T CELL RECONSTITUTION AFTER STEM CELL AUTOGRAFTING

干细胞自体移植后 T 细胞重建

• 批准号: 6170806
• 负责人: JAN STOREK
• 金额: $ 27.46万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170806
• 关键词: CD34 molecule; CD4 molecule; T lymphocyte; age difference; autoimmune disorder; cell proliferation; clinical research; hematopoietic stem cells; hematopoietic tissue transplantation; human subject; human therapy evaluation; radiation therapy

DESCRIPTION: (Verbatim from Investigator's abstract): Background: The recovery of CD4 T cells after high-dose chemo/radiotherapy in adult patients with cancer or autoimmune diseases is very slow (years) and may result in only limited T cell repertoire. A similar problem exists in AIDS patients treated with highly active anti-retroviral therapy. With the ultimate goal of designing strategies to improve the T cell regeneration after T lymphocytopenia, here we propose to study the mechanism of the T cell regeneration. Hypothesis: We hypothesize that after T-lymphocytopenia a substantial number of regenerating T cells originate from hemopoietic progenitors in young individuals whereas only few, if any, T cells originate from hemopoietic progenitors in older individuals. Instead, in the older individuals, the vast majority of T cells originate from the expansion of preexisting T cells. Methods: This hypothesis will be tested in severely lymphocytopenic patients with autoimmune diseases who have received high-dose chemo/radiotherapy plus anti-thymocyte globulin followed by autologous transplantation of hemopoietic (CD34+) cells. An extremely limited number of T cell clones survive such transplant conditioning/ CD34+ cell purification. Therefore, it is relatively easy (easier and more informative than in patients with only moderate T lymphocytopenia) to track down the fate of the surviving T cell clones and to detect T cells newly generated from hemopoietic progenitors post-transplant, using the following techniques: spectratyping, sequencing of the T cell receptor genes within a single spectratyping band, and quantifying T cells that contain T cell receptor-rearrangement excision circles (TREC). Outcome: If the above hypothesis is true, the repertoire of T cells, that is severely limited within the first several months after transplant, will later diversify in young (less than 5-years-old) whereas it will stay severely limited in older (greater than 45-years-old) patients. Also, if the hypothesis is true, the number of TREC-containing T cells post-transplant will be significantly higher in the young compared to the older patients. This will give impetus for developing strategies to enable older patients to generate T cells from hemopoietic progenitors, e.g., using thymopoietic cytokines or thymus grafting.

描述：(逐字摘自调查人员摘要)： 背景：中国人大剂量放化疗后CD4T细胞的恢复 患有癌症或自身免疫性疾病的成人患者非常缓慢(几年)，并可能 结果只产生了有限的T细胞库。艾滋病也存在类似的问题 接受高效抗逆转录病毒治疗的患者。与终极的 改善T细胞移植后T细胞再生的策略设计目标 淋巴细胞减少，在这里我们建议研究T细胞的机制 再生。 假设：我们假设在T淋巴细胞减少后，相当数量的 再生T细胞来源于年轻的造血祖细胞 而只有极少数(如果有的话)T细胞来自造血细胞 年长个体中的祖细胞。相反，在年长的个体中，大量的 大多数T细胞来源于先前存在的T细胞的扩增。 方法：这一假说将在严重淋巴细胞减少的患者中进行检验。 接受大剂量化疗/放疗加化疗的自身免疫性疾病 抗胸腺细胞球蛋白与自体造血干细胞移植 (CD34+)细胞。数量极其有限的T细胞克隆在这样的环境中存活下来 移植条件/CD34+细胞纯化。因此，它是相对的 Easy(与仅有中等T细胞的患者相比，更容易且信息量更大 淋巴细胞减少)，以追踪幸存的T细胞克隆的命运并 检测移植后造血祖细胞新生成的T细胞， 使用以下技术：T细胞的光谱分型、测序 单一谱带内的受体基因，并量化T细胞 含有T细胞受体重排切除环(TREC)。 结果：如果上述假设为真，T细胞的谱系，即 在移植后的头几个月内受到严重限制，稍后将 在年轻人(不到5岁)中实现多样化，但仍将严重 仅限于年龄较大(大于45岁)的患者。另外，如果假设 如果是真的，移植后含有TREC的T细胞的数量将是 与老年患者相比，年轻患者明显更高。这将是 推动制定策略，使老年患者能够产生T细胞 来自造血祖细胞的细胞，例如使用胸腺细胞因子或 胸腺移植。