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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3575-3583. Prepublished online as a Blood First Edition Paper on November 10, 2005; DOI 10.1182/blood-2005-05-2118. This Article Full Text (PDF) All Versions of this Article: 2005-05-2118v1 107/9/3575    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Blanco, B. Articles by San Miguel, J. F Search for Related Content PubMed PubMed Citation Articles by Blanco, B. Articles by San Miguel, J. F Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 1, 2005 Accepted October 7, 2005 Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines Belen Blanco, Jose A Perez-Simon*, Luis I Sanchez-Abarca, Xonia Carvajal-Vergara, Juan Mateos-Mazon, Belen Vidriales, Natalia Lopez-Holgado, Mercedes Alberca, Eva Villaron, David Schenkein, Patricia Maiso, Atanasio Pandiella, and Jesus F San Miguel Servicio de Hematologia and Centro de Investigacion del Cancer, Salamanca, Spain * Corresponding author; email: pesimo{at}usal.es. We explored the ability of the proteasome inhibitor bortezomib, which prevents Nuclear Factor kB (NF-B) 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, CD3/CD28, allogeneic dendritic cells or through mixed lymphocyte cultures. NF-B expression increased in activated T-lymphocytes as compared to resting T-cells. Interestingly, the higher the NF-B 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 IFN 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Basler, C. 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Herrero-Sanchez, C. Rodriguez-Serrano, C. Santamaria, et al. Treatment with bortezomib of human CD4+ T cells preserves natural regulatory T cells and allows the emergence of a distinct suppressor T-cell population Haematologica, July 1, 2009; 94(7): 975 - 983. [Abstract] [Full Text] [PDF] C. A. Dasanu and D. T. Alexandrescu Does Bortezomib Induce De Facto Varicella Zoster Virus Reactivation in Patients With Multiple Myeloma? J. Clin. Oncol., May 1, 2009; 27(13): 2293 - 2294. [Full Text] [PDF] X. Wang, A. Ottosson, C. Ji, X. Feng, M. Nordenskjold, J.-I. Henter, B. Fadeel, and C. Zheng Proteasome inhibition induces apoptosis in primary human natural killer cells and suppresses NKp46-mediated cytotoxicity Haematologica, April 1, 2009; 94(4): 470 - 478. [Abstract] [Full Text] [PDF] L. Rosinol, J. A. Perez-Simon, A. Sureda, J. de la Rubia, F. de Arriba, J. J. Lahuerta, J. D. Gonzalez, J. Diaz-Mediavilla, B. Hernandez, J. Garcia-Frade, et al. 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