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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.
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IMMUNOBIOLOGY
Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines
Belén Blanco,
José A. Pérez-Simón,
Luis I. Sánchez-Abarca,
Xonia Carvajal-Vergara,
Juan Mateos,
Belén Vidriales,
Natalia López-Holgado,
Patricia Maiso,
Mercedes Alberca,
Eva Villarón,
David Schenkein,
Atanasio Pandiella, and
Jesús San Miguel
From the Servicio de Hematología and Centro de Investigación del Cáncer, Salamanca, Spain.
We explored the ability of the proteasome inhibitor bortezomib, which prevents nuclear factor  B (NF-B) activation, to block T-cell activation, proliferation, and survival within alloreactive compared with resting T cells. For this purpose, T cells were stimulated with PHA,  CD3/CD28, or allogeneic dendritic cells or through mixed lymphocyte cultures. NF-B expression increased in activated T lymphocytes compared with resting T cells. Of interest, 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 that 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 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 decreased not only 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 graft-versus-host disease (GVHD).
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