International Immunology Advance Access published online on August 13, 2007
International Immunology, doi:10.1093/intimm/dxm078
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Anti-thymocyte globulin (ATG) prevents autoimmune encephalomyelitis by expanding myelin antigen-specific Foxp3+ regulatory T cells
1 Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, HIM 780, Boston, MA 02115, USA
2 U.S. Scientific Development, Genzyme Corporation, Framingham, MA 01701, USA
3 Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Correspondence to: Correspondence to: M. Oukka; E-mail: moukka{at}rics.bwh.harvard.edu
The T cell-depleting polyclonal antibody, anti-thymocyte globulin (ATG) has long been used in organ transplantation to treat acute rejection episodes. More recently, it is also being used as part of an induction regimen to protect allografts. It has been proposed that ATG might deplete effector T cells (T-effs) while sparing regulatory T cells (T-regs). In order to test whether ATG is effective in autoimmune disease, we used Foxp3gfp ‘knock-in’ mice in combination with a myelin oligodendrocyte glycoprotein (MOG)35–55/IAb tetramer to study more closely the effect of ATG treatment on antigen-specific T cell responses in vivo during MOG-induced experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple Sclerosis. ATG treatment enhanced the expansion of MOG-specific T-regs (CD4+Foxp3+) in MOG-immunized mice. T-effs were depleted, but on a single-cell basis, the effector function of residual T-effs was not compromised by ATG. Thus, ATG tipped the balance of T-effs and T-regs and skewed an auto-antigen-specific immune reaction from a pathogenic T cell response to a potentially protective T-reg response. In both acute and relapsing remitting disease models, ATG treatment resulted in the attenuation from EAE, both in a preventive and early therapeutic setting. We conclude that ATG treatment enforces the development of a dominant immunoregulatory environment which may be advantageous for the treatment of T cell-driven autoimmune diseases.
Keywords: anti-thymocyte globulin, T-reg cell, antigen-specific, EAE, multiple sclerosis
* These authors contributed equally to this study.
Received 20 March 2007, accepted 30 May 2007.
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