Mechanism of interferon therapy of multiple sclerosis: Studies in an animal model

Interferon (IFN) tau is a type I EFN that was originally identified as a pregnancy recognition hormone produced by trophoblast cells. It is as potent an antiviral agent as IFNalpha and EFNbeta, but lacks the toxicity associated with high concentrations of these IFNs in tissue culture and in animal studies. Previously it has been shown that interferon tau pretreatment inhibits the development of both acute and chronic mouse experimental allergic encephalomyelitis (EAE), an animal model for the human demyelinating disease multiple sclerosis (MS). Here, we show that IFNtau induced remission in SJL/J mice that had ongoing chronic active EAE disease, and protected mice against secondary relapses. IFNtau treatment reversed lymphocyte infiltration and microglial activation in the central nervous system. Mice that were treated with IFNtau had lower levels of anti-MBP (myelin basic protein) antibodies than untreated mice in both chronic and acute forms of EAE. MBP induced proliferation in B cells from EAE mice, but treatment with IFNtau either in vivo or in vitro blocked this activation. Furthermore, IFNtau inhibited MEBP activation of T cells from EAE mice. Thus, IFNtau inhibits the humoral arm as well as the cellular arm of the autoimmune disease EAR IFNtau prevents EAE in mice by induction of suppressor cells and suppressor factors. Suppressor cells can be induced by IFNtau in tissue culture and in vivo by either intraperitoneal injection or by oral administration to mice. Incubation of suppressor cells with MBP-sensitized T cells blocked or delayed the MBP-induced proliferation. Further, intraperitoneal injection of suppressor cells into mice blocked induction of EAE by MBP. Suppressor cells possessed the CD4 T cell phenotype, and produced soluble suppressor factors that inhibited MBP activation of T cells from EAE mice. The suppressor factors were found to be IL-10 and TGFbeta, which acted synergistically to inhibit the MBP activation of T cells from EAE mice. These findings are important for understanding the mechanism(s) by which type I IFNs protect against autoimmune disease.