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CD4⁺CD25⁺ Regulatory T Cells Inhibit Experimental Anti-Glomerular Basement Membrane Glomerulonephritis in Mice

Dominik Wolf^*, Kathrin Hochegger, Anna M. Wolf, Holger F. Rumpold^*, Guenther Gastl^*, Herbert Tilg, Gert Mayer, Eberhard Gunsilius^* and Alexander R. Rosenkranz

^* Clinical Division of Hematology and Oncology; Clinical Division of Nephrology, and Clinical Division of Gastroenterology and Hepatology, Clinical Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria

Address correspondence to: Dr. Alexander R. Rosenkranz, Innsbruck Medical University, Clinical Division of Nephrology, Anichstrasse 35, 6020 Innsbruck, Austria. Phone: +43-512-504-81333; Fax: +43-512-504-23309; E-mail: alexander.rosenkranz{at}uibk.ac.at

Received for publication October 9, 2004. Accepted for publication February 13, 2005.

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 10⁶ 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 10⁶ 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-, TNF-, and TGF-1 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.

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