Understanding T Cell Rapamycin Resistance

在这个项目中，我们已经发现，免疫T细胞，是扩大离体在 雷帕霉素的存在可以产生对雷帕霉素的抗性， 提供了共刺激和细胞因子信号。重要的是，我们已经证明，一个伟大的 在雷帕霉素中可以产生多种功能性T细胞亚群，包括Th 1，Th 2， Tc 1、Tc 2和调节性T细胞亚群。重要的是，我们发现， 获得雷帕霉素抗性也获得凋亡抗性表型;这种生物学具有 因为在过继性T细胞转移后，这种雷帕霉素-和 抗凋亡T细胞增加了体内存活，因此介导更有效的 相对于对照T细胞的免疫T细胞反应。我们观察到这种生物学现象 用鼠T细胞和人T细胞。基于这一认识，我们启动了试点项目， NIH临床中心使用雷帕霉素抗性T细胞进行治疗的临床试验 白血病淋巴瘤和肾细胞癌

In this project, we have found that immune T cells that are expanded ex vivo in the presence of rapamycin can develop resistance to rapamycin provided that necessary co-stimulation and cytokine signals are provided. Importantly, we have shown that a great variety of functional T cell subsets can be generated in rapamycin, including the Th1, Th2, Tc1, Tc2, and regulatory T cell subsets. Of significance, we have found that T cells that acquire rapamycin-resistance also attain an apoptosis resistance phenotype; this biology has functional significance because upon adoptive T cell transfer, such rapamycin- and apoptosis-resistant T cell have increased in vivo survival and therefore mediate more potent immune T cell reactions relative to control T cells. We have observed that this biology occurs with both murine T cells and human T cells. Given this understanding, we have initiated pilot clinical trials at the NIH Clinical Center using rapamycin-resistant T cells for the therapy of leukemia, lymphoma, and renal cell carcinoma.