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The role of IL-2 in the activation and expansion of regulatory T-cells and the development of experimental autoimmune encephalomyelitis

Rouse, M;Nagarkatti, M;Nagarkatti, PS;

Multiple sclerosis (MS) is an autoimmune disease that affects 400,000 people in the US. It is a chronic, disabling disease with no cure, and the current treatment includes use of immunosuppressive drugs that often exhibit toxic side effects. Thus, there is a pressing need for alternate and more effective treatment strategies that target the components of inflammatory cells. In recent years, regulatory T-cells (Tregs) have been found to play an important role in preventing the development of autoimmunity. Thus, expansion of Tregs in vivo has the therapeutic potential against autoimmune diseases. Because Tregs constitutively express IL-2 receptors (IL-2Rs), we tested the effect of administration of IL-2 on the development of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). We used IL-2 both before (pre-treatment) or after (post-treatment) immunization with myelin oligodendrocyte glycoprotein (MOG35-55) peptide to induce EAE. The data demonstrated that pre-treatment with a moderate dose of IL-2 caused significant amelioration of EAE. Tissue histopathology of the central nervous system also confirmed the effectiveness of IL-2 pre-treatment by decreasing cellular infiltration in the spinal cord and preserving tissue integrity. IL-2 pretreatment expanded Treg cells while preventing the induction of Th17 during EAE development. In contrast, post-treatment with IL-2 failed to suppress EAE despite induction of Tregs. Together, these studies demonstrate that while expansion of Tregs using IL-2, prior to immunization or the onset of disease, can suppress the immune response, their role is limited after the antigen-specific response is triggered. Because IL-2 is used to treat certain types of cancers, and Tregs have applications in preventing the rejection of transplants, our studies also provide useful information on the use and limitations of Tregs in such clinical manifestations.