Strategies to induce marked prolongation of secondary skin allograft survival in alloantigen-primed mice
Strategies to induce marked prolongation of secondary skin allograft survival in alloantigen-primed mice
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DOI：
10.1111/j.1600-6143.2007.02143.x
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发表时间：
2008-04-01
影响因子：
8.8
通讯作者：
Maki, T.
中科院分区：
文献类型：
--
作者：
Minamimura, K.;Sato, K.;Maki, T.
同种异体反应性记忆T细胞介导加速排斥反应。我们研究了多克隆抗T细胞抗体（ALS）和雷帕霉素（RAPA）对幼稚或同种异体抗原致敏小鼠皮肤移植物存活的影响。ALS延长了幼稚和同种异体抗原致敏小鼠的移植物存活。ALS引起的T细胞耗竭与CD 4（+）CD 44（hi）OX 40（+）和CD 8（+）CD 44（hi）CD 122（+）记忆T细胞增加相关。在ALS中加入RAPA可延长未处理小鼠的移植物存活，但对同种异体抗原致敏小鼠的继发性同种异体移植物存活没有影响。在过继转移实验中，RAPA抑制同种异体抗原刺激的增殖和幼稚T细胞的同种异体移植排斥反应。相反，同种异体抗原致敏的记忆T细胞，特别是CD 4（+）CD 44（hi）OX 40（+）和CD 8（+）CD 44（hi）CD 122（+）T细胞，在应答同种异体抗原时对RAPA具有抗性，并在RAPA存在时介导加速排斥。通过使用高剂量ALS克服了同种异体抗原致敏小鼠对RAPA的抗性，其实现了二次皮肤同种异体移植物存活的显著延长（> 100天）。抑制CD 122（+）T细胞和/或OX 40/OX 40 L共刺激阻断，结合低剂量ALS和RAPA，也是有效的。这些结果表明，通过采用高剂量ALS或靶向CD 122（+）CD 8（+）T细胞和/或OX 40/OX 40 L共刺激通路的T细胞耗竭和RAPA策略，可在同种异体致敏个体中实现耐受。
Alloreactive memory T cells mediate accelerated rejection. We investigated the effect of polyclonal anti-T-cell antibody (ALS) and rapamycin (RAPA) on skin allograft survival in naive or alloantigen-primed mice. ALS prolonged graft survival in both naive and alloantigen-primed mice. T-cell depletion by ALS was associated with increased CD4(+)CD44(hi)OX40(+) and CD8(+)CD44(hi)CD122(+) memory T cells. Addition of RAPA to ALS extended graft survival in naive mice, but had no effect on secondary allograft survival in alloantigen-primed mice. In adoptive transfer experiments, RAPA inhibited alloantigen-stimulated proliferation and allograft rejection by naive T cells. In contrast, alloantigen-primed memory T cells, particularly CD4(+)CD44(hi)OX40(+) and CD8(+)CD44(hi)CD122(+) T cells, were resistant to RAPA in response to alloantigen and mediated accelerated rejection in the presence of RAPA. Resistance to RAPA by alloantigen-primed mice was overcome by the use of high-dose ALS, which achieved marked prolongation of secondary skin allograft survival (> 100 days). Inhibition of CD122(+) T cells and/or OX40/OX40L costimulation blockade, combined with low-dose ALS and RAPA, was also effective. These results demonstrate that tolerance may be achieved in allosensitized individuals by T-cell depletion- and RAPA-based strategies employing high-dose ALS or targeting CD122(+)CD8(+) T cells and/or the OX40/OX40L costimulatory pathway.