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Therapeutic benefit of treatment with anti-thymocyte globulin and latent TGF-β1 in the MRL/lpr lupus mouse model

Immunotherapy Research Department, Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA johanne.kaplan{at}genzyme.com

L Woodworth

Immunotherapy Research Department, Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA

K Smith

Immunotherapy Research Department, Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA

J Coco

Immunotherapy Research Department, Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA

A Vitsky

Immunotherapy Research Department, Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA

JM McPherson

Immunotherapy Research Department, Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA

The pathogenesis of systemic lupus erythematosus is believed to involve defects in regulatory T cell (Treg) activity and abnormal activation of B and T lymphocytes. The purpose of this study was to test the therapeutic potential of rabbit anti-mouse thymocyte globulin (ATG), a lymphocyte-depleting agent, in conjunction with transforming growth factor (TGF)-β1, a factor involved in the induction and expansion of Tregs. MRL/lpr mice with active disease were treated with ATG followed by a 12-day course of latent TGF-β1 during the period of lymphocyte repopulation. Treatment with ATG + latent TGF-β1 synergistically inhibited the progression of proteinuria and albuminuria and provided a significant improvement in long-term survival. This therapeutic benefit correlated histologically with reduced glomerular pathology and protein cast formation. The mechanism of action did not involve suppression of autoantibody formation but may involve the activity of CD4⁺CD25⁺FoxP3⁺ Tregs, which were found to be induced by ATG + TGF-β1 treatment in vitro.

Key Words: Lupus • TGF-β • Treg or regulatory T cells • anti-thymocyte globulin • MRL/lpr

Lupus, Vol. 17, No. 9, 822-831 (2008)
DOI: 10.1177/0961203308091635


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