GENETICS AND MECHANISMS OF DLI EFFECTS FOLLOWING NON-MYELOBLATIVE HCT

非清髓性 HCT 后 DLI 效应的遗传学和机制

• 批准号: 7158094
• 负责人: DAVID H SACHS
• 金额: $ 29.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7158094
• 关键词: antineoplastics; antitumor antibody; bioengineering /biomedical engineering; cell line; cell migration; cell proliferation; clinical research; graft versus host disease; hematopoietic tissue transplantation; homologous transplantation; hybrid antibody; inflammation; injection /infusion; leukemia; leukocyte activation /transformation; lymphocyte; lymphoma; miniature swine; model design /development; molecular dynamics; neoplasm /cancer radiation therapy; neoplastic cell; nonhuman therapy evaluation; stem cell transplantation; tissue donors; transfection

Non-myeloablative hematopoietic cell transplantation (HCT) followed by delayed donor leukocyte infusion (DLI) is a promising immunotherapeutic approach to treat hematologic malignancies including leukemias and lymphomas. Major limitations of this approach, however, include the risks of graft failure, graft-versus-host disease, (GVHD) and infection. MGH MHC-inbred miniature swine provide a pre-clinical model for studies of transplantation biology with responses to HCT resembling those of humans. Preliminary data suggest that a novel, minimally myelosuppressive preparative regimen leads to stable multilineage chimerism following highdose haploidentical HCT, without causing GVHD. In this proposal we aim to 1) determine the immunological mechanisms involved in controlling hbst-versus-graft (HVG) and GVH responses that allow engraftment without GVHD across MHC barriers in this model. These studies will be performed in close collaboration with Projects 1 and 2 to extend the mechanistic studies in rodent models. We will then 2) optimize the swine model to facilitate translation of this protocol to the clinic and analyze the importance of specific genetic disparities (haploidentical class I and II, class I only, class II only) on engraftment, GVHD and the effects of subsequent DLI. In collaboration with Project 4, we will test novel strategies to improve stem cell harvests following cytokine mobilization through parathyroid hormone (PTH) stimulation. Increased numbers of stem cells in the leukapheresis product following PTH stimulation and cytokine mobilization may enable stable engraftment using lower doses of cells more easily attainable in the clinic. It is hoped that results of these studies will permit the development of tailored approaches to the use of DLI in chimeric patients depending on their HLA disparities from the donor. In addition, we plan to 3) further develop the swine model to allow direct assessment of graft-versus-tumor effects of HCT and DLI. For this purpose, we will establish tumor cell lines derived from inbred miniature swine and adapt these tumor lines for in vivo growth in pigs. With the recent availability of histocompatible miniature swine, and tumor lines derived from these highly inbred animals, we have the unique opportunity to develop transplantable tumors in a preclinical large animal model. These studies could provide a foundation for future immunotherapeutic approaches for the treatment of hematological malignancies that may be translated toward treatment of human disease.

非毛囊造血细胞移植（HCT），然后是延迟的供体白细胞输注 （DLI）是一种有希望的免疫治疗方法，用于治疗血液系统恶性肿瘤，包括白血病和 淋巴瘤。但是，这种方法的主要局限性包括移植失败的风险 疾病，（GVHD）和感染。 MGH MHC-Inbred Miniature Swine为研究提供了临床前模型 对HCT的反应类似于人类的移植生物学。初步数据表明 小说，最小的骨髓抑制剂制剂疗法导致高点后稳定的多片嵌合体 单倍型HCT，不会引起GVHD。在此提案中，我们的目标是1）确定免疫学 控制HBST-versus-Graft（HVG）和GVH响应涉及的机制，允许植入 在此模型中，在MHC障碍物中没有GVHD。这些研究将与 项目1和2扩展啮齿动物模型中的机械研究。然后，我们将2）优化猪 促进该方案转换为诊所的模型并分析特定遗传的重要性 在植入，GVHD和效果的差异（仅I级I级，仅I级，仅II类）） 随后的DLI。与项目4合作，我们将测试新的策略以改善干细胞收获 通过甲状旁腺激素（PTH）刺激动员细胞因子后。茎的数量增加 PTH刺激和细胞因子动员后的白细胞膜发行产物中的细胞可能使稳定 在诊所中更容易地使用较低剂量的细胞植入。希望这些结果 研究将允许开发量身定制的方法，以在嵌合患者中使用DLI 在他们与捐助者的HLA差异上。此外，我们计划3）进一步开发猪模型以允许 直接评估HCT和DLI的移植物肿瘤效应。为此，我们将建立肿瘤细胞 源自近交微型猪并适应这些肿瘤线以在猪体内生长。与 最新的组织兼容微型猪和源自这些高度近交的肿瘤线的可用性 动物，我们有独特的机会在临床前大型动物模型中开发可移植的肿瘤。 这些研究可以为未来的免疫治疗方法提供基础 血液学恶性肿瘤可能会转化为治疗人类疾病。