title: Mesenchymal stromal cells fail to prevent acute graft-versus-host disease and graft rejection after dog leukocyte antigen-haploidentical bone marrow transplantation.
abstract: Mesenchymal stromal cells (MSCs) have been shown to have immunosuppressive effects in vitro. To test the hypothesis that these effects can be harnessed to prevent graft-versus-host disease (GVHD) and graft rejection after hematopoietic cell transplantation (HCT), we administered a combination of 3 different immortalized marrow-derived MSC lines (15-30 × 10⁶ MSCs/kg/day, 2-5 times/week) or third-party primary MSC (1.0 × 10⁶ MSCs/kg/day, 3 times/week) to canine recipients (n = 15) of dog leukocyte antigen-haploidentical marrow grafts prepared with 9.2 Gy of total body irradiation. Additional pharmacological immunosuppression was not given after HCT. Before their in vivo use, the MSC products were shown to suppress alloantigen-induced T cell proliferation in a dose-dependent, major histocompatibility complex-unrestricted, and cell contact-independent fashion in vitro. Among 14 evaluable dogs, 7 (50%) rejected their grafts and 7 engrafted, with ensuing rapidly fatal acute GVHD (50%). These observations were not statistically different from outcomes obtained with historical controls (n = 11) not given MSC infusions (P = .69). Thus, survival curves for MSC-treated dogs and controls were virtually superimposable (median survival, 18 vs 15 days, respectively). Finally, outcomes of dogs given primary MSCs (n = 3) did not appear to be different from those given clonal MSCs (n = 12). In conclusion, our data fail to demonstrate MSC-mediated protection against GVHD and allograft rejection in this model.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. mmielcar@fhcrc.org
authors.forename: Marco
authors.initials: M
authors.lastname: Mielcarek
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
authors.forename: George E
authors.initials: GE
authors.lastname: Georges
authors.forename: Ludmila
authors.initials: L
authors.lastname: Golubev
authors.forename: Alla
authors.initials: A
authors.lastname: Nikitine
authors.forename: Billanna
authors.initials: B
authors.lastname: Hwang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Nash
authors.forename: Beverly
authors.initials: B
authors.lastname: Torok-Storb
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000401:mortality; D002478:Cells, Cultured; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D004285:Dogs; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006648:Histocompatibility; D007165:Immunosuppression Therapy / Q000379:methods*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells / Q000276:immunology / Q000637:transplantation; D016019:Survival Analysis; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D012333:RNA, Messenger
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