Infusion of Sulfosuccinimidyl-4-[N-maleimidomethyl]cyclohexane-1-carboxylate-Conjugated MOG35-55-Coupled Spleen Cells Effectively Prevents and Reverses Experimental Autoimmune Encephalomyelitis in Mice.

Lanfang Zhang,Yixian Guo,Chang-Qing Xia

doi:10.1155/2015/129682

Abstract

In this study, we have evaluated our recently developed method for antigen-cell coupling using sulfosuccinimidyl-4-[N-maleimidomethyl]cyclohexane-1-carboxylate (sulfo-SMCC) heterobifunctional crosslinker in prevention and reversal of experimental autoimmune encephalomyelitis (EAE). We demonstrate that infusion of MOG35–55-coupled spleen cells (MOG-SP) significantly prevents and reverses EAE. Further studies show that the protected animals exhibit significantly delayed EAE upon EAE reinduction. Moreover, adoptive transfer of CD4+ T cells from the protected mice to naïve syngeneic mice renders the recipient mice resistant to EAE induction. Unexpectedly, CD4+ T cell proliferation is similar upon ex vivo stimulation by MOG35–55 amongst all groups. However, further analysis of those proliferating CD4+ T cells shows remarkable differences in Foxp3+ regulatory T cells (70% in MOG-SP groups versus 10–25% in control groups) and in IL-17+ cells (2-3% in MOG-SP groups versus 6–9% in control groups). In addition, we discover that MOG-SP treatment also significantly attenuates MOG35–55-responding IFN-γ-producing Th1 cells. These findings suggest that MOG-SP treatment induces EAE protective MOG35–55-specific regulatory T cells and suppresses EAE pathogenic Th17 and Th1 cells. Our study provides a novel approach for antigen-based EAE immunotherapy, which can potentially be translated into clinical application for immunotherapy of multiple sclerosis.

Highlights

Experimental autoimmune encephalomyelitis (EAE) is an induced autoimmune disease of the central nervous system (CNS) in rodent animals with the features of inflammation, demyelination, axonal loss, and gliosis [1]
To avoid injection of late stage apoptotic cells, we placed ultraviolet B (UVB)-irradiated MOG35–55-coupled spleen cells (MOG-spleen cells (SPs)) on ice immediately after irradiation and injected the irradiated cells intravenously within 2 h to allow cell apoptotic process to start in vivo
As demonstrated in our previous study that majority of UVB-irradiated cells underwent apoptosis within 24 h [23], we found that if UVB-irradiated myelin oligodendrocyte glycoprotein (MOG)-SPs were left in culture for 24 h, 90–95% of them became dead cells at early or late stages

Summary

Introduction

Experimental autoimmune encephalomyelitis (EAE) is an induced autoimmune disease of the central nervous system (CNS) in rodent animals with the features of inflammation, demyelination, axonal loss, and gliosis [1]. EAE and human MS result from the breakdown of self-tolerance and are thought to be associated with increased self-reactive Th17 cells [4,5,6,7], as well as impaired regulatory T cells [8, 9]. Stephen Miller’s group developed an effective approach in preventing and treating EAE by infusion of spleen cells coupled with myelin proteins treated by ethylene carbodiimide (ECDI) [14, 15]. This therapy is effective in ameliorating other immunemediated disorders such as type 1 diabetes [16, 17] and allograft rejection [18].

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Conclusion