T CELL RECONSTITUTION AFTER STEM CELL AUTOGRAFTING

干细胞自体移植后 T 细胞重建

• 批准号: 6017567
• 负责人: JAN STOREK
• 金额: $ 27.43万
• 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/6017567
• 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：（逐字摘自研究者摘要）： 背景：大剂量化疗/放疗后CD 4 T细胞的恢复， 患有癌症或自身免疫性疾病的成年患者非常缓慢（数年）， 导致仅有限的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。其最终 目的是设计策略，以改善T细胞再生后， 淋巴细胞减少症，在这里，我们建议研究T细胞的机制， 再生 假设：我们假设T淋巴细胞减少后， 再生T细胞来源于年轻人的造血祖细胞 然而，只有很少的T细胞，如果有的话，来自造血干细胞。 老年人的祖先。相反，在年长的个体中， 大多数T细胞来源于预先存在的T细胞的扩增。 方法：将在严重淋巴细胞减少症患者中检验这一假设 患有自身免疫性疾病的患者接受了大剂量化疗/放疗， 抗胸腺细胞球蛋白后自体移植造血细胞 (CD34+）细胞。只有极少数的T细胞克隆能够存活下来， 移植预处理/CD 34+细胞纯化。因此，相对而言， 容易（比只有中度T的患者更容易，信息量更大） 淋巴细胞减少症）追踪存活的T细胞克隆的命运， 检测移植后从造血祖细胞新产生的T细胞， 使用以下技术：光谱分析、T细胞测序 受体基因在单个谱带内，并定量T细胞， 含有T细胞受体重排切除环（TREC）。 结果：如果上述假设是正确的，T细胞的库，即 移植后的头几个月内严重受限， 在年轻时（不到5岁）多样化，而它将保持严重 仅限于老年（大于45岁）患者。此外，如果假设 是真的，移植后含有TREC的T细胞的数量将是 年轻患者的死亡率明显高于老年患者。这将 推动制定战略，使老年患者能够产生T 来自造血祖细胞的细胞，例如，使用胸腺生成细胞因子或 胸腺移植