Pharmacotherapy: concepts of pathogenesis and emerging treatments. Co-stimulation and T cells as therapeutic targets.
Full activation and differentiation of resting T cells into effector T cells requires at least two signals, the first through engagement of the T cell antigen receptor (TCR) by the antigen-major histocompatibility complex (MHC) on antigen-presenting cells (APCs), and the second by engagement of co-stimulatory molecules such as CD28, on T cells by ligands such as CD80/86 on APCs. Effector T cell differentiation is associated with proliferation, secretion of cytokines and expression of additional surface molecules. These inducible structures may have stimulatory (ICOS, OX40 and 4-1BB) or inhibitory (cytotoxic T-lymphocyte antigen (CTLA)-4) potential. To the extent that T cells have a role in particular immune-mediated diseases, interruption of T cell co-stimulation is a potentially worthwhile approach to the treatment of those conditions. This article summarises the experience in treating rheumatological disease by perturbation of T cell co-stimulation, and also describes structures that could be future targets for this type of therapeutic approach.
Gizinski
Alison M
AM
Division of Rheumatology, Department of Internal Medicine and Rheumatic Disease Core Center, University of Michigan, Ann Arbor, Michigan 48109, USA. agizinsk@med.umich.edu
Fox
David A
DA
Sarkar
Sujata
S
D000069594:Abatacept; D017951:Antigen Presentation / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D018501:Antirheumatic Agents / Q000276:immunology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000628:therapy; D018122:B7-1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002986:Clinical Trials as Topic; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000276:immunology / Q000627:therapeutic use; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D018501:Antirheumatic Agents; D018122:B7-1 Antigen; D018106:CD28 Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept