Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines
Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines
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DOI：
10.1182/blood-2005-05-2118
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发表时间：
2006-05-01
期刊：
影响因子：
20.3
通讯作者：
San Miguel, J
中科院分区：
文献类型：
--
作者：
Blanco, B;Pérez-Simón, JA;San Miguel, J
我们探讨了蛋白酶体抑制剂硼替佐米（可阻止核因子κ B（NF-κ B）活化）阻断同种异体反应性T细胞活化、增殖和存活的能力，并与静息T细胞进行了比较。为此，用PHA、α CD 3/α CD 28或同种异体树突状细胞或通过混合淋巴细胞培养物刺激T细胞。与静息T细胞相比，活化T淋巴细胞中NF-κ B表达增加。值得注意的是，NF-κ B表达越高，硼替佐米诱导的增殖阻断越强烈。此外，在混合淋巴细胞反应（MLR）培养后，同种异体反应性T细胞比静息T细胞对硼替佐米诱导的凋亡敏感2个对数。这种效应是由于活化的T细胞之间的凋亡的选择性诱导，这与半胱天冬酶的激活和抗凋亡的bcl-2蛋白的裂解有关，并且通过加入pancaspase抑制剂Z-VAD-FMK被部分废除。此外，在二次MLR后，当来自同一供体的细胞用作刺激细胞时，先前用硼替佐米培养的T淋巴细胞中活化T细胞的数量显著减少。相比之下，当第三方供体细胞用作刺激细胞时，在先前暴露于或未暴露于药物的T淋巴细胞之间未观察到显著差异，表明对主要供体抗原具有同种异体反应性的T淋巴细胞的高度特异性耗竭。硼替佐米的加入不仅降低了活化T淋巴细胞的增殖和活力，而且降低了IFN γ和IL-2的水平，在用硼替佐米以10至100 nM的剂量培养的活化T细胞中，IFN γ和IL-2的水平显著降低。总之，在临床环境中达到的浓度下，硼替佐米可诱导选择性细胞凋亡并降低同种异体反应性T淋巴细胞中的Th 1反应，而几乎不影响未受刺激的T细胞。这些结果为硼替佐米治疗移植物抗宿主病（GVHD）的临床应用奠定了基础。
We explored the ability of the proteasome inhibitor bortezomib, which prevents nuclear factor kappa B (NF-kappa 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, alpha CD3/alpha CD28, or allogeneic dendritic cells or through mixed lymphocyte cultures. NF-kappa B expression increased in activated T lymphocytes compared with resting T cells. Of interest, the higher the NF-kappa 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 gamma 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).