Understanding T Cell Rapamycin Resistance

了解 T 细胞雷帕霉素耐药性

• 批准号: 8553052
• 负责人: DANIEL FOWLER
• 金额: $ 33.61万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553052
• 关键词: Allogenic; Animal Model; Apoptosis; Apoptotic; Autophagocytosis; Biology; Cancer Cell Growth; Cells; Cellular biology; Clinical; Clinical Trials; Complication; Cytokine Signaling; Differentiation and Growth; Hematopoietic Stem Cell Transplantation; Homologous Transplantation; Human; Immune; Immune system; Mediating; Mus; Natural Product Drug; Pharmaceutical Preparations; Phenotype; Process; Reaction; Regulatory T-Lymphocyte; Relative (related person); Renal Cell Carcinoma; Research; Resistance; Resistance development; Role; Sirolimus; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; United States National Institutes of Health; cancer cell; graft vs host disease; in vivo; leukemia/lymphoma; mTOR protein

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 recently found that rapamycin causes polarized T cells to undergo a process known as autophagy; the anti-apoptotic phenotype of rapamycin-generated T cells is dependent upon autophagy. 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.

在这个项目中，我们发现，在雷帕霉素存在的情况下离体扩增的免疫T细胞可以产生对雷帕霉素的耐药性，前提是提供必要的共刺激和细胞因子信号。 重要的是，我们已经证明雷帕霉素可以产生多种功能性 T 细胞亚群，包括 Th1、Th2、Tc1、Tc2 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的 T 细胞也获得了凋亡抗性表型；这种生物学具有功能意义，因为在过继性 T 细胞转移后，这种抗雷帕霉素和抗凋亡的 T 细胞在体内存活率增加，因此相对于对照 T 细胞介导更有效的免疫 T 细胞反应。 我们最近发现雷帕霉素会导致极化 T 细胞经历一种称为自噬的过程；雷帕霉素产生的 T 细胞的抗凋亡表型依赖于自噬。我们观察到这种生物学现象在小鼠 T 细胞和人类 T 细胞中都会发生。鉴于这一认识，我们已在 NIH 临床中心启动了使用雷帕霉素耐药 T 细胞治疗白血病、淋巴瘤和肾细胞癌的试点临床试验。