Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients.
Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4(+) T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.
Muraro
Paolo A
PA
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. murarop@ninds.nih.gov
Douek
Daniel C
DC
Packer
Amy
A
Chung
Katherine
K
Guenaga
Francisco J
FJ
Cassiani-Ingoni
Riccardo
R
Campbell
Catherine
C
Memon
Sarfraz
S
Nagle
James W
JW
Hakim
Frances T
FT
Gress
Ronald E
RE
McFarland
Henry F
HF
Burt
Richard K
RK
Martin
Roland
R
D000328:Adult; D000595:Amino Acid Sequence; D018952:Antigens, CD34 / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D033581:Stem Cell Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D018952:Antigens, CD34; D011948:Receptors, Antigen, T-Cell
J Exp Med. 2000 Aug 21;192(4):557-64
10952725
Blood Rev. 2003 Dec;17(4):233-40
14556778
Blood. 2002 Feb 1;99(3):768-84
11806976
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2989-94
11880642
J Exp Med. 2002 Mar 18;195(6):789-94
11901204
Mult Scler. 2002 Apr;8(2):142-54
11990872
J Immunol. 2002 May 15;168(10):5042-6
11994456
Nat Rev Immunol. 2002 Aug;2(8):547-56
12154374
Trends Mol Med. 2002 Oct;8(10):469-76
12383769
Blood. 2003 Apr 1;101(7):2711-20
12433688
Eur Neurol. 2003;49(3):137-41
12646755
Biol Blood Marrow Transplant. 2003 Mar;9(3):198-205
12652471
Haematologica. 2003 Mar;88(3):306-14
12651270
Blood. 2003 Oct 1;102(7):2373-8
12842989
Blood. 2003 Oct 1;102(7):2364-72
12763935
J Neurol Neurosurg Psychiatry. 2004 Apr;75(4):643-4
15026517
J Clin Invest. 2004 Mar;113(6):788-94
15067307
Brain. 2004 May;127(Pt 5):996-1008
14985264
Neurology. 1983 Nov;33(11):1444-52
6685237
Blood. 1991 May 15;77(10):2237-41
1709378
Proc Natl Acad Sci U S A. 1993 May 1;90(9):4319-23
8483950
Blood. 1994 Jan 15;83(2):587-95
7506956
J Immunol. 1994 May 15;152(10):5109-19
8176227
Eur J Immunol. 1994 Nov;24(11):2882-8
7525310
N Engl J Med. 1995 Jan 19;332(3):143-9
7800006
J Immunol. 1995 Jun 1;154(11):6182-90
7538544
Immunogenetics. 1995;42(6):455-500
8550092
J Immunol. 1996 May 15;156(10):3587-90
8621891
Bone Marrow Transplant. 1997 Jan;19(2):149-56
9116612
Blood. 1997 May 15;89(10):3700-7
9160675
Immunol Today. 1997 Sep;18(9):450-4
9293162
Blood. 1997 Nov 1;90(9):3789-98
9345067
Bone Marrow Transplant. 1997 Oct;20(8):631-8
9383225
Bone Marrow Transplant. 1998 Mar;21(6):537-41
9543056
Int Immunol. 1998 Mar;10(3):311-23
9576619
Nature. 1998 Dec 17;396(6712):690-5
9872319
Cancer Res. 1999 Jul 1;59(13):3107-11
10397252
Blood. 2005 Mar 15;105(6):2601-7
15546956
Ann Neurol. 1983 Mar;13(3):227-31
6847134
Immunity. 1999 Dec;11(6):733-42
10626895
Lancet. 2000 May 27;355(9218):1875-81
10866444
J Immunol. 2000 Aug 15;165(4):1733-7
10925249
Biol Blood Marrow Transplant. 2000;6(5A):563-75
11071262
J Immunol Methods. 2000 Dec 1;246(1-2):131-43
11121554
Ann Hematol. 2003 May;82(5):263-70
12739062
J Immunol. 2003 Jul 1;171(1):432-7
12817027
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8389-94
12829791
Curr Opin Neurol. 2003 Jun;16(3):299-305
12858065
Neurology. 2001 Jul 10;57(1):62-8
11445629