J Clin Invest, March 2002, Volume 109, Number 5, 671-679
Copyright ©2002 by the American Society for Clinical Investigation
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Article
Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model
Thomas M. Zollner1, Maurizio Podda1, Christine Pien2, Peter J. Elliott2, Roland Kaufmann1 and Wolf-Henning Boehncke1
1 Department of Dermatology, J.W. Goethe University of Frankfurt, Frankfurt, Germany 2 Millennium Pharmaceuticals Inc., Cambridge, Massachusetts, USA
Address correspondence to: Thomas M. Zollner, Schering AG, Research Business Unit Dermatology, Müllerstrasse 178, D-13342 Berlin, Germany. Phone: 49-30-468-17235; Fax: 49-30-468-97235; E-mail: Thomas.Zollner@Schering.de.
Received for publication March 13, 2001, and accepted in revised form January 28, 2002.
There is increasing evidence that bacterial superantigens contribute to inflammation and T cell responses in psoriasis. Psoriatic inflammation entails a complex series of inductive and effector processes that require the regulated expression of various proinflammatory genes, many of which require NF-B for maximal trans-activation. PS-519 is a potent and selective proteasome inhibitor based upon the naturally occurring compound lactacystin, which inhibits NF-B activation by blocking the degradation of its inhibitory protein IB. We report that proteasome inhibition by PS-519 reduces superantigen-mediated T cell–activation in vitro and in vivo. Proliferation was inhibited along with the expression of very early (CD69), early (CD25), and late T cell (HLA-DR) activation molecules. Moreover, expression of E-selectin ligands relevant to dermal T cell homing was reduced, as was E-selectin binding in vitro. Finally, PS-519 proved to be therapeutically effective in a SCID-hu xenogeneic psoriasis transplantation model. We conclude that inhibition of the proteasome, e.g., by PS-519, is a promising means to treat T cell–mediated disorders such as psoriasis. |
