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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Use of Systemic Proteasome Inhibition as an Immune-Modulating Agent in Disease

Author(s): Lauren H. Mattingly, Ruth A. Gault and William J. Murphy

Volume 7, Issue 1, 2007

Page: [29 - 34] Pages: 6

DOI: 10.2174/187153007780059397

Price: $65

Abstract

Bortezomib is the first proteasome inhibitor to be used clinically for the treatment of multiple myeloma and has been suggested as a possible treatment for a wide variety of hematologic and solid malignancies. Recent data suggests that potent immunomodulatory effects can also occur with systemic proteasome inhibition. This has been recently shown to occur in a graft-versus host disease model following bone marrow transplantation in mice. The suggested direct immunological effects of bortezomib treatment to include a decrease in anti-apoptotic protein levels, an increase in expression of TNF-family receptors (specifically Apo2L/TRAIL), induction of apoptosis, and inhibition of the transcription factor NF- κB. The NF- κB pathway has been associated with the regulation of numerous immune and inflammatory response mediators. In this review, we will present recent information concerning the potential therapeutic implications of bortezomib for a range of immune disorders. These findings would suggest that bortezomib treatment may be of clinical significance to suppress solid organ transplant rejection, autoreactive T cell responses, pro-inflammatory cytokine production, and consequently disease progression and pathology in autoimmunity.

Keywords: Autoimmunity, proteasome inhibition, bortezomib, multiple sclerosis, graft versus host disease, autoreactive T cell, transplantation


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