Mesenchymal stromal cells fail to prevent acute graft-versus-host disease and graft rejection after dog leukocyte antigen-haploidentical bone marrow transplantation.
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.
Mielcarek
Marco
M
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. mmielcar@fhcrc.org
Storb
Rainer
R
Georges
George E
GE
Golubev
Ludmila
L
Nikitine
Alla
A
Hwang
Billanna
B
Nash
Richard A
RA
Torok-Storb
Beverly
B
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
D016207:Cytokines; D012333:RNA, Messenger
Exp Hematol. 2003 Oct;31(10):881-9
14550803
Transplantation. 1985 Sep;40(3):323-8
2412323
Biol Blood Marrow Transplant. 2005 May;11(5):389-98
15846293
Exp Cell Res. 2005 Apr 15;305(1):33-41
15777785
Vet Res Commun. 2005 Feb;29(2):103-10
15730134
Exp Hematol. 2003 May;31(5):413-20
12763140
Lancet. 2008 May 10;371(9624):1579-86
18468541
Eur J Nucl Med Mol Imaging. 2006 Oct;33(10):1171-7
16763813
Exp Hematol. 2002 Jan;30(1):42-8
11823036
Curr Opin Hematol. 2006 Nov;13(6):419-25
17053453
Blood. 1996 Jan 15;87(2):574-80
8555479
Leukemia. 2007 Sep;21(9):1992-9
17625609
Tissue Antigens. 1998 Oct;52(4):397-401
9820606
Scand J Immunol. 2003 Jan;57(1):11-20
12542793
Biol Blood Marrow Transplant. 2006 Sep;12(9):899-904
16920555
Biol Blood Marrow Transplant. 2011 Apr;17(4):465-75
20457265
Int J Hematol. 2004 Nov;80(4):370-6
15615264
Leukemia. 2007 Aug;21(8):1733-8
17541394
Blood. 2003 May 1;101(9):3722-9
12506037
Br J Haematol. 2002 Sep;118(4):1128-31
12199796
J Clin Oncol. 2000 Jan;18(2):307-16
10637244
Transplantation. 1994 Sep 27;58(6):701-6
7940690
Blood. 1995 Feb 15;85(4):997-1005
7849321
Lancet. 2004 May 1;363(9419):1439-41
15121408
Blood. 2001 Dec 1;98(12):3447-55
11719387
Ann N Y Acad Sci. 2009 Sep;1176:101-17
19796238
Biol Blood Marrow Transplant. 2010 Jun;16(6):838-47
20109568
Blood. 2005 Dec 1;106(12):4002-8
16105977
Cells Tissues Organs. 2001;169(1):12-20
11340257
Transplantation. 2006 May 27;81(10):1390-7
16732175
Blood. 2005 Feb 15;105(4):1815-22
15494428
Nucl Med Commun. 2003 Nov;24(11):1149-54
14569169
Proc Natl Acad Sci U S A. 1980 Aug;77(8):4756-9
6933522
Bone Marrow Transplant. 1995 Oct;16(4):557-64
8528172
J Immunol. 2006 Jun 15;176(12):7761-7
16751424
Blood. 2002 Aug 15;100(4):1509-11
12184274
Transplantation. 1996 Sep 27;62(6):876-7
8824495
Blood. 2004 Jun 15;103(12):4619-21
15001472