CD4+CD25+ regulatory T cells inhibit experimental anti-glomerular basement membrane glomerulonephritis in mice.
CD4+CD25+ regulatory T cells (Treg) are of critical importance for the maintenance of tolerance. The kidney is frequently involved in autoimmune diseases, such as lupus erythematosus or glomerulonephritis (GN). Therefore, the therapeutic efficacy of Treg in a T cell-dependent murine model of experimental anti-glomerular basement membrane (anti-GBM) GN was tested. Transfer of 1 x 10(6) CD4+CD25+ T cells (day -1) into mice that were previously immunized with rabbit IgG (day -3) and subsequently received an injection of anti-GBM rabbit serum (day 0) significantly attenuated the development of proteinuria when compared with animals that received an injection of 1 x 10(6) CD4+CD25- T cells (control group). Treg injection induced a dramatic decrease of glomerular damage as well as a marked decrease of CD4+ T cell, CD8+ T cell, and macrophage infiltration. Of note, deposition of immune complexes was not prevented by Treg, showing that Treg rather inhibited cell-mediated organ damage than priming of the humoral immune response. Accordingly, a significant reduction of IFN-gamma, TNF-alpha, and TGF-beta1 mRNA in kidneys from animals that received Treg injection was observed. Tracking of enhanced green fluorescence protein-transgenic Treg revealed a predominant migration to secondary lymphoid organs with a significant increase of regulatory T cells (CD4+CD25+CD69-CD45RB(low)) in the lymph nodes. In contrast, enhanced green fluorescence protein-and FoxP3-positive cells by reverse transcription-PCR and CD4+CD25+CD69-CD45RB(low) T cells by flow cytometry in the kidney of nephritic animals were not detected. This report provides first evidence that Treg are potent suppressors of anti-GBM GN. Treg therefore might be of therapeutic value for the treatment of severe GN in humans.
Wolf
Dominik
D
Clinical Division of Hematology and Oncology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
Hochegger
Kathrin
K
Wolf
Anna M
AM
Rumpold
Holger F
HF
Gastl
Guenther
G
Tilg
Herbert
H
Mayer
Gert
G
Gunsilius
Eberhard
E
Rosenkranz
Alexander R
AR
D019264:Adoptive Transfer; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D001323:Autoantibodies / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007165:Immunosuppression Therapy / Q000379:methods; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; D015704:CD4 Antigens; D015375:Receptors, Interleukin-2