Therapeutic Blockade of TCR Signal Transduction and Co-Stimulation in Autoimmune Disease

Abstract

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).