Prospects for antigen-specific tolerance based therapies for the treatment of multiple sclerosis.
A primary focus in autoimmunity is the breakdown of central and peripheral tolerance resulting in the survival and eventual activation of autoreactive T cells. As CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for onset and progression of most autoimmune diseases, they are a logical target for therapeutic strategies. One method for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T cell activation. In this review, we discuss tolerance strategies with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of peptide-specific tolerance strategies, focusing on ethylene carbodiimide (ECDI)-peptide-coupled cells (Ag-SP) and nonmitogenic anti-CD3, which specifically target the T cell receptor (TCR) in the absence of costimulatory signals. These approaches induce a TCR signal of insufficient strength to cause CD4(+) T cell activation and instead lead to functional T cell anergy/deletion and activation of Ag-specific induced regulatory T cells (iTregs) while avoiding generalized long-term immunosuppression.
Turley
Danielle M
DM
Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Tarry 6-718, 303 E. Chicago Ave, Chicago, IL 60611, USA.
Miller
Stephen D
SD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001324:Autoantigens; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002234:Carbodiimides; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy; D006801:Humans; D018928:Immunity, Mucosal; D007165:Immunosuppression Therapy / Q000379:methods* / Q000639:trends; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy*; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017634:Self Tolerance; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D002234:Carbodiimides; D010455:Peptides; D011948:Receptors, Antigen, T-Cell