UC San Diego

Multiple sclerosis (MS) is an autoimmune disease that results in demyelination and neurodegeneration of the central nervous system (CNS). This disease has a chronic progressive or a relapsing course that is partially recapitulated in murine models such as experimental autoimmune encephalomyelitis (EAE). Toll-like receptors (TLRs) are a family of pattern-recognition receptors (PRRs) that mediates the innate and adaptive immune responses. TLR tolerance is a phenomenon in which repeated stimulation of a TLR will lead to hyporesponsiveness. To test the potential for TLR7 hyporesponsiveness to limit CNS inflammation, SJL/J mice immunized with proteolipid protein (PLP)139-151 were treated with the synthetic TLR7 agonist 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, designated here as 1V136). Daily low-dose 1V136 treatment significantly decreased disease severity. Concordantly, the number of spinal cord (SC)-infiltrating immune cells was significantly reduced in 1V136-treated mice. A microglia-enriched cell population tested for response to TLR agonists confirmed that 1V136 treatment induces hyporeponsiveness to subsequent TLR7 stimulation. Splenocytes from 1V136-treated mice exhibited a specific decrease in interleukin (IL)-17 and interferon (IFN)- [gamma] secretion. Serum samples from 1V136-treated mice showed no difference in the humoral immune response. In summary, chronic treatment with 1V136 can induce innate immune system hyporesponsiveness and inhibit a normal adaptive immune response. The direct effects of 1V136 on the CNS may contribute to a reduction in the clinical severity of a murine model of MS