Cytokines and Murine Autoimmune Encephalomyelitis: Inhibition or Enhancement of Disease with Antibodies to Select Cytokines, or by Delivery of Exogenous Cytokines Using a Recombinant Vaccinia Virus System

Abstract

To examine the complex role of cytokines in the pathogenesis of actively induced murine EAE we measured the levels of a number of cytokines (IL-6, IFN gamma and TNF) in the spinal cord and CSF of mice with active experimental autoimmune encephalomyelitis (EAE) and found them all to be elevated. We next treated mice with antibodies to these three cytokines, which were over expressed in the CNS, to determine if they would alter disease and found the following: anti-IL-6 had no significant effect on disease, anti-IFN gamma exacerbated disease, and anti-TNF either enhanced, had no effect or inhibited EAE depending on the antibody used. We then treated mice with exogenous cytokines, delivered using a recombinant vaccinia virus system, and found that the IL-6 and TNF virus constructs inhibited EAE whereas the IFN gamma construct had no effect on disease. Other cytokine recombinant viruses were also tested and it was found that the IL-1 beta, IL-2 and IL-10 viruses inhibited EAE while an IL-4 virus either had no effect or enhanced disease. We do not know the mechanism of action of the various cytokines in this system, but irrespective of the mechanism(s), this work clearly demonstrates that delivery of select cytokines using recombinant virus-cytokine constructs can provide a powerful means of down-regulating experimental organ-specific autoimmune disease.

Amelioration of Experimental Autoimmune Encephalomyelitis in IL-4Rα−/− Mice Implicates Compensatory Up-Regulation of Th2-Type Cytokines

“…IL-6 displays dual pro-and anti-inflammatory roles, depending on its origin, amount, and presence of other cytokines. 38 In the context of EAE, results vary with those of Willenborg and colleagues 39 showing that application of exogenous IL-6 inhibited EAE, whereas Gijbels and colleagues 40 reported that administration of neutralizing antibodies to IL-6 reduced EAE. Although initially thought to be proinflammatory, 41 many studies indicate that IL-6 has prominent anti-inflammatory and immunosuppressive effects and may negatively regulate the acute phase response.…”

IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis

“…Gijbels et al (19) reported that treatment of anti-IL-6 antibody was protective against the development of EAE. By contrast, Willenborg et al (20) reported that anti-IL-6 therapy has no significant protective effect in EAE. Therefore, the role of IL-6 in EAE remains unclear.…”

Cytokine gene therapy of autoimmune demyelination revisited using herpes simplex virus type-1-derived vectors

“…19 There is only one report dealing with the therapeutic efficacy of systemic injection of viral vectors engineered with cytokine genes in mice affected by EAE. 28 Viral vectors derived from the WR strain of vaccinia virus (VV) and engineered to produce IL-6, TNF␣, IL-1␤, IL-2, IL-10, IL-4 or IFN␥ were intravenously injected, at the time of immunization and 6 days later, in SJL/J or (SJL/J × BALB/C)F1 hybrid mice affected by syngeneic spinal cord homogenate-induced EAE. A disease ameliorating effect was observed in EAE mice when the IL-6, TNF␣, IL-1␤, IL-2, IL-10 but not IL-4 or IFN␥ gene-containing vectors were used.…”