1,25-dihydroxyvitamin D3 induces stable and reproducible therapeutic tolerogenic dendritic cells with specific epigenetic modifications.
DNA methylation
cell therapy
dendritic cells
epigenetics
immunotherapy
tolerance induction
Journal
Cytotherapy
ISSN: 1477-2566
Titre abrégé: Cytotherapy
Pays: England
ID NLM: 100895309
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
15
06
2020
revised:
30
11
2020
accepted:
04
12
2020
pubmed:
20
1
2021
medline:
5
10
2021
entrez:
19
1
2021
Statut:
ppublish
Résumé
Autologous, antigen-specific, tolerogenic dendritic cells (tolDCs) are presently assessed to reverse and possibly cure autoimmune diseases such as type 1 diabetes (T1D). Good Manufacturing Practice production and clinical implementation of such cell therapies critically depend on their stability and reproducible production from healthy donors and, more importantly, patient-derived monocytes. Here the authors demonstrate that tolDCs (modulated using 1,25-dihydroxyvitamin D3 and dexamethasone) displayed similar features, including protein, transcriptome and epigenome profiles, between two international clinical centers and between T1D and healthy donors, validating reproducible production. In addition, neither phenotype nor function of tolDCs was affected by repeated stimulation with inflammatory stimuli, underscoring their stability as semi-mature DCs. Furthermore, tolDCs exhibited differential DNA methylation profiles compared with inflammatory mature DCs (mDCs), and this was already largely established prior to maturation, indicating that tolDCs are locked into an immature state. Finally, approximately 80% of differentially expressed known T1D risk genes displayed a corresponding differential DNA methylome in tolDCs versus mDCs and metabolic and immune pathway genes were also differentially methylated and expressed. In summary, tolDCs are reproducible and stable clinical cell products unaffected by the T1D status of donors. The observed stable, semi-mature phenotype and function of tolDCs are exemplified by epigenetic modifications representative of immature-stage cells. Together, the authors' data provide a strong basis for the production and clinical implementation of tolDCs in the treatment of autoimmune diseases such as T1D.
Identifiants
pubmed: 33461863
pii: S1465-3249(20)30965-8
doi: 10.1016/j.jcyt.2020.12.003
pmc: PMC8715888
mid: NIHMS1684618
pii:
doi:
Substances chimiques
Calcitriol
FXC9231JVH
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
242-255Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK081705
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Organisme : NIDDK NIH HHS
ID : DP3 DK106917
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK065073
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL106089
Pays : United States
Informations de copyright
Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article.
Références
J Proteome Res. 2012 Feb 3;11(2):941-71
pubmed: 22103328
Diabetes. 2009 Jan;58(1):138-45
pubmed: 18835928
Diabetes. 2002 Jul;51(7):2119-25
pubmed: 12086941
Front Immunol. 2019 Feb 05;10:79
pubmed: 30804929
J Exp Med. 2000 Nov 6;192(9):1213-22
pubmed: 11067871
Genome Biol. 2010;11(10):R106
pubmed: 20979621
Eur J Immunol. 2009 Nov;39(11):3147-59
pubmed: 19688742
J Biol Chem. 2011 May 27;286(21):18347-53
pubmed: 21454628
Blood. 2003 Jun 15;101(12):4862-9
pubmed: 12543858
Eur J Immunol. 2012 Mar;42(3):771-82
pubmed: 22488365
Lancet Diabetes Endocrinol. 2019 Jan;7(1):65-74
pubmed: 30528100
Cell Rep. 2015 Feb 10;10(5):711-725
pubmed: 25660022
Genes Immun. 2017 Sep;18(3):176-183
pubmed: 28794505
J Exp Med. 2001 Jan 15;193(2):F5-9
pubmed: 11208869
Lancet. 2014 Jan 4;383(9911):69-82
pubmed: 23890997
J Immunol. 2008 Mar 1;180(5):3166-75
pubmed: 18292540
Epigenetics Chromatin. 2014 Aug 20;7:21
pubmed: 25161698
Cell. 2000 Mar 3;100(5):575-85
pubmed: 10721994
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Front Immunol. 2019 May 16;10:1112
pubmed: 31164890
Lancet Diabetes Endocrinol. 2020 Jun;8(6):470-472
pubmed: 32723484
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Front Immunol. 2015 Oct 19;6:528
pubmed: 26539195
Lancet. 1995 Feb 25;345(8948):491-2
pubmed: 7861877
Bioinformatics. 2018 Sep 1;34(17):i884-i890
pubmed: 30423086
Curr Diab Rep. 2017 Aug 16;17(10):89
pubmed: 28815391
Eur J Immunol. 2009 May;39(5):1334-43
pubmed: 19350558
J Immunol. 2017 Jan 15;198(2):729-740
pubmed: 27927966
Proc Natl Acad Sci U S A. 2016 May 24;113(21):E3002-11
pubmed: 27162351
Inflammopharmacology. 2013 Dec;21(6):397-406
pubmed: 23846739
Diabetes Care. 2011 Sep;34(9):2026-32
pubmed: 21680720
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
J Immunol. 2010 Aug 1;185(3):1412-8
pubmed: 20574005
BMJ Open. 2019 Sep 9;9(9):e030309
pubmed: 31501122
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
J Biol Chem. 2012 May 11;287(20):16335-45
pubmed: 22431725
Genome Res. 2010 Oct;20(10):1352-60
pubmed: 20736230
Ann Rheum Dis. 2017 Jan;76(1):227-234
pubmed: 27117700
Ann Rheum Dis. 2010 Nov;69(11):2042-50
pubmed: 20551157
Nucleic Acids Res. 2009 Jan;37(1):1-13
pubmed: 19033363
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1678-E1687
pubmed: 28196884
J Autoimmun. 2016 Apr;68:23-9
pubmed: 26782299
Trends Genet. 2009 Mar;25(3):129-36
pubmed: 19185382
J Neuroinflammation. 2016 May 20;13(1):113
pubmed: 27207486
Nat Rev Genet. 2018 Feb;19(2):81-92
pubmed: 29033456
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6938-6943
pubmed: 30886108
Nat Rev Nephrol. 2019 Jun;15(6):327-345
pubmed: 30894700
Clin Exp Immunol. 2019 Oct;198(1):57-70
pubmed: 31116879
Curr Opin Genet Dev. 2018 Jun;50:7-16
pubmed: 29453110
Mol Cell Endocrinol. 2017 Sep 15;453:52-67
pubmed: 28461074
Immunol Lett. 2008 Feb 15;116(1):55-63
pubmed: 18192028
J Crohns Colitis. 2015 Dec;9(12):1071-8
pubmed: 26303633
Horm Metab Res. 2005 Nov;37(11):680-3
pubmed: 16308836
Sci Transl Med. 2015 Jun 3;7(290):290ra87
pubmed: 26041704
Clin Exp Rheumatol. 2015 Jul-Aug;33(4 Suppl 92):S97-103
pubmed: 26458178
Diabetes. 2012 May;61(5):1281-90
pubmed: 22403299
J Immunol. 2002 Mar 15;168(6):2634-43
pubmed: 11884427
Annu Rev Immunol. 2012;30:1-22
pubmed: 22136168
Nat Immunol. 2000 Oct;1(4):353-7
pubmed: 11017109
PeerJ. 2016 Aug 30;4:e2300
pubmed: 27635311
Lancet. 2001 Nov 3;358(9292):1500-3
pubmed: 11705562