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Ex Vivo Generated Regulatory T Cells Modulate Experimental Autoimmune Myasthenia Gravis¹

Revital Aricha^*, Tali Feferman^*, Sara Fuchs^2,* and Miriam C. Souroujon^*,

^* Department of Immunology, The Weizmann Institute of Science, Rehovot; and Department of Natural Sciences, The Open University of Israel, Raanana, Israel

Naturally occurring CD4⁺CD25⁺ regulatory T (Treg) cells are key players in immune tolerance and have therefore been suggested as potential therapeutic tools for autoimmune diseases. In myasthenia gravis (MG), reduced numbers or functionally impaired Treg cells have been reported. We have observed that PBL from myasthenic rats contain decreased numbers of CD4⁺CD25^highFoxp3⁺ cells as compared with PBL from healthy controls, and we have tested whether Treg cells from healthy donors can suppress experimental autoimmune MG in rats. Because the number of naturally occurring Treg cells is low, we used an approach for a large-scale ex vivo generation of functional Treg cells from CD4⁺ splenocytes of healthy donor rats. Treg cells were generated ex vivo from CD4⁺ cells by stimulation with anti-CD3 and anti-CD28 Abs in the presence of TGF-β and IL-2. The obtained cells expressed high levels of CD25, CTLA-4, and Foxp3, and they were capable of suppressing in vitro proliferation of T cells from myasthenic rats in response to acetylcholine receptor, the major autoantigen in myasthenia. Administration of ex vivo-generated Treg cells to myasthenic rats inhibited the progression of experimental autoimmune MG and led to down-regulation of humoral acetylcholine receptor-specific responses, and to decreased IL-18 and IL-10 expression. The number of CD4⁺CD25⁺ cells in the spleen of treated rats remained unchanged, but the subpopulation of CD4⁺CD25⁺ cells expressing Foxp3 was significantly elevated. Our findings imply that Treg cells play a critical role in the control of myasthenia and could thus be considered as potential agents for the treatment of MG patients.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from The Muscular Dystrophy Association of America, The Association Française Contre les Myopathies, The European Commission (Grants QLG1-CT-2001-10918, QLRT-2001-00225, and LSHN-CT-2006-037833), and The Wood-Byer Foundation.

² Address correspondence and reprint requests to Dr. Sara Fuchs, Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. E-mail address: sara.fuchs{at}weizmann.ac.il

³ Abbreviations used in this paper: MG, myasthenia gravis; AChR, acetylcholine receptor; EAMG, experimental autoimmune MG; Treg cell, regulatory T cell; evCD4⁺CD25⁺, ex vivo-generated CD4⁺CD25⁺; nCD4⁺CD25⁺, naturally occurring CD4⁺CD25⁺; nCD4⁺CD25^–, naturally occurring CD4⁺CD25^–.

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