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LF 15-0195 Treatment Protects against Central Nervous System Autoimmunity by Favoring the Development of Foxp3-Expressing Regulatory CD4 T Cells¹

Valérie Duplan^2,*, Gaëlle Beriou^2,, Jean-Marie Heslan, Corinne Bruand^*, Patrick Dutartre, Lennart T. Mars^*, Roland S. Liblau^*, Maria-Cristina Cuturi and Abdelhadi Saoudi^3,*

^* Institut National de la Santé et de la Recherche Médicale Unité 563, Institut Fédératif de recherche 30, and Université Paul Sabatier, Hôpital Purpan, Toulouse, France; Institut National de la Santé et de la Médicale Unité 643 and Institut de Transplantation et de Recherche en Transplantation, Centre Hospitalier Universitaire Hôtel-Dieu, Nantes, France; and Laboratoires Fournier, Daix, France

Experimental autoimmune encephalomyelitis (EAE) is an instructive model for the human demyelinating disease multiple sclerosis. Lewis (LEW) rats immunized with myelin-basic protein (MBP) develop EAE characterized by a single episode of paralysis, from which they recover spontaneously and become refractory to a second induction of disease. LF 15-0195 is a novel molecule that has potent immunosuppressive effects in several immune-mediated pathological manifestations, including EAE. In the present study, we show that a 30-day course of LF 15-0195 treatment not only prevents MBP-immunized LEW rats from developing EAE but also preserves their refractory phase to reinduction of disease. This effect is Ag driven since it requires priming by the autoantigen during the drug administration. In contrast to other immunosuppressive drugs, short-term treatment with this drug induces a persistent tolerance with no rebound of EAE up to 4 mo after treatment withdrawal. This beneficial effect of LF 15-0195 on EAE does not result from the deletion of MBP-specific V8.2 encephalitogenic T cells. In contrast, this drug favors the differentiation of MBP-specific CD4 T cells into Foxp3-expressing regulatory T cells that, upon adoptive transfer in syngeneic recipients, prevent the development of actively induced EAE. Finally, we demonstrate that the tolerance induced by LF 15-0195 treatment is not dependent on the presence of TGF-. Together, these data demonstrate that short-term treatment with LF 15-0195 prevents MBP-immunized LEW rats from EAE by favoring the development of Foxp-3-expressing regulatory CD4 T cells.

This article has been cited by other articles:

				R. A. O'Connor, K. H. Malpass, and S. M. Anderton The Inflamed Central Nervous System Drives the Activation and Rapid Proliferation of Foxp3+ Regulatory T Cells J. Immunol., July 15, 2007; 179(2): 958 - 966. [Abstract] [Full Text] [PDF]