T CELL RECONSTITUTION AFTER STEM CELL AUTOGRAFTING

干细胞自体移植后 T 细胞重建

• 批准号: 6510906
• 负责人: JAN STOREK
• 金额: $ 29.08万
• 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/6510906
• 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：（研究者摘要的逐字记录）： 背景：高剂量化疗/放疗后 CD4 T 细胞的恢复 患有癌症或自身免疫性疾病的成年患者的发病过程非常缓慢（数年），并且可能 导致仅产生有限的 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 设计策略以改善 T 细胞再生后的目标 淋巴细胞减少症，这里我们建议研究T细胞的机制 再生。 假设：我们假设 T 淋巴细胞减少症后，大量 再生T细胞起源于年轻的造血祖细胞 个体，而只有少数（如果有的话）T 细胞源自造血系统 老年人的祖先。相反，在老年人中，大量的 大多数 T 细胞源自先前存在的 T 细胞的扩增。 方法：该假设将在严重淋巴细胞减少症患者中进行检验 患有自身免疫性疾病并接受过大剂量化疗/放疗的人 抗胸腺细胞球蛋白随后自体造血移植 (CD34+) 细胞。在这种情况下存活下来的 T 细胞克隆数量极为有限 移植调理/CD34+细胞纯化。因此，相对而言 容易（比仅有中度 T 的患者更容易且信息更丰富） 淋巴细胞减少症）追踪幸存 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：光谱分析、T 细胞测序 单个谱带内的受体基因，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 细胞的全部功能，即 移植后的头几个月内受到严重限制，以后会 在年轻人（5岁以下）中多样化，但这种情况将持续严重 仅限于老年（大于 45 岁）患者。另外，如果假设 是真的，移植后含有 TREC 的 T 细胞数量将是 与老年患者相比，年轻患者明显更高。这将 推动制定策略，使老年患者能够生成 T 来自造血祖细胞的细胞，例如使用胸腺生成细胞因子或 胸腺嫁接。