Interleukin-11 is a Key Mediator of IVIg Therapy in Experimental Multiple Sclerosis

Background:  Intravenous immunoglobulin (IVIg) has been used as an “off-label” treatment for patients with relapse-remitting MS, and has shown to be beneficial by reducing relapse frequency, MRI lesions, and slowing disease progression. However, the unique capability of this drug to treat a wide variety of autoimmune disorders and lack of consensus behind its mechanism has contributed to increasing costs and demands. IVIg has been shown to successfully treat experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. In previous studies, we have demonstrated a unique finding, where a dramatic surge (>1000-fold increase) in interleukin-11 (IL-11) was observed post IVIg injection. Interestingly, IL-11 has been shown to play an important role in myelin formation and promoting oligodendrocyte survival. 

Objectives:  We hypothesize that induction of the anti-inflammatory and immune modulating IL-11 cytokine following IVIg treatment provides, at least in part, the effector mechanism for IVIg in experimental MS.

Methods:  EAE was induced and scored in wild-type (WT) and IL-11 receptor knockout mice (IL-11Rα^-/-), which were given either IVIg or human serum albumin (HSA) daily at a concentration of 1g/kg. Cell proliferation was assessed using 3H-thymidine and cytokine production was tested from cultures of spleen/lymph node cells.

Results:  IL-11 was found to be up-regulated at numerous time points in IVIg treated mice. No IL-11 was detected in mice treated with HSA. IVIg almost completely ameliorates EAE symptoms in WT mice, while HSA control mice showed a classic trend of relapse-remitting EAE. IL-11Rα^-/- mice showed resistance to the effects of IVIg and, unlike IVIg treated WT mice, had a higher incidence and severity of the disease compared to HSA. T cell proliferation was reduced by IVIg in both mouse groups. Although both WT and IL-11Rα^-/- mice showed down-regulation of pro-inflammatory cytokine production from IVIg treatment, effects on IL-17 were equivocal.

Conclusions:  The inability of IVIg to attenuate EAE in IL-11Rα^-/- mice suggests that, at least in part, the production of IL-11 is responsible for the IVIg amelioration of EAE. Although the mechanism of IL-11 remains unknown, our preliminary results suggest that it may play a role in suppression of IL-17 production and/or trafficking of antigen-specific T-cells. Our studies indicate that further research into the role of IL-11 production following IVIg therapy is warranted.