Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease.
BACKGROUND
Multipotent mesenchymal stromal cells suppress T-cell function in vitro, a property that has underpinned their use in treating clinical steroid-refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. However the potential of mesenchymal stromal cells to resolve graft-versus-host disease is confounded by a paucity of pre-clinical data delineating their immunomodulatory effects in vivo.


METHODS
We examined the influence of timing and dose of donor-derived mesenchymal stromal cells on the kinetics of graft-versus-host disease in two murine models of graft-versus-host disease (major histocompatibility complex-mismatched: UBI-GFP/BL6 [H-2(b)]→BALB/c [H-2(d)] and the sibling transplant mimic, UBI-GFP/BL6 [H-2(b)]→BALB.B [H-2(b)]) using clinically relevant conditioning regimens. We also examined the effect of mesenchymal stromal cell infusion on bone marrow and spleen cellular composition and cytokine secretion in transplant recipients.


RESULTS
Despite T-cell suppression in vitro, mesenchymal stromal cells delayed but did not prevent graft-versus-host disease in the major histocompatibility complex-mismatched model. In the sibling transplant model, however, 30% of mesenchymal stromal cell-treated mice did not develop graft-versus-host disease. The timing of administration and dose of the mesenchymal stromal cells influenced their effectiveness in attenuating graft-versus-host disease, such that a low dose of mesenchymal stromal cells administered early was more effective than a high dose of mesenchymal stromal cells given late. Compared to control-treated mice, mesenchymal stromal cell-treated mice had significant reductions in serum and splenic interferon-γ, an important mediator of graft-versus-host disease.


CONCLUSIONS
Mesenchymal stromal cells appear to delay death from graft-versus-host disease by transiently altering the inflammatory milieu and reducing levels of interferon-γ. Our data suggest that both the timing of infusion and the dose of mesenchymal stromal cells likely influence these cells' effectiveness in attenuating graft-versus-host disease.
Christensen
Melinda E
ME
Bone Marrow Transplant Team, Mater Medical Research Institute, South Brisbane QLD 4101 Australia.
Turner
Brie E
BE
Sinfield
Laura J
LJ
Kollar
Katarina
K
Cullup
Hannah
H
Waterhouse
Nigel J
NJ
Hart
Derek N J
DN
Atkinson
Kerry
K
Rice
Alison M
AM
D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D016207:Cytokines; D018836:Inflammation Mediators; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma
Scand J Immunol. 2004 Sep;60(3):307-15
15320889
Leukemia. 2008 Mar;22(3):593-9
18185520
Bone Marrow Transplant. 2007 May;39(10):637-45
17369865
Blood. 2002 May 15;99(10):3838-43
11986244
Lancet. 2004 May 1;363(9419):1439-41
15121408
Blood. 2005 May 15;105(10):4120-6
15692068
Semin Cell Dev Biol. 2007 Dec;18(6):846-58
18024097
Stem Cells. 2006 Nov;24(11):2582-91
16873762
J Immunol. 2006 Aug 15;177(4):2080-7
16887966
J Immunol. 2006 Jun 15;176(12):7761-7
16751424
Blood. 2006 Jul 1;108(1):390-9
16522809
Cell Stem Cell. 2008 Feb 7;2(2):141-50
18371435
Cytotherapy. 2010 May;12(3):361-70
20078382
Eur J Immunol. 2008 Jun;38(6):1745-55
18493986
Int J Hematol. 2004 Nov;80(4):370-6
15615264
Stem Cells Dev. 2004 Jun;13(3):263-71
15186722
J Clin Invest. 2003 Dec;112(12):1880-6
14679183
Stem Cells. 2006 Jan;24(1):74-85
16099998
Lancet. 2008 May 10;371(9624):1579-86
18468541
Cells Tissues Organs. 2001;169(1):12-20
11340257
Transplantation. 2006 May 27;81(10):1390-7
16732175
Stem Cells. 2007 Apr;25(4):875-84
17185606
Exp Hematol. 2003 Oct;31(10):890-6
14550804
Exp Hematol. 2008 Oct;36(10):1370-6
18619727
Transplantation. 2008 Oct 15;86(7):968-76
18852664
Immunol Lett. 2007 Jun 15;110(2):91-100
17507101
Biol Blood Marrow Transplant. 2009 Jul;15(7):804-11
19539211
J Tissue Eng. 2010 Aug 01;2010:345806
21350643
Blood. 2004 Jun 15;103(12):4619-21
15001472