myelin-proteolipid-protein-(178-191) and Multiple-Sclerosis

Therapeutic success of B cell-targeting approaches in multiple sclerosis (MS) has intensified research into the pathogenic and regulatory roles these cells play in demyelinating disease. Dissecting the function of B cells in the MS mouse model experimental autoimmune encephalomyelitis (EAE) is largely confined to induction with either the myelin oligodendrocyte glycoprotein epitope MOG

Topics: Animals; B-Lymphocytes; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Protein Domains

Topics: Animals; Autoantigens; Autoimmunity; CD8-Positive T-Lymphocytes; Cells, Cultured; Central Nervous System; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Immune Tolerance; Interferon gamma Receptor; Interferon-gamma; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis; Myelin Proteolipid Protein; Myelin Sheath; Peptide Fragments; Receptors, Interferon

This study introduces a flexible format for tolerogenic vaccination that incorporates IFN-β and neuroantigen (NAg) in the Alum adjuvant. Tolerogenic vaccination required all three components, IFN-β, NAg, and Alum, for inhibition of experimental autoimmune encephalomyelitis (EAE) and induction of tolerance. Vaccination with IFN-β + NAg in Alum ameliorated NAg-specific sensitization and inhibited EAE in C57BL/6 mice in pretreatment and therapeutic regimens. Tolerance induction was specific for the tolerogenic vaccine Ag PLP178-191 or myelin oligodendrocyte glycoprotein (MOG)35-55 in proteolipid protein- and MOG-induced models of EAE, respectively, and was abrogated by pretreatment with a depleting anti-CD25 mAb. IFN-β/Alum-based vaccination exhibited hallmarks of infectious tolerance, because IFN-β + OVA in Alum-specific vaccination inhibited EAE elicited by OVA + MOG in CFA but not EAE elicited by MOG in CFA. IFN-β + NAg in Alum vaccination elicited elevated numbers and percentages of FOXP3

Topics: Adjuvants, Immunologic; Alum Compounds; Animals; Bystander Effect; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental; Forkhead Transcription Factors; Humans; Immune Tolerance; Interferon-beta; Interleukin-2 Receptor alpha Subunit; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Sclerosis; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; T-Lymphocytes, Regulatory; Vaccines

Studies of MS histopathology are largely dependent on suitable animal models. While light microscopic analysis gives an overview of tissue pathology, it falls short in evaluating detailed changes in nerve fiber morphology. The ultrastructural data presented here and obtained from studies of myelin oligodendrocyte glycoprotein (MOG):35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice delineate that axonal damage and myelin pathology follow different kinetics in the disease course. While myelin pathology accumulated with disease progression, axonal damage coincided with the initial clinical disease symptoms and remained stable over time. This pattern applied both to irreversible axolysis and early axonal pathology. Notably, these histopathological patterns were reflected by the normal-appearing white matter (NAWM), suggesting that the NAWM is also in an active neurodegenerative state. The data underline the need for neuroprotection in MS and suggest the MOG model as a highly valuable tool for the assessment of different therapeutic strategies.

Topics: Animals; Axons; Encephalomyelitis, Autoimmune, Experimental; Female; Kinetics; Lumbar Vertebrae; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Recombinant Fusion Proteins; Spinal Cord

Relapsing experimental autoimmune encephalomyelitis (R-EAE) in the SJL mouse is a Th1-mediated autoimmune demyelinating disease model for human multiple sclerosis and is characterized by infiltration of the central nervous system (CNS) by Th1 cells and macrophages. Disease relapses are mediated by T cells specific for endogenous myelin epitopes released during acute disease, reflecting a critical role for epitope spreading in the perpetuation of chronic central CNS pathology. We asked whether blockade of the CD40-CD154 (CD40L) costimulatory pathway could suppress relapses in mice with established R-EAE. Anti-CD154 antibody treatment at either the peak of acute disease or during remission effectively blocked clinical disease progression and CNS inflammation. This treatment blocked Th1 differentiation and effector function rather than expansion of myelin-specific T cells. Although T-cell proliferation and production of interleukin (IL)-2, IL-4, IL-5, and IL-10 were normal, antibody treatment severely inhibited interferon-gamma production, myelin peptide-specific delayed-type hypersensitivity responses, and induction of encephalitogenic effector cells. Anti-CD154 antibody treatment also impaired the expression of clinical disease in adoptive recipients of encephalitogenic T cells, suggesting that CD40-CD154 interactions may be involved in directing the CNS migration of these cells and/or in their effector ability to activate CNS macrophages/microglia. Thus, blockade of CD154-CD40 interactions is a promising immunotherapeutic strategy for treatment of ongoing T cell-mediated autoimmune diseases.

Topics: Animals; Antibodies; CD4-Positive T-Lymphocytes; CD40 Ligand; Cell Differentiation; Cell Division; Central Nervous System; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Hypersensitivity, Delayed; Immunotherapy; Inflammation; Interferon-gamma; Interleukins; Membrane Glycoproteins; Mice; Mice, Inbred Strains; Multiple Sclerosis; Myelin Proteolipid Protein; Myelin Sheath; Peptide Fragments; Th1 Cells

The synthetic amino acid copolymer, copolymer 1 (Cop 1) induces T suppressor (Ts) lines/clones, which are confined to the Th2 pathway, cross react with myelin basic protein (MBP), but not with other myelin antigens on the level of Th2 cytokine secretion. Nevertheless, Cop 1 Ts cells inhibited the IL-2 response of a proteolipid protein (PLP) specific line. Furthermore, Cop 1 Ts cells ameliorated EAE induced by two unrelated encephalitogenic epitopes of PLP: p139-151 and p178-191, that produced different forms of disease. This bystander suppression demonstrated by the Cop 1 Ts cells may explain the therapeutic effect of Cop 1 in EAE and MS.

Topics: Animals; Clone Cells; Cross Reactions; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Glatiramer Acetate; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteolipid Protein; Peptide Fragments; Peptides; Th2 Cells