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

Authors: Howard, Laurence M.; Kohm, Adam P.; Castaneda, Carol L.; Miller, Stephen D.

Source: Current Drug Targets - Inflammation & Allergy, Volume 4, Number 2, April 2005 , pp. 205-216(12)

Publisher: Bentham Science Publishers

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).

Keywords: autoimmunity; inflammation; co-stimulation; blockade; therapy; t cell receptor; cd3; cd28; cd40; cd80

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568010053586228

Affiliations: 1: Department of Microbiology- Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.

Publication date: 2005-04-01

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