Current Drug Target -Inflammation & Allergy

Kurt S Zaenker
Institute of Immunology and Experimental Oncology
University Witten/Herdecke
Stockumerstraße 10
Witten, 58448
Germany

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

Author(s): Laurence M. Howard, Adam P. Kohm, Carol L. Castaneda and Stephen D. Miller

Affiliation: Department of Microbiology- Immunology, Northwestern University Medical School, 303 East ChicagoAvenue, Chicago, IL 60611, USA.

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

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).

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Article Details

VOLUME: 4
ISSUE: 2
Page: [205 - 216]
Pages: 12
DOI: 10.2174/1568010053586228