vs. host disease. BALTIMORE, Nov 09, 2006 (BUSINESS WIRE) — Osiris Therapeutics, Inc.
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Wang, L., Zhao, R.C. Mesenchymal stem cells targeting the GVHD. SCI CHINA SER C 52, 603–609 (2009). https://doi.org/10.1007/s11427-009-0091-7
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DOI: https://doi.org/10.1007/s11427-009-0091-7