Therapeutic Modulation of Experimental Autoimmune Encephalomyelitis by Gamma Secretase Inhibition




Cummings, Matthew Aaron

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The acquisition of pro-inflammatory phenotypes constitutes a checkpoint in the progression toward autoimmunity. Small molecule inhibitors of γ-secretase (γSI) have been shown to suppress TH1 differentiation and reduce the severity of experimental autoimmune encephalomyelitis (EAE), presumably by affecting Notch signaling. To understand the mechanisms through which γSI alter autoimmune T cell responses, we utilized an adoptive transfer model of EAE. We found that γSI treatment in vivo reduced EAE severity after adoptive transfer of myelin-specific TCR-transgenic T cells. This was accompanied with a decrease in the production of IFNγ by T cells ex-vivo. To determine the mechanisms of reduced EAE, we tested the effects of γSI on TH1 and TH17 differentiation. Culture with γSI reduced the expression of IFNγ and IL-17 without altering T cell activation or proliferation. The expression of Tbet and RORgt was strongly reduced by γSI while the number of FoxP3-expressing T cells increased. Additionally the in vitro treatment of naïve CD4+ T cells with γSI during TH17 induction prevented adoptive EAE. Taken together, these results suggested that γSI regulate effector T cell responses by preventing TH1 and TH17 differentiation and promoting the generation of regulatory T cells.

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