Targeting T cell costimulation in autoimmune disease.
Many factors contribute to the pathogenesis of autoimmune diseases. Targets for treating such debilitating diseases will become more apparent by understanding the nature of immune activation. This review examines the possibility of targeting costimulation and discusses the molecules found on the T cell and the antigen-presenting cell (APC) that participate in T cell activation. Although new molecules continue to be discovered, the functions of B7-1 (CD80), B7-2 (CD86), CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), inducible costimulator (ICOS), programmed death 1 (PD-1), OX 40 (CD134) and CD40 ligand (CD40L, CD154) are now sufficiently understood that immunologists are targeting them to manipulate T cells to slow the progression of autoimmune diseases or treat tumours through the increase in T cell activation. CD28, ICOS, OX 40 and CD40L are considered the costimulatory molecules that increase T cell activation. However, ICOS and OX 40 appear to act on memory cells while CD28 is predominantly a naive T cell activator. Most therapies in the treatment of autoimmunity that target these molecules work through blockade of their function with receptor specific immunoglobulin (Ig). CTLA-4 and PD-1 are considered to be the inhibitory T cell costimulators. While stimulating CTLA-4 has not been a widely used therapy, using soluble CTLA-4Ig to block B7 and disrupt the B7/CD28 pathway is fairly common. The majority of therapeutic use for PD-1 stems from targeting PD-1 with its natural ligand. It is hoped that therapies targeting costimulation may provide a means of conserving the patient's normal T cell repertoire and immune function whilst eliminating or suppressing autoreactive T cells and thus provide a more efficient means to treat autoimmune disease.
Stuart
Rodney W
RW
Department of Neurology and the Center for Immunology, University of Texas Southwestern, 5323 Harry Hines Blvd, Dallas, TX 75390-9036, USA.
Racke
Michael K
MK
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000187:drug effects / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects / Q000276:immunology; D000954:Antigens, Surface / Q000187:drug effects / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D018122:B7-1 Antigen / Q000187:drug effects / Q000276:immunology; D051940:B7-2 Antigen / Q000187:drug effects / Q000276:immunology; D018106:CD28 Antigens / Q000187:drug effects / Q000276:immunology; D023201:CD40 Ligand / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen; D015195:Drug Design; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D053278:OX40 Ligand; D061026:Programmed Cell Death 1 Receptor; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C556692:ICOS protein, human; C556694:Icos protein, mouse; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D060889:Inducible T-Cell Co-Stimulator Protein; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C089251:TNFSF4 protein, human; C505717:Tnfrsf4 protein, mouse; D048069:Tumor Necrosis Factors; D023201:CD40 Ligand