Effective IFN-β therapy in B cell-independent EAE was associated with reduced inflammatory T cells in the CNS and skewed splenic B cells towards an immature population and away from a germinal center population.
Our present results show that a single injection of IFN-β at the onset of the clinical course reduces the severity of the EAE, enhancing the presence of MDSCs within the smaller demyelinated areas.
Therefore, CatH deficiency impaired TLR3-mediated activation of IRF3 and consequent secretion of IFN-β from dendritic cells, leading to the enhancement of Th1 cell differentiation and consequent early disease onset of EAE.
Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β.
Moreover, in our in vivo experiments, the gene transfer of IFN-β-gal-9 fusion protein-expressing plasmid DNA into EAE mice showed beneficial therapeutic effects without cytopenia, a known side effect of IFN-β.
Gene therapy was found to be more effective than cell therapy in ameliorating several clinical parameters in both EAE models, presumably due to the continuous expression of IFN-β.
An evaluation of blood-brain barrier (BBB) function, using Evans Blue, showed that injection of pMx-IFN-β suppressed the BBB disruptions normally observed in EAE mice, while BBB disruptions remained evident in the untreated EAE mice.
Passive transfer-EAE via IFNβ-competent T<sub>enc</sub> cells to mice lacking IFNβ and active induced-EAE in mice lacking its receptor, IFNAR, in the brain (Nes<sup>Cre</sup>:Ifnar<sup>fl/fl</sup>) result in defective FoxA1<sup>+</sup>T<sub>regs</sub> generation and aggravated neuroinflammation.
We found that strong activation of innate immunity induced Nod-like receptor protein 3 (NLRP3) inflammasome-independent and interferon-β (IFNβ)-resistant EAE (termed type B EAE), whereas EAE induced by weak activation of innate immunity requires the NLRP3 inflammasome and is sensitive to IFNβ treatment.
Taken together, we showed that using AD-MSCs expressing IFN-β as an anti-inflammatory agent, offer evidence supporting that the stem cell therapies in EAE conceivably will improve the valuable effects of IFN-β in this autoimmune disease.
Importantly, injected MSCs-IFN β migrated into inflamed CNS and significantly reduced further injury of blood-brain barrier (BBB) permeability in EAE mice.
Resultant N-terminal truncated IFN mimetics functioned intracellularly as antivirals as well as therapeutics against experimental allergic encephalomyelitis without the undesirable side effects that limit the therapeutic efficacy of IFNβ in treatment of multiple sclerosis.
The potentiation of IFN-β expression by R(+)WIN55,212-2 is critical for manifesting its protective effects in the murine MS model EAE as evidenced by its reduced therapeutic efficacy in the presence of an anti-IFN-β antibody.
Complementary in vivo studies in a mouse model showed that treatment with IFN-β enhanced expression of IL-27, and reduced IL-17 in the CNS and periphery and attenuated the clinical signs of experimental autoimmune encephalomyelitis (EAE).