Mannan-MOG35-55 Reverses Experimental Autoimmune Encephalomyelitis, Inducing a Peripheral Type 2 Myeloid Response, Reducing CNS Inflammation, and Preserving Axons in Spinal Cord Lesions

Abstract

CNS autoantigens conjugated to oxidized mannan (OM) induce antigen-specific T cell tolerance and protect mice against autoimmune encephalomyelitis (EAE). To investigate whether OM-peptides treat EAE initiated by human MHC class II molecules, we administered OM-conjugated murine myelin oligodendrocyte glycoprotein peptide 35-55 (OM-MOG) to humanized HLA-DR2b transgenic mice (DR2b.Ab°), which are susceptible to MOG-EAE. OM-MOG protected DR2b.Ab° mice against MOG-EAE by both prophylactic and therapeutic applications. OM-MOG reversed clinical symptoms, reduced spinal cord inflammation, demyelination, and neuronal damage in DR2b.Ab° mice, while preserving axons within lesions and inducing the expression of genes associated with myelin (Mbp) and neuron (Snap25) recovery in B6 mice. OM-MOG-induced tolerance was peptide-specific, not affecting PLP178-191-induced EAE or polyclonal T cell proliferation responses. OM-MOG-induced immune tolerance involved rapid induction of PD-L1- and IL-10-producing myeloid cells, increased expression of Chi3l3 (Ym1) in secondary lymphoid organs and characteristics of anergy in MOG-specific CD4+ T cells. The results show that OM-MOG treats MOG-EAE in a peptide-specific manner, across mouse/human MHC class II barriers, through induction of a peripheral type 2 myeloid cell response and T cell anergy, and suggest that OM-peptides might be useful for suppressing antigen-specific CD4+ T cell responses in the context of human autoimmune CNS demyelination.

The Efficacy of Fecal Microbiota Transplantation in Experimental Autoimmune Encephalomyelitis: Transcriptome and Gut Microbiota Profiling

“…Edil3 has been shown to act as an endogenous homeostasis factor in the central nervous system, protecting neuroinflammation and demyelination through the IL-17/neutrophil inflammatory axis [ 51 ]. Snap25 plays a critical role in synaptic function and is considered an important indicator of neuronal recovery after EAE treatment [ 52 ]. Nrn1 is involved in the survival and differentiation of nerve cells, the growth of axons and dendrites, and the formation and maturation of synapses.…”

Novel Approaches in the Immunotherapy of Multiple Sclerosis: Cyclization of Myelin Epitope Peptides and Conjugation with Mannan

“…Mannan targets antigens to the mannose receptor, antigens endocytosed for MHC class I or II presentation, and modulation of appropriate T cells [45,[53][54][55][76][77][78][79][80][81]. In relation to autoimmune disorders, mannan conjugates (i) represent a new class of immunoregulators that directly and selectively target a population of immune cells that are implicated in the pathogenesis and progression of disease; (ii) provide first line treatment that selectively tolerates or inactivates disease-inducing cells in patients and also prevents progression of disease by stopping diversification of the autoimmune response to additional epitopes; (iii) allows easier formulation of newly discovered molecules within the mannan matrix platform; and (iv) can achieve block-buster status as a global vaccine drug for efficient treatment of MS [27][28][29][30]. The cyclic-MOG 35-55 peptide, cyclized at the C-and N-terminal amino acids (cyclic-MOG 35-55 ), altered the 3D conformation of the linear MOG 35-55 peptide (Figure 5).…”

“…Results show that mannan-conjugated myelin peptides protect mice against EAE through the expansion of antigen-specific Th1 and Th17 cells with impaired proliferation responses and DC-induced co-stimulatory signals that are required for licensing them to become fully pathogenic T cells [ 28 ]. In another study by Dagkonaki et al [ 29 ], CNS autoantigens conjugated to oxidized mannan were shown to induce antigen-specific T cell tolerance and protection against EAE in mice ( Table 1 ). The results showed that peptides conjugated with mannan induce peripheral type 2 myeloid cell responses and T cell anergy, and suggests that mannan-peptide conjugates may be useful for suppressing antigen-specific CD4+ T-helper cell responses in the context of human autoimmune CNS demyelination [ 29 ].…”

“…In another study by Dagkonaki et al [ 29 ], CNS autoantigens conjugated to oxidized mannan were shown to induce antigen-specific T cell tolerance and protection against EAE in mice ( Table 1 ). The results showed that peptides conjugated with mannan induce peripheral type 2 myeloid cell responses and T cell anergy, and suggests that mannan-peptide conjugates may be useful for suppressing antigen-specific CD4+ T-helper cell responses in the context of human autoimmune CNS demyelination [ 29 ].…”

“…The utilized strategies to approach the disease are (Figure 1): (a) Use linear MBP, PLP, and MOG epitopes with or without amino acid mutations to gain insights into the molecular basis of the disease. This information is aided by nuclear magnetic resonance (NMR) studies and structural information of the epitope ligand bound to the MHC [19]; (b) Perform cyclization of these epitopes to increase their stability [20][21][22][23][24][25][26]; (c) Conjugate selective epitopes with mannan [27][28][29][30]; (d) Synthesis of non-peptide mimetic analogs to decrease their flexibility and increase their therapeutic index; (e) Apply nanotechnology as a means of antigen delivery [31][32][33][34][35][36][37][38][39] Brain Sci. 2021, 11, x FOR PEER REVIEW 2 of 15 degenerative disease is initiated by autoreactive T helper (Th) cells and affects approximately 2.5 million people worldwide.…”