Intravenous injection of a D1 protein of the Smith proteins postpones murine lupus and induces type 1 regulatory T cells.
T cells that recognize nucleoproteins are required for the production of anti-dsDNA Abs involved in lupus development. SmD1 83-119 (a D1 protein of the Smith (Sm) proteins, part of small nuclear ribonucleoprotein) was recently shown to provide T cell help to anti-dsDNA Abs in the NZB/NZW model of lupus. Using this model in the present study, we showed that high dose tolerance to SmD1 (600-1000 microg i.v. of SmD1(83-119) peptide/mo) delays the production of autoantibodies, postpones the onset of lupus nephritis as confirmed by histology, and prolongs survival. Tolerance to SmD1 83-119 was adoptively transferred by CD90+ T cells, which also reduce T cell help for autoreactive B cells in vitro. One week after SmD1 83-119 tolerance induction in prenephritic mice, we detected cytokine changes in cultures of CD90+ T and B220+ B cells with decreased IFN-gamma and IL-4 expression and an increase in TGFbeta. Increased frequencies of regulatory IFN-gamma+ and IL10+ CD4+ T cells were later detected. Such regulatory IL-10+/IFN-gamma+ type 1 regulatory T cells prevented autoantibody generation and anti-CD3-induced proliferation of naive T cells. In conclusion, these results indicate that SmD1 83-119 peptide may play a dominant role in the activation of helper and regulatory T cells that influence autoantibody generation and murine lupus.
Riemekasten
Gabriela
G
Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany. gabriela.riemekasten@charite.de
Langnickel
Dirk
D
Enghard
Philipp
P
Undeutsch
Reinmar
R
Humrich
Jens
J
Ebling
Fanny M
FM
Hocher
Berthold
B
Humaljoki
Tiina
T
Neumayer
Hans
H
Burmester
Gerd-R
GR
Hahn
Bevra H
BH
Radbruch
Andreas
A
Hiepe
Falk
F
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000378:metabolism; D001324:Autoantigens / Q000008:administration & dosage* / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000276:immunology; D007108:Immune Tolerance; D007275:Injections, Intravenous; D008181:Lupus Nephritis / Q000276:immunology* / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D017411:Ribonucleoproteins, Small Nuclear / Q000008:administration & dosage* / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D055517:snRNP Core Proteins
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D016207:Cytokines; D006131:Growth Inhibitors; D010446:Peptide Fragments; D017411:Ribonucleoproteins, Small Nuclear; D055517:snRNP Core Proteins