Jan STYCZNSKI, Krysztof KALWAK, Monika MIELCAREK, Darius BORUCZKOWSKI, Dominika GALADYSZ, Slawomir RUMINSKI, Iwona CZAPLICKA-SZMAUS, Magdelena MURZYN, Artur OLKOWICZ, Katarzyna DRABKO, Miroslaw MARKIEWICZ, Katarzyna PAWELEC, Maciej BORUCZKOWSKI, Tomzs OLDAK

Third-party Wharton?s jelly mesenchymal stem cells for treatment of steroid-resistant acute and chronic graft-versus-host disease: a report of 10 cases

Severe graft-versus-host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Bone marrow mesenchymal stem cells (BM-MSCs) display immunosuppressive activity and have been previously shown to improve the outcome of GvHD therapy. We describe the use of umbilical cord mesenchymal stem cells (WJ-MSCs) expanded in serum-free medium for the treatment of acute GvHD (aGvHD) and chronic GvHD (cGvHD) in 10 patients. After 1 to 3 WJ-MSC infusions at a median dose of 1.5 × 106 cells/kg recipient body weight, a complete or partial response was observed in 4/7 patients with aGvHD and in 2/3 patients with cGvHD. Five out of 6 patients (83.3%) from the responders group and only 1 out of 4 nonresponders (25%) survived the follow-up. The deaths occurred in patients with acute GvHD. In the responders group, 2 patients showed complete remission of GvHD while symptoms of 4 patients were alleviated and the intensity of immunosuppressive therapy could be reduced. No serious adverse effects were observed. In conclusion, WJ-MSCs appear to be safe and can be successfully applied in the treatment of acute and chronic GvHD, but the therapeutic conditions should be optimized in prospective studies to maximize their efficacy.

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Amorin B, Alegretti AP, Valim V, Pezzi A, Laureano AM, da Silva MA, Wieck A, Silla L (2014). Mesenchymal stem cell therapy and acute graft-versus-host disease: a review. Hum Cell 27: 137–150.
Ball LM, Bernardo ME, Roelofs H, van Tol MJ, Contoli B, Zwaginga JJ, Avanzini MA, Conforti A, Bertaina A, Giorgiani G et al. (2013). Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus-host disease. Br J Haematol 163: 501–509.
Blazar BR, Murphy WJ, Abedi M (2012). Advances in graft-versus host disease biology and therapy. Nat Rev Immunol 12: 443– 458.
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM (2002). Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99: 3838–3843.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8: 315–317.
English K, Ryan JM, Tobin L, Murphy MJ, Barry FP, Mahon BP (2009). Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells. Clin Exp Immunol 156: 149–160.
Fu Y, Wang Q, Zhou J, Liu S, Fang B, Wei X, Song Y (2013). Reduced intensity conditioning and co-transplantation of unrelated peripheral stem cells combined with umbilical cord mesenchymal stem/stroma cells for young patients with refractory severe aplastic anemia. Int J Hematol 98: 658–663.
Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A (2005). Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7: 393–395.
Karlsson H, Samarasinghe S, Ball LM, Sundberg B, Lankester AC, Dazzi F, Uzunel M, Rao K, Veys P, Le Blanc K et al. (2008). Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses. Blood 112: 532–541.
Kebriaei P, Isola L, Bahceci E, Holland K, Rowley S, McGuirk J, Devetten M, Jansen J, Herzig R, Schuster M et al. (2009). Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant 15: 804–811.
Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F (2003). Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101: 3722–3729.
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M et al. (2008). Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371: 1579–1586.
Le Blanc K, Mougiakakos D (2012). Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 12: 383–396.
Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, Ringdén O (2004). Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363: 1439–1441.
Li XH, Gao CJ, Da WM, Cao YB, Wang ZH, Xu LX, Wu YM, Liu B, Liu ZY, Yan B et al. (2014). Reduced intensity conditioning, combined transplantation of haploidentical hematopoietic stem cells and mesenchymal stem cells in patients with severe aplastic anemia. PLoS One 9:e89666.
Li ZY, Wang CQ, Lu G, Pan XY, Xu KL (2014). Effects of bone marrow mesenchymal stem cells on hematopoietic recovery and acute graft-versus-host disease in murine allogeneic umbilical cord blood transplantation model. Cell Biochem Biophys 70: 115– 122.
Lim JY, Park MJ, Im KI, Kim N, Jeon EJ, Kim EJ, Cho ML, Cho SG (2014). Combination cell therapy using mesenchymal stem cells and regulatory T-cells provides a synergistic immunomodulatory effect associated with reciprocal regulation of TH1/TH2 and th17/treg cells in a murine acute graft-versus-host disease model. Cell Transplant 23: 703–714.
Lu LL, Liu YJ, Yang SG, Zhao QJ, Wang X, Gong W, Han ZB, Xu ZS, Lu YX, Liu D et al. (2006). Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 91: 1017–1026.
Maccario R, Podestà M, Moretta A, Cometa A, Comoli P, Montagna D, Daudt L, Ibatici A, Piaggio G, Pozzi S et al. (2005). Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/ suppressive phenotype. Haematologica 90: 516–525.
Oviedo A, Yañez R, Colmenero I, Aldea M, Rubio A, Bueren JA, Lamana ML (2013). Reduced efficacy of mesenchymal stromal cells in preventing graft-versus-host disease in an in vivo model of haploidentical bone marrow transplant with leukemia. Cell Transplant 22: 1381–1394.
Pavletic SZ, Fowler DH (2012). Are we making progress in GVHD prophylaxis and treatment? Hematology Am Soc Hematol Educ Program 2012: 251–264.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999). Multilineage potential of adult human mesenchymal stem cells. Science 284: 143–147.
Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB (2010). Pro-inflammatory cytokines, IFNgamma and TNFalpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS One 5: e9016.
Ringdén O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lönnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z et al. (2006). Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81: 1390– 1397.
Saeidi M, Masoud A, Shakiba Y, Hadjati J, Mohyeddin Bonab M, Nicknam MH, Latifpour M, Nikbin B (2013). Immunomodulatory effects of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells on differentiation, maturation and endocytosis of monocyte-derived dendritic cells. Iran J Allergy Asthma Immunol 12: 37–49.
Secco M, Zucconi E, Vieira NM, Fogaça LL, Cerqueira A, Carvalho MD, Jazedje T, Okamoto OK, Muotri AR, Zatz M (2008). Multipotent stem cells from umbilical cord: cord is richer than blood! Stem Cells 26: 146–150.
Tabbara IA, Zimmerman K, Morgan C, Nahleh Z (2002). Allogeneic hematopoietic stem cell transplantation: complications and results. Arch Intern Med 162: 1558–1566.
Troyer DL, Weiss ML (2008). Wharton’s jelly-derived cells are a primitive stromal cell population. Stem Cells 26: 591–599.
Wang Y, Chen X, Cao W, Shi Y (2014). Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol 15: 1009–1016.
Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I, Troyer D, McIntosh KR (2008). Immune properties of human umbilical cord Wharton’s jelly-derived cells. Stem Cells 26: 2865–2874.
Weng JY, Du X, Geng SX, Peng YW, Wang Z, Lu ZS, Wu SJ, Luo CW, Guo R, Ling W et al. (2010). Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant 45: 1732–1740.
Wu KH, Chan CK, Tsai C, Chang YH, Sieber M, Chiu TH, Ho M, Peng CT, Wu HP, Huang JL (2011). Effective treatment of severe steroid-resistant acute graft-versus-host disease with umbilical cord-derived mesenchymal stem cells. Transplantation 91: 1412–1416.
Wu Y, Cao Y, Li X, Xu L, Wang Z, Liu P, Yan P, Liu Z, Wang J, Jiang S et al. (2014). Cotransplantation of haploidentical hematopoietic and umbilical cord mesenchymal stem cells for severe aplastic anemia: successful engraftment and mild GVHD. Stem Cell Res 12: 132–138.
Yoo KH, Jang IK, Lee MW, Kim HE, Yang MS, Eom Y, Lee JE, Kim YJ, Yang SK, Jung HL et al. (2009). Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol 259: 150–156.
Zhou H, Guo M, Bian C, Sun Z, Yang Z, Zeng Y, Ai H, Zhao RC (2010). Efficacy of bone marrow-derived mesenchymal stem cells in the treatment of sclerodermatous chronic graft-versus-host disease: clinical report. Biol Blood Marrow Transplant 2010 16: 403–412.