myelin-proteolipid-protein-(178-191) and Inflammation

T cell receptor engagement and the B7-CD28 / CTLA-4 signaling pathways play critical roles in T cell activation and regulation. CD28 engagement results in T cell activation, differentiation and survival while CTLA-4 signals block IL-2 production, cell cycle progression and T cell differentiation. We explored the role of CTLA-4 in peripheral tolerance induced by intravenous administration of ethylene carbodiimide-fixed, antigen-coupled splenocytes in the PLP139 - 151-induced relapsing experimental autoimmune encephalomyelitis system. Tolerance induction with PLP139 - 151-coupled splenocytes correlates with low B7 expression on the fixed antigen-presenting cells, conditions that would favor CTLA-4-mediated inhibition. Administration of CTLA-4Ig or anti-CTLA-4 concomitant with the 'tolerogenic' stimulus, however, failed to reverse tolerance induction. In contrast, blocking CTLA-4 at the time of secondary 'immunogenic' encounter with antigen reversed the tolerant state. These findings indicate that CTLA-4 is required to maintain the unresponsive state of the tolerized T cells upon antigenic stimulation under inflammatory conditions and, therefore, have important implications for therapeutic regulation of autoimmune disease.

Topics: Abatacept; Amino Acid Sequence; Animals; Antigens, CD; Antigens, Differentiation; Autoantigens; Autoimmune Diseases; B7-1 Antigen; B7-2 Antigen; Capsid; Capsid Proteins; Cells, Cultured; Clonal Anergy; CTLA-4 Antigen; Encephalomyelitis, Autoimmune, Experimental; Female; Hypersensitivity, Delayed; Immune Tolerance; Immunization; Immunoconjugates; Inflammation; Lymphocyte Activation; Membrane Glycoproteins; Mice; Mice, Mutant Strains; Molecular Sequence Data; Myelin Basic Protein; Myelin Proteolipid Protein; Ovalbumin; Peptide Fragments; Receptors, Antigen, T-Cell; Specific Pathogen-Free Organisms; T-Lymphocyte Subsets; Thymectomy

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