myelin-proteolipid-protein-(178-191) and Disease-Models--Animal

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

Altered peptide ligands (APLs) have routinely been studied in clonal populations of Th cells that express a single T cell receptor (TCR), but results generated in this manner poorly predict the effects of APLs on polyclonal Th cells in vivo, contributing to the failure of phase II clinical trials of APLs in autoimmune diseases such as multiple sclerosis (MS). We have used a panel of APLs derived from an encephalitogenic epitope of myelin proteolipid protein to investigate the relationship between antigen cross-reactivity in a polyclonal environment, encephalitogenicity, and the capacity of an APL to provide protection against experimental autoimmune encephalomyelitis (EAE) in SJL mice. In general, polyclonal Th cell lines specific for encephalitogenic APLs cross-reacted with other encephalitogenic APLs, but not with non-encephalitogenic APLs, and vice versa. This, alongside analysis of TCR Vβ usage, suggested that encephalitogenic and non-encephalitogenic subgroups of APLs expand largely non-cross-reactive Th cell populations. As an exception to the rule, one non-encephalitogenic APL, L188, induced proliferation in polyclonal CD4

Topics: Amino Acid Sequence; Animals; Antigen-Presenting Cells; Cell Proliferation; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Flow Cytometry; Freund's Adjuvant; Mice; Myelin Proteolipid Protein; Peptide Fragments; Receptors, Antigen, T-Cell, alpha-beta; RNA, Messenger; T-Lymphocytes; Th1 Cells

Interaction of very late antigen-4 (VLA-4) with its ligand vascular cell adhesion molecule-1 (VCAM-1) is required for central nervous system (CNS) migration of encephalitogenic T cells in relapsing experimental autoimmune encephalomyelitis (R-EAE). Anti-VLA-4 monoclonal antibody (mAb) treatment prior to EAE onset inhibits disease induction; however, treatment initiated after the appearance of clinical symptoms increases relapse rates, augments Th1 responses, and enhances epitope spreading perhaps due to the activation of costimulatory signals. To negate the potential costimulatory activity of intact anti-VLA-4, we examined the ability of BIO 5192, a small-molecule VLA-4 antagonist, to regulate active proteolipid protein 139-151 (PLP139-151)-induced R-EAE. BIO 5192 administered one week after peptide priming (ie, before clinical disease onset) delayed the clinical disease onset but led to severe disease exacerbation upon treatment removal. BIO 5192 treatment initiated during disease remission moderately enhanced clinical disease while mice were on treatment and also resulted in posttreatment exacerbation. Interestingly, BIO 5192 treatment begun at the peak of acute disease accelerated entrance into disease remission and inhibited relapses, but treatment removal again exacerbated disease. Enhanced disease was caused by the release of encephalitogenic cells from the periphery and the rapid accumulation of T cells in the CNS. Collectively, these results further demonstrate the complexity of VLA-4/VCAM interactions, particularly in a relapsing-remitting autoimmune disease.

Topics: Amino Acid Sequence; Animals; Blood-Brain Barrier; Cell Adhesion; Central Nervous System; Chemotaxis, Leukocyte; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Integrin alpha4beta1; Mice; Mice, Inbred Strains; Molecular Sequence Data; Multiple Sclerosis, Relapsing-Remitting; Myelin Proteolipid Protein; Oligopeptides; Peptide Fragments; Phenylurea Compounds; Recurrence; Th1 Cells; Vascular Cell Adhesion Molecule-1

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