[en] Background aims. Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation caused by donor T cells reacting against host tissues. Previous studies have suggested that mesenchymal stromal cells (MSCs) could exert potent immunosuppressive effects. Methods. The ability of human bone marrow derived MSCs to prevent xenogeneic GVHD in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice and in NOD/SCID/interleukin-2Rg(null) (NSG) mice transplanted with human peripheral blood mononuclear cells (PBMCs) was assessed. Results. Injection of 200 106 human PBMCs intraperitoneally (IP) into sub-lethally (3.0 Gy) irradiated NOD/SCID mice also given anti-asialo GM1 antibodies IP 1 day prior and 8 days after transplantation induced lethal xenogeneic GVHD in all tested mice. Co-injection of 2 106 MSCs IP on day 0 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs. Similarly, injection of 30 106 human PBMCs IP into sub-lethally (2.5 Gy) irradiated NSG mice induced a lethal xenogeneic GVHD in all tested mice. Injection of 3 106 MSCs IP on days 0, 7, 14 and 21 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs. Conclusions. Injection of MSCs did not prevent xenogeneic GVHD in these two humanized mice models.
Disciplines :
Hematology
Author, co-author :
Bruck, France ✱
Belle, Ludovic ✱; Université de Liège > GIGA-R : Hématologie
LECHANTEUR, Chantal ; Centre Hospitalier Universitaire de Liège - CHU > Thérapie cellulaire
Deeg HJ. How I treat refractory acute GVHD. Blood. 2007; 109:4119-26.
Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, et al. Graft-versus-tumor effects after allogeneichematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol. 2005;23:1993-2003.
Reddy P, Arora M, Guimond M, Mackall CL, Weisdorf D. GVHD: A continuing barrier to the safety of allogeneic transplantation. Biol Blood Marrow Transplant. 2009;15:162-8.
Baron F, Labopin M, Niederwieser D, Vigouroux S, Cornelissen JJ, Malm C, et al. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation [published online ahead of print May 22, 2012]. Leukemia.
Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood. 2001;98:3192-204.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143-7.
Noort WA, Kruisselbrink AB, In't Anker PS, Kruger M, van Bezooijen RL, de Paus RA, et al. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(?) cells in NOD/SCID mice. Exp Hematol. 2002;30: 870-8.
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838-43.
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.
Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003;101:3722-9.
LeBlancK,RingdenO. Immunobiology of humanmesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11:321-34.
Le Blanc K, Ringden O. Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med. 2007; 262:509-25.
Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499-506.
Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30:42-8.
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;24:2582-91.
Polchert D, Sobinsky J, Douglas G, Kidd M, Moadsiri A, Reina E, et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol. 2008;38:1745-55.
Christensen ME, Turner BE, Sinfield LJ, Kollar K, Cullup H, Waterhouse NJ, et al. Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graftversus-host disease. Haematologica. 2010;95:2102-10.
Sudres M, Norol F, Trenado A, Gregoire S, Charlotte F, Levacher B, et al.Bonemarrowmesenchymal stemcells suppress lymphocyte proliferation in vitro but fail to prevent graft-versushost disease in mice. J Immunol. 2006;176:7761-7.
PrigozhinaTB,Khitrin S, Elkin G, Eizik O,Morecki S, Slavin S. Mesenchymal stromal cells lose their immunosuppressive potential after allotransplantation. Exp Hematol. 2008;36: 1370-6.
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;141:224-34.
Mielcarek M, Storb R, Georges GE, Golubev L, Nikitine A, Hwang B, et al. Mesenchymal stromal cells fail to prevent acute graft-versus-host disease and graft rejection after dogleukocyte-antigen haploidentical bone marrow transplantation. Biol Blood Marrow Transplant. 2011;17:214-25.
Miura M, Miura Y, Padilla-Nash HM, Molinolo AA, Fu B, Patel V, et al. Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation. Stem Cells. 2006;24:1095-103.
Meisel R, Brockers S, Heseler K, Degistirici O, Bulle H, Woite C, et al. Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia. 2011;25:648-54.
Ball LM, Bernardo ME, Roelofs H, Lankester A, Cometa A, Egeler RM, et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood. 2007;110: 2764-7.
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: A phase II study. Lancet. 2008;371:1579-86.
Ning H, Yang F, Jiang M, Hu L, Feng K, Zhang J, et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: Outcome of a pilot clinical study. Leukemia. 2008;22: 593-9.
Bernardo ME, Ball LM, Cometa AM, Roelofs H, Zecca M, Avanzini MA, et al. Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation. Bone Marrow Transplant. 2011;46:200-7.
Baron F, Lechanteur C, Willems E, Bruck F, Baudoux E, Seidel L, et al. Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLAmismatched allogeneic transplantation following nonmyeloablative conditioning. Biol Blood Marrow Transplant. 2010;16:838-47.
Martin PJ, Uberti JP, Soiffer RJ, Klingemann H, Waller EK, Daly AS, et al. Prochymal improves response rates in patients with steroid-refractory acute graft versus host disease (SRGVHD) involving the liver and gut: Results of a randomized, placebo-controlled, multicenter phase III trial in GVHD. Biol Blood Marrow Transplant. 2010;16(Suppl. 2): S169-70.
Horwitz EM, Maziarz RT, Kebriaei P. MSCs in hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17(1 Suppl.):S21-9.
Briquet A, Dubois S, Bekaert S, Dolhet M, Beguin Y, Gothot A. Prolonged ex vivo culture of human bone marrow mesenchymal stem cells influences their supportive activity toward NOD/SCID-repopulating cells and committed progenitor cells of B lymphoid and myeloid lineages. Haematologica. 2010;95:47-56.
Pirson L, Baron F, Meuris N, Giet O, Castermans E, Greimers R, et al. Despite inhibition of hematopoietic progenitor cell growth in vitro, the tyrosine kinase inhibitor 278 F. Bruck et al. imatinib does not impair engraftment of human CD133? cells into NOD/SCIDbeta2mNull mice. Stem Cells. 2006;24: 1814-21.
Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM, et al. Quantitative analysis of fetal DNA in maternal plasma and serum: Implications for noninvasive prenatal diagnosis. Am J Hum Genet. 1998;62:768-75.
Castermans E, Baron F, Willems E, Schaaf-Lafontaine N, Meuris N, Gothot A, et al. Evidence for neo-generation of T cells by the thymus after non-myeloablative conditioning. Haematologica. 2008;93:240-7.
Castermans E, Hannon M, Dutrieux J, Humblet-Baron S, Seidel L, Cheynier R, et al. Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. Haematologica. 2011;96:298-306.
Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, et al. NOD/SCID/gamma(null)(c) mouse: An excellent recipient mouse model for engraftment of human cells. Blood. 2002;100:3175-82.
Baron F, Storb R. Mesenchymal stromal cells: A new tool against graft-versus-host disease? Biol Blood Marrow Transplant. 2012;18:822-40.
Tsuchida M, Brown SA, Tutt LM, Tan J, Seehafer DL, Harris JP, et al. A model of human anti-T-cell monoclonal antibody therapy in SCID mice engrafted with human peripheral blood lymphocytes. Clin Transplant. 1997;11: 522-8.
Sandhu JS, Gorczynski R, Shpitz B, Gallinger S, Nguyen HP, Hozumi N. A human-model of xenogeneic graft-versus-host disease in SCID mice engrafted with human peripheral-blood lymphocytes. Transplantation. 1995;60:179-84.
Hiramatsu H, Nishikomori R, Heike T, Ito M, Kobayashi K, Katamura K, et al. Complete reconstitution of human lymphocytes from cord blood CD34(?) cells using the NOD/SCID/gamma c(null) mice model. Blood. 2003;102:873-80.
Ito R, Katano I, Kawai K, Hirata H, Ogura T, Kamisako T, et al. Highly sensitive model for xenogenic GVHD using severe immunodeficient NOG mice. Transplantation. 2009; 87:1654-8.
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;21:1992-9.
Bruck F, Baron F, Dubois S, Briquet A, Hanon-Absil M, Belle L, et al. Rapamycin delays xenogeneic acute graft versus host disease (AGVHD) in NOD/SCID/Il2R gamma null (NSG) mice: Impact of regulatory T cells. Biol Blood Marrow Transplant. 2011;17:S332.
Yoshizaki A, Yanaba K, Yoshizaki A, Iwata Y, Komura K, Ogawa F, et al. Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum. 2010;62:2476-87.
Min CK, Kim BG, Park G, Cho B, Oh IH. IL-10-transduced bone marrow mesenchymal stem cells can attenuate the severity of acute graft-versus-host disease after experimental allogeneic stem cell transplantation. Bone Marrow Transplant. 2007;39:637-45.
