LLME TREATED T LYMPHOCYTE THERAPY AFTER ALLOGENEIC BMT

同种异体 BMT 后进行 LLME 治疗的 T 淋巴细胞治疗

• 批准号: 6522679
• 负责人: NEAL FLOMENBERG
• 金额: $ 35.33万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-26 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522679
• 关键词: T lymphocyte; bone marrow transplantation; clinical trial phase I; graft versus host disease; hematopoietic stem cells; hematopoietic tissue transplantation; homologous transplantation; human subject; human therapy evaluation; immunosuppression; immunosuppressive; patient oriented research

DESCRIPTION (Provided by applicant): Allogeneic bone marrow transplantation has emerged as the preferred therapy for a variety of disorders. Unfortunately, outcome is limited by development of graft-versus-host disease (GVHD) and by the opportunistic infections which often ensue as a consequence of efforts to prevent or treat GVHD. Following the resolution of neutropenia early after BMT, infectious risk correlates with the patients' CD4 counts, much as is the case in HIV infected patients. CD4 counts remain low for 4-6 months after either T-cell depleted or T-cell replete marrow transplants. In contrast CD8 counts have the ability to rapidly recover with either form of BMT. GVHD appears to be mediated by T cells bearing cytotoxic effector granules. These cells can be selectively destroyed through the action of Leucyl Leucine Methyl Ester (LLME), which undergoes polymerization by dipeptidyl peptidase-I, one of the components of cytotoxic granules. LLME treatment destroys approximately 90 percent of the CD8 T cells, but only 10 percent of the CD4 cells. After LLME treatment, large numbers of mismatched T cells can be adoptively transferred in animals without GVHD. Prior clinical trials of LLME were successful in preventing GVHD, but limited by stem cell toxicity and graft failure when the marrow was treated. Since that time, T cell depletion techniques have been improved, such that the majority of patients can be successfully engrafted with little or no GVHD, even when thetransplants are performed across major histocompatibility barriers. The limitation of these approaches is the prolonged CD4 deficiency and opportunistic infections which ensue. We therefore hypothesize that transplant outcome can be substantially improved by treating recipients of T cell- depleted transplants with donor lymphocyte infusions (DLI) which have been treated with LLME. This will potentially provide safe transfer of large numbers of CD4 T cells and small numbers of CD8 T cells without appreciable GVHD risk. The prior problems of stem cell toxicity will be avoided, as the patients will previously have been engrafted. CD8 recovery would occur through the stem cell graft and CD4 recovery through the DLI. The proposed grant will support a trial to administer increasing numbers of LLME-treated DLI to patients and monitor patients for CD4 recovery and other parameters of immune reconstitution as well as for development of GVHD.

描述（由申请人提供）：同种异体骨髓移植具有 成为各种疾病的首选疗法。很遗憾， 结果受到移植抗宿主病（GVHD）的发展和 由于努力而导致的机会主义感染 预防或治疗GVHD。在BMT之后早期的中性粒细胞减少症之后， 感染风险与患者的CD4计数相关，情况也很 在艾滋病毒感染的患者中。 CD4计数在任何一个后持续4-6个月 T细胞耗尽或T细胞的骨髓移植。相比之下CD8计数 具有通过任何一种BMT的形式快速恢复的能力。 GVHD似乎是由带有细胞毒性效应子颗粒的T细胞介导的。 这些细胞可以通过亮氨酸的作用选择性破坏 甲基酯（LLME），该酯通过二肽基肽酶-I进行聚合， 细胞毒性颗粒的成分之一。 LLME治疗破坏 大约90％的CD8 T细胞，但只有10％的CD4 细胞。 LLME处理后，大量不匹配的T细胞可以是 在没有GVHD的动物中采用转移。 LLME的先前临床试验 成功预防GVHD，但受干细胞毒性和移植物的限制 治疗骨髓时失败。从那时起，T细胞耗竭 技术已得到改进，因此大多数患者可以是 即使是thementplants 在主要的组织相容性障碍物上进行。这些的局限性 方法是延长的CD4缺乏和机会性感染 随后。 因此，我们假设移植结果可以大大改善 通过治疗用供体淋巴细胞的T细胞耗尽移植的接受者 用LLME处理的输注（DLI）。这可能会 提供大量CD4 T细胞和少量CD8的安全转移 T细胞没有明显的GVHD风险。干细胞毒性的先前问题 将避免，因为患者以前会植入。 CD8 恢复将通过干细胞移植和CD4通过 DLI。拟议的赠款将支持审判以管理越来越多的人数 对患者进行LLME治疗的DLI，并监测患者的CD4恢复和其他 免疫重建的参数以及GVHD的发展。