Therapeutic blockade of TCR signal transduction and co-stimulation in autoimmune disease.
Autoimmune diseases are initiated and maintained by presentation of self antigen through complex interactions between different cells of the immune system. In most autoimmune disorders, autoantigen-specific responses are induced by the activation of specific T cells with self peptides displayed on activated antigen presenting cells (APCs). These T cells may then activate and drive B cell responses that either initiate or contribute to chronic disease pathogenesis. In order to activate the T cell, two signals are required: T cell receptor (TCR) engagement by autoantigen presented in the context of self MHC class II and costimulation (CD28-CD80/CD86 interactions). Feedback must also be provided to the APC through MHC class II engagement by the TCR and through costimulatory events controlling T cell differentiation and effector function (CD154-CD40 interactions, among others). With this in mind, numerous strategies have been developed to block the engagement and activation of self-reactive cells. We review and discuss recent progress in understanding the efficacy and underlying molecular mechanisms of three separate immunotherapeutic strategies targeting the TCR and costimulatory molecules: i) blocking TCR signaling (using non-mitogenic anti-CD3 monoclonal antibody); ii) blocking CD28 costimulation (anti-B7 monoclonal antibody blockade); and iii) blocking CD40 engagement on APCs (anti-CD154 monoclonal antibody blockade).
Howard
Laurence M
LM
Departmentof Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA. s-d-miller@northwestern.edu
Kohm
Adam P
AP
Castaneda
Carol L
CL
Miller
Stephen D
SD
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D018106:CD28 Antigens / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000187:drug effects; D023201:CD40 Ligand / Q000187:drug effects; D019672:Genes, T-Cell Receptor / Q000187:drug effects*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects*; D013268:Stimulation, Chemical
D018106:CD28 Antigens; D019013:CD40 Antigens; D023201:CD40 Ligand