Targeting the TCR: T-cell receptor and peptide-specific tolerance-based strategies for restoring self-tolerance in CNS autoimmune disease.
A principal theme in autoimmunity is the breakdown of central tolerance resulting in the persistence and eventual activation of autoreactive T cells. Because CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for the onset and progression of most autoimmune diseases, they are a logical target for therapeutic interventions. One technique for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T-cell activation. In this review, we discuss promising techniques with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of non-mitogenic anti-CD3 and peptide-specific tolerance strategies that specifically target the T-cell receptor (TCR) in the absence of costimulatory signals. These approaches produce a TCR signal of insufficient strength to cause CD4(+) T-cell activation and instead induce functional T-cell anergy or deletion while avoiding generalized long-term immunosuppression.
Kohm
Adam P
AP
Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Turley
Danielle M
DM
Miller
Stephen D
SD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D020274:Autoimmune Diseases of the Nervous System / Q000276:immunology / Q000628:therapy*; D017252:CD3 Complex / Q000276:immunology; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007167:Immunotherapy / Q000379:methods*; D018448:Models, Immunological; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy; D010455:Peptides / Q000276:immunology* / Q000627:therapeutic use; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2