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).

IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells

“…Although interfering with T-cell receptor and costimulatory signals required for activation of naïve self-reactive T cells has been successful to prevent autoimmunity in some models (28), it has typically not been effective once disease is established. One suspected reason for this failure is that T E/M cells may be the main pathogenic cells perpetuating the response.…”

UR-1505, a New Salicylate, Blocks T Cell Activation through Nuclear Factor of Activated T Cells

“…In this study, we have shown that UR-1505, a new immunomodulator agent chemically related to salicylic acid, blocked T-cell activation, which might be a useful strategy for the treatment of autoimmune diseases, given the key role of T-cell activation in the onset of these diseases (Chow et al, 2005;Goudy and Tisch, 2005;Howard et al, 2005;Walter and Santamaría, 2005). It is important that the prevention of T-cell activation produced by UR-1505 was done in a lower range of concentrations (0.1 -0.3 mM) than those reported previously for acetylsalicylic acid (2-4 mM) (Paccani et al, 2002).…”

Update on pathophysiologic and immunotherapeutic approaches for the treatment of multiple sclerosis

“…Aufgrund tierexperimenteller Untersuchungen weiß man, dass der Antigenrezeptor pathogener autoaggressiver T-Lymphozyten aus einer sehr begrenzten Anzahl der theoretisch verfügbaren CDR aufgebaut ist [3]. Durch Immunisierung von Ratten mit synthetischen Peptiden der CDR2- [92] oder CDR3-Region [90] autoagressiver MBP-spezifischer T-Zellen konnte man die Entstehung einer EAE verhindern und die Progression nach Manifestation der Erkrankung verkürzen [203]. In ersten klinischen Studien wurden MS-Patienten mit synthetischen von den CDR-Regionen verschiedener Elemente (V5 und V6) abgeleiteten Peptiden immunisiert [34].…”

“…Man nimmt an, dass diese äußerst relevant für die Regulation der T-Zell-Aktivierung sowie für die Aufrechterhaltung des Gleichgewichtes zwischen Th1-und Th2-Helferzellen sind [110]. Daher wird der therapeutischen Blockade wichtiger kostimulatorischer Signalkaskaden zunehmende Aufmerksamkeit geschenkt [92].…”