Soluble Mannosylated Myelin Peptide Inhibits the Encephalitogenicity of Autoreactive T Cells during Experimental Autoimmune Encephalomyelitis

Abstract

We have previously shown that immunization with a mannosylated myelin peptide in complete adjuvant induces tolerance instead of disease in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis. In this report we demonstrate that treatment with a soluble mannosylated epitope of proteolipid protein (M-PLP(139-151)) significantly inhibits disease mediated by autoreactive myelin-specific T cells during EAE. Treatment with M-PLP(139-151), applied in different EAE models, significantly reduced the incidence of disease and the severity of clinical symptoms. Delayed-type hypersensitivity responses were abolished after peptide treatment, emphasizing the impact on peripheral T-cell reactivity. Histological analysis of spinal cord tissue from mice treated with M-PLP(139-151) revealed the presence of only few macrophages and T cells. Moreover, little expression of interferon-gamma, interleukin-23, or major histocompatibility complex class II antigen was detected. Immune modulation by M-PLP(139-151) was primarily antigen-specific because an irrelevant mannosylated peptide showed no significant effect on delayed-type hypersensitivity responses or on the course of EAE. Therefore, mannosylated antigens may represent a novel therapeutic approach for antigen-specific modulation of autoreactive T cells in vivo.

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

“…First, antigen targeting toward the MR via antigen mannosylation has been demonstrated to induce antigen-specific T-cell tolerance (3). Such T-cell irresponsiveness has been shown to inhibit the development of experimental autoimmune encephalomyelitis after injection of mannosylated myelin peptide (4). Second, MR engagement on monocyte-derived DCs induces an immune-suppressive phenotype (32,33).…”

“…Because the induction of a strong cytotoxic T-cell response against tumor-specific antigens is a crucial process in many tumor vaccination strategies, antigen targeting toward the MR seemed to be a promising approach. However, in in vivo tumor models, antigen targeting toward the MR did not result in a strong cytotoxic T-cell response but, instead, led to the induction of antigen-specific T-cell tolerance (3,4). Therefore, we analyzed whether the MR has a regulatory effect on the induction of immune responses by means distinct from antigen uptake and presentation, and we investigated a direct influence of the MR on T-cell activation.…”

Mannan-conjugated myelin peptides prime non-pathogenic Th1 and Th17 cells and ameliorate experimental autoimmune encephalomyelitis

“…Also lymph node cells isolated 827 from mice that had been immunized with mannosylated PLP 139-151 828 showed equal cytokine and chemokine production but reduced prolifer-829 ation responses compared to cells primed with non-mannosylated 830 PLP 139-151 (Kel et al, 2008). This defect was associated with poor Th1 ef-831 fector functions as shown by reduced IgG2a antibody levels, reduced 832 DTH responses and EAE symptoms (Kel et al, 2007;Luca et al, 2005). 833 However, unlike tolerance induced by OM-MOG, which was resistant 834 to PTx, that induced by mannosylated peptides was abrogated by 835 PTx administration (Kel et al, 2008).…”

“…It most closely resembles tolerance induced by mannosylated 821 antigens, as previously described by Nagelkerken and his group. Like (Kel et al, 2007;Luca et al, 2005). Also lymph node cells isolated 827 from mice that had been immunized with mannosylated PLP 139-151 828 showed equal cytokine and chemokine production but reduced prolifer-829 ation responses compared to cells primed with non-mannosylated 830 PLP 139-151 (Kel et al, 2008).…”

“…In other approaches, peptide antigens were targeted 87 to the MR which is expressed at high levels on APC and captures and 88 presents soluble ligands with selectivity for heavily glycosylated proteins 89 on the surface of yeasts, bacteria and parasites (Sallusto et al, 1995). 90 Peptides that are mannosylated with added sugar units (Engering 91 et al, 1997;Tan et al, 1997) or chemically conjugated to the mannan 92 polysaccharide (Apostolopoulos et al, 2000) show greatly enhanced following immunization with PLP 139-151 (Kel et al, 2007(Kel et al, , 2008Luca 101 et al, 2005). These findings again support the participation of APC 102 in mediating tolerance to mannosylated self-antigens and indicate 103 that targeting antigens to MR may be a powerful strategy to suppress 104 autoimmune responses.…”