Flt3L Treatment of Bone Marrow Donors Increases Graft Plasmacytoid Dendritic Cell Content and Improves Allogeneic Transplantation Outcomes.
Allogeneic transplantation
Flt3L
Graft-versus-host disease
Graft-versus-leukemia
Plasmacytoid dendritic cells
Journal
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
ISSN: 1523-6536
Titre abrégé: Biol Blood Marrow Transplant
Pays: United States
ID NLM: 9600628
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
21
07
2018
accepted:
26
11
2018
pubmed:
7
12
2018
medline:
9
4
2020
entrez:
4
12
2018
Statut:
ppublish
Résumé
A higher number of donor plasmacytoid dendritic cells (pDCs) is associated with increased survival and reduced graft-versus-host disease (GVHD) in human recipients of unrelated donor bone marrow (BM) grafts, but not granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood grafts. We show that in murine models, donor BM pDCs are associated with increased survival and decreased GVHD compared with G-CSF-mobilized pDCs. To increase the content of pDCs in BM grafts, we studied the effect of FMS-like tyrosine kinase 3 ligand (Flt3L) treatment of murine BM donors on transplantation outcomes. Flt3L treatment (300 μg/kg/day) resulted in a schedule-dependent increase in the content of pDCs in the BM. Mice treated on days -4 and -1 had a >5-fold increase in pDC content without significant changes in numbers of HSCs, T cells, B cells, and natural killer cells in the BM graft. In an MHC-mismatched murine transplant model, recipients of Flt3L-treated T cell-depleted (TCD) BM (TCD F-BM) and cytokine-untreated T cells had increased survival and decreased GVHD scores with fewer Th1 and Th17 polarized T cells post-transplantation compared with recipients of equivalent numbers of untreated donor TCD BM and T cells. Gene array analyses of pDCs from Flt3L-treated human and murine donors showed up-regulation of adaptive immune pathways and immunoregulatory checkpoints compared with pDCs from untreated BM donors. Transplantation of TCD F-BM plus T cells resulted in no loss of the graft-versus-leukemia (GVL) effect compared with grafts from untreated donors in 2 murine GVL models. Thus, Flt3L treatment of BM donors is a novel method for increasing the pDC content in allografts, improving survival, and decreasing GVHD without diminishing the GVL effect.
Identifiants
pubmed: 30503387
pii: S1083-8791(18)30774-2
doi: 10.1016/j.bbmt.2018.11.029
pmc: PMC10373795
mid: NIHMS1055290
pii:
doi:
Substances chimiques
Adjuvants, Immunologic
0
Membrane Proteins
0
flt3 ligand protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1075-1084Subventions
Organisme : NCI NIH HHS
ID : P30 CA138292
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI145231
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188523
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI145231
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier Inc.
Références
Blood. 1998 Feb 15;91(4):1101-34
pubmed: 9454740
F1000Res. 2014 Jul 01;3:146
pubmed: 25309732
J Exp Med. 2003 Jul 21;198(2):293-303
pubmed: 12874262
J Immunol. 2001 Aug 15;167(4):1862-6
pubmed: 11489962
Blood. 1996 Oct 15;88(8):3230-9
pubmed: 8963063
Blood. 2017 Jan 5;129(1):13-21
pubmed: 27821504
Blood. 2015 May 7;125(19):2937-47
pubmed: 25833958
PLoS One. 2015 Aug 11;10(8):e0135217
pubmed: 26263178
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6347-52
pubmed: 17404233
Leukemia. 2015 Jun;29(6):1441-4
pubmed: 25634684
Biol Blood Marrow Transplant. 2009 Nov;15(11):1347-53
pubmed: 19822293
Blood. 2002 Mar 1;99(5):1825-32
pubmed: 11861301
Blood. 2008 Nov 1;112(9):3713-22
pubmed: 18698004
Hum Pathol. 1984 Mar;15(3):202-5
pubmed: 6698540
J Virol. 2005 Jan;79(1):17-27
pubmed: 15596797
Annu Rev Immunol. 2013;31:563-604
pubmed: 23516985
Immunity. 2001 Apr;14(4):377-86
pubmed: 11336683
Blood. 2010 Aug 5;116(5):819-28
pubmed: 20435882
Blood. 1993 May 15;81(10):2496-502
pubmed: 8490166
Clin Adv Hematol Oncol. 2005 May;3(5):415-9, 428
pubmed: 16167015
Biol Blood Marrow Transplant. 2006 Jan;12(1):31-47
pubmed: 16399567
J Immunol. 2009 Jan 15;182(2):912-20
pubmed: 19124734
Nat Immunol. 2008 Nov;9(11):1244-52
pubmed: 18849989
Bone Marrow Transplant. 1998 Jun;21 Suppl 3:S13-5
pubmed: 9712485
JAMA Oncol. 2016 Dec 01;2(12):1583-1589
pubmed: 27532508
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Sci Transl Med. 2010 Mar 31;2(25):25ra24
pubmed: 20424013
Blood. 2012 Jan 26;119(4):1075-85
pubmed: 22130799
J Clin Oncol. 1996 Jun;14(6):1957-60
pubmed: 8656266
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Blood. 1992 Dec 15;80(12):2964-8
pubmed: 1467511
Genome Biol. 2010;11(10):R106
pubmed: 20979621
Nat Immunol. 2000 Oct;1(4):305-10
pubmed: 11017101
Bone Marrow Transplant. 2016 Mar;51(3):333-43
pubmed: 26642333
Annu Rev Biochem. 1990;59:129-70
pubmed: 1695830
Blood. 2004 Jun 1;103(11):4330-5
pubmed: 14962904
Front Immunol. 2016 Nov 21;7:523
pubmed: 27917176
Int Immunol. 2005 Jan;17(1):1-14
pubmed: 15585605
Oncoimmunology. 2014 Dec 15;3(10):e958957
pubmed: 25941585
J Clin Oncol. 2014 Aug 1;32(22):2365-72
pubmed: 24982459
Orphanet J Rare Dis. 2007 Sep 04;2:35
pubmed: 17784964
N Engl J Med. 1969 Sep 25;281(13):691-7
pubmed: 4186068
Curr Opin Mol Ther. 2008 Aug;10(4):343-9
pubmed: 18683098
J Exp Med. 2015 Jul 27;212(8):1303-21
pubmed: 26169940
Biol Blood Marrow Transplant. 2013 Sep;19(9):1331-9
pubmed: 23810844
Nat Immunol. 2002 Mar;3(3):272-80
pubmed: 11850626
Nat Rev Immunol. 2009 Dec;9(12):833-44
pubmed: 19935803
J Immunol. 2005 Jul 1;175(1):189-95
pubmed: 15972647
Bone Marrow Transplant. 2015 Jul;50(7):924-30
pubmed: 25915810
Blood. 1999 Nov 1;94(9):3222-33
pubmed: 10556211
Immunology. 2013 Sep;140(1):22-30
pubmed: 23621371