Rapamycin inhibits relapsing experimental autoimmune encephalomyelitis by both effector and regulatory T cells modulation

Abstract 

Rapamycin is an oral immunosuppressant drug previously reported to efficiently induce naturally occurring CD4⁺CD25⁺FoxP3⁺ regulatory T (_nT_reg) cells re-establishing long-term immune self-tolerance in autoimmune diseases. We investigated the effect of rapamycin administration to SJL/j mice affected by PLP_139–151-induced relapsing–remitting experimental autoimmune encephalomyelitis (RR-EAE). We found that oral or intraperitoneal treatment at the peak of disease or at the end of the first clinical attack, dramatically ameliorated the clinical course of RR-EAE. Treatment suspension resulted in early reappearance of disease. Clinical response was associated with reduced central nervous system demyelination and axonal loss. Rapamycin induced suppression of IFN-γ, and IL-17 release from antigen-specific T cells in peripheral lymphoid organs. While CD4⁺FoxP3⁺ cells were unaffected, we observed disappearance of CD4⁺CD45RB^high effector T (T_eff) cells and selective expansion of T_reg cells bearing the CD4⁺CD45RB^lowFoxP3⁺CD25⁺CD103⁺ extended phenotype. Finally, the dual action of rapamycin on both T_eff and T_reg cells resulted in modulation of their ratio that closely paralleled disease course. Our data show that rapamycin inhibits RR-EAE, provide evidence for the immunological mechanisms, and indicate this compound as a potential candidate for the treatment of multiple sclerosis.

Keywords: T regulatory cells, EAE, Multiple sclerosis, Rapamycin, FoxP3