Immature and maturation-resistant human dendritic cells generated from bone marrow require two stimulations to induce T cell anergy in vitro.
Immature dendritic cells (DC) represent potential clinical tools for tolerogenic cellular immunotherapy in both transplantation and autoimmunity. A major drawback in vivo is their potential to mature during infections or inflammation, which would convert their tolerogenicity into immunogenicity. The generation of immature DC from human bone marrow (BM) by low doses of GM-CSF (lowGM) in the absence of IL-4 under GMP conditions create DC resistant to maturation, detected by surface marker expression and primary stimulation by allogeneic T cells. This resistence could not be observed for BM-derived DC generated with high doses of GM-CSF plus IL-4 (highGM/4), although both DC types induced primary allogeneic T cell anergy in vitro. The estabishment of the anergic state requires two subsequent stimulations by immature DC. Anergy induction was more profound with lowGM-DC due to their maturation resistance. Together, we show the generation of immature, maturation-resistant lowGM-DC for potential clinical use in transplant rejection and propose a two-step-model of T cell anergy induction by immature DC.
Berger
Thomas G
TG
Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
Schulze-Koops
Hendrik
H
Schäfer
Michaela
M
Müller
Ester
E
Lutz
Manfred B
MB
D001854:Bone Marrow Cells / Q000166:cytology*; D017635:Clonal Anergy; D003713:Dendritic Cells / Q000166:cytology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology*
D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
Nature. 1998 Mar 19;392(6673):245-52
9521319
J Immunol. 2008 Nov 15;181(10):6923-33
18981112
Blood. 2001 Jun 1;97(11):3470-7
11369639
Trends Immunol. 2008 Jun;29(6):272-9
18468488
Immunity. 2003 Mar;18(3):367-79
12648454
Hum Immunol. 2009 May;70(5):345-52
19405173
Transplant Proc. 2009 Mar;41(2):537-8
19328920
Transplantation. 2008 Nov 15;86(9):1275-82
19005410
Blood. 2009 May 7;113(19):4575-85
19204323
Eur J Immunol. 2000 Jul;30(7):1813-22
10940870
Eur J Immunol. 2003 Nov;33(11):3154-63
14579284
Immunobiology. 2008;213(9-10):751-8
18926290
J Immunol. 1999 Mar 1;162(5):2775-84
10072524
Cold Spring Harb Symp Quant Biol. 1989;54 Pt 2:605-10
2534840
Blood. 2003 May 1;101(9):3581-9
12511411
Eur J Immunol. 2000 Jul;30(7):1807-12
10940869
Immunol Rev. 2008 Aug;224:141-65
18759925
J Clin Invest. 2001 Sep;108(6):895-903
11560959
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):351-8
11773639
J Immunol. 2000 May 1;164(9):4465-70
10779746
Transplantation. 2007 Jul 27;84(2):196-206
17667811
Immunol Rev. 2006 Aug;212:8-27
16903903
Curr Opin Organ Transplant. 2008 Aug;13(4):350-7
18685329
Nat Med. 1999 Nov;5(11):1249-55
10545990
J Immunol Methods. 1999 Feb 1;223(1):77-92
10037236
J Immunol. 1991 Nov 15;147(10):3261-7
1658142
Hum Immunol. 2009 May;70(5):340-4
19275918
Immunity. 2001 May;14(5):495-8
11371351
J Exp Med. 1990 Oct 1;172(4):1065-70
1976734
J Exp Med. 2000 Sep 18;192(6):823-33
10993913
FEBS Lett. 2005 Jul 4;579(17):3660-8
15963988
J Immunol. 1991 Jan 15;146(2):485-91
1670944
Cell. 2008 May 30;133(5):775-87
18510923
J Exp Med. 2000 Nov 6;192(9):1213-22
11067871
J Immunol. 2002 Oct 1;169(7):3574-80
12244147
Transplantation. 1996 Sep 15;62(5):659-65
8830833
Eur J Immunol. 1993 Apr;23(4):935-42
8458379
Curr Opin Immunol. 2004 Apr;16(2):209-16
15023415
PLoS One. 2008;3(12):e3842
19052636
J Exp Med. 1995 Aug 1;182(2):459-65
7543139
Immunity. 2007 Oct;27(4):610-24
17936032
Nat Rev Immunol. 2007 Aug;7(8):599-609
17612584
J Immunol Methods. 1996 Sep 27;196(2):137-51
8841452
J Leukoc Biol. 2005 Apr;77(4):535-43
15618296
J Clin Invest. 1998 Jan 1;101(1):252-62
9421488
Nat Rev Immunol. 2007 Aug;7(8):650-4
17653127
Clin Exp Immunol. 2008 Oct;154(1):107-14
18727627
Handb Exp Pharmacol. 2009;(188):233-49
19031029
Immunol Rev. 2006 Aug;212:28-50
16903904