Abstract
Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination and consequent neuron injury. Although the pathogenesis of MS is largely unknown, a breach in immune self-tolerance to myelin followed by development of autoreactive encephalitogenic T cells is suggested to play the central role. The myelin basic protein (MBP) is believed to be one of the main targets for autoreactive lymphocytes. Recently, immunodominant MBP peptides encapsulated into the mannosylated liposomes, referred as Xemys, were shown to suppress development of experimental autoimmune encephalomyelitis, a rodent model of MS, and furthermore passed the initial stage of clinical trials. Here, we investigated the role of individual polypeptide components [MBP peptides 46–62 (GH17), 124–139 (GK16), and 147–170 (QR24)] of this liposomal peptide therapeutic in cytokine release and activation of immune cells from MS patients and healthy donors. The overall effects were assessed using peripheral blood mononuclear cells (PBMCs), whereas alterations in antigen-presenting capacities were studied utilizing plasmacytoid dendritic cells (pDCs). Among three MBP-immunodominant peptides, QR24 and GK16 activated leukocytes, while GH17 was characterized by an immunosuppressive effect. Peptides QR24 and GK16 upregulated CD4 over CD8 T cells and induced proliferation of CD25+ cells, whereas GH17 decreased the CD4/CD8 T cell ratio and had limited effects on CD25+ T cells. Accordingly, components of liposomal peptide therapeutic differed in upregulation of cytokines upon addition to PBMCs and pDCs. Peptide QR24 was evidently more effective in upregulation of pro-inflammatory cytokines, whereas GH17 significantly increased production of IL-10 through treated cells. Altogether, these data suggest a complexity of action of the liposomal peptide therapeutic that does not seem to involve simple helper T cells (Th)-shift but rather the rebalancing of the immune system.
Highlights
Multiple sclerosis (MS) is an autoimmune disease of unknown etiology affecting 2.5 million people worldwide between the ages of 20 and 50 and is histologically characterized by axonial demyelinization and neuronal death [1]
To study the effect of myelin basic protein (MBP) peptides from the liposomal peptide therapeutic on the expression of surface activation markers, purified peripheral blood mononuclear cells (PBMCs) from MS and HDs were incubated with individual peptides GH17, GK16, and QR24 and further stained for human leukocyte antigen (HLA-DR), CD4, CD8, CD25, and CD80 (Figure 1)
The number of HLA-DR+ cells in PBMCs from HDs changed from 2.1% (PBS) to 1.5, 2.3, and 4.6% on incubation with GH17, GK16, and QR24, respectively
Summary
Multiple sclerosis (MS) is an autoimmune disease of unknown etiology affecting 2.5 million people worldwide between the ages of 20 and 50 and is histologically characterized by axonial demyelinization and neuronal death [1]. It is believed that loss of the myelin is the result of the appearance of a pool of myelin-reactive lymphocytes [2] occurring due to the breakage of immune tolerance [3]. Studies using animal models confirmed the essential role of one of the major components of the myelin sheath, the myelin basic protein (MBP), in MS pathogenesis, as transfer of MBP-sensitized T cells induced experimental autoimmune encephalomyelitis (EAE), a disease in mice similar to MS [4]. Huseby et al demonstrated that the MBP-specific CD8+ T cells can trigger severe EAE [7], suggesting that autoimmune neurodegeneration may be mediated by CD8+ lymphocytes as well. Direct evidence of existence of myelin-specific cytotoxic lymphocytes targeting oligodendrocytes in vitro has been reported [8], supporting the importance of MBP in the pathogenesis of MS
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