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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (2548)	11/14/2005 1:10:29 AM
From: tuck	Respond to of 3044

[Velcade versus Graft Versus Host Disease] >>Blood. 2005 Nov 10; [Epub ahead of print] Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blanco B, Perez-Simon JA, Sanchez-Abarca LI, Carvajal-Vergara X, Mateos-Mazon J, Vidriales B, Lopez-Holgado N, Alberca M, Villaron E, Schenkein D, Maiso P, Pandiella A, San Miguel JF. Servicio de Hematologia and Centro de Investigacion del Cancer, Salamanca, Spain. We explored the ability of the proteasome inhibitor bortezomib, which prevents Nuclear Factor kB (NF-kappaB) activation, to block T-cell activation, proliferation and survival within alloreactive as compared to resting T-cells. For this purpose, T-cells were stimulated with PHA, alphaCD3/alphaCD28, allogeneic dendritic cells or through mixed lymphocyte cultures. NF-kappaB expression increased in activated T-lymphocytes as compared to resting T-cells. Interestingly, the higher the NF-kappaB expression, the more intense the proliferative blockade induced by bortezomib. Moreover, after mixed lymphocyte reaction (MLR) cultures, alloreactive T-cells were 2 logs more sensitive to bortezomib-induced apoptosis than the resting T-cell counterpart. This effect was due to a selective induction of apoptosis among activated T-cells which was related to caspase activation and cleavage of the antiapoptotic bcl-2 protein and was partially abolished by the addition of the pancaspase inhibitor Z-VAD-FMK. In addition, after secondary MLR, the number of activated T-cells was significantly reduced among T-lymphocytes previously cultured with bortezomib when cells from the same donor were used as stimulating cells. By contrast, when third party donor's cells were used as stimulating cells, no significant differences were observed between T lymphocytes previously exposed or not to the drug, indicating a highly specific depletion of T-lymphocytes alloreactive against primary donor antigens. The addition of bortezomib not only decreased the proliferation and viability of activated T-lymphocytes but also the levels of IFNgamma and IL-2 which were significantly decreased among activated T-cells cultured with bortezomib at doses ranging from 10 to 100 nM. In conclusion, at concentrations reached in the clinical setting, bortezomib induces selective apoptosis and decreases Th1 response among alloreactive T-lymphocytes while it barely affects unstimulated T-cells. These results establish the basis for the clinical use of bortezomib in the management of GVHD.<< Cheers, Tuck