GRAFT VERSUS TUMOR

移植物抗肿瘤

• 批准号: 6203007
• 负责人: RICHARD J JONES
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-27 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203007
• 关键词: SDS polyacrylamide gel electrophoresis; T lymphocyte; acute leukemia; acute lymphocytic leukemia; antigen antibody reaction; antigen presenting cell; antineoplastics; apoptosis; artificial immunosuppression; bone marrow transplantation; cell cycle; cell differentiation; cellular immunity; cellular oncology; chronic myelogenous leukemia; clinical research; clinical trials; colony stimulating factor; cytotoxicity; flow cytometry; gene expression; genetically modified animals; graft versus host disease; growth factor; homologous transplantation; hormone regulation /control mechanism; human subject; human therapy evaluation; immunoprecipitation; interleukin 2; laboratory mouse; leukemia; leukocyte activation /transformation; lymphokine activated killer cell; lymphoma; molecular oncology; monoclonal antibody; natural killer cells; neoplasm /cancer immunotherapy; neoplastic transformation; oncogenes; pentoxifylline; tissue /cell culture; tumor suppressor genes; western blottings

Allogeneic BMT was first considered as a method of providing tumor- free marrow. It has been shown in the laboratory and clinic that there are immunologic anti-tumor effects of allogeneic BMT. This effect has been linked to the occurrence of Graft versus Host disease (GVHD). The ability to exploit this Graft versus-Leukemia (GVL) effect has been difficult. The goal of this project is to expand our understanding of this allogeneic anti-tumor effect by studying it in the laboratory in animal models and from patient samples obtained from the proposed clinical trials. We will try to augment the GVL effects of Donor Leukocyte Infusions (DLI) by subverting the mechanisms underlying the establishment of graft-host tolerance following allogeneic BMT. Although we will examine immunologic responses in animal models of DLA and GVHD (acute, chronic, and autologous) for GVL, our major emphasis will be on the balance between T cell activation and tolerance in controlling allogeneic responses. We will explore the role of antigen presenting cells which we postulate play a pivotal role (by their presence or absence) in regulating GVL. Immunologic responses of patients in a DLI trials will be characterized using functional and flow cytometric techniques. Finally, we will determine the optimal IL-2 dose to augment the GVL effect seen after lymphocyte depleted marrow grafts in a clinical and laboratory trial. IL-2 will be dose escalated based on effects on NK and T cell function measured in the laboratory instead of a traditional maximum tolerated dose escalation study. At the end of this project we should have an improved understanding of GVL and of methods to try to maximize the GVL effect.

同种异体 BMT 最初被认为是一种提供肿瘤治疗的方法。 游离骨髓。实验室和临床均表明 同种异体BMT具有免疫抗肿瘤作用。这 效应与移植物抗宿主的发生有关 疾病（GVHD）。利用这种移植物抗白血病的能力 （GVL）效果一直很困难。该项目的目标是 扩大我们对这种同种异体抗肿瘤作用的理解 在实验室的动物模型和患者身上进行研究 从拟议的临床试验中获得的样本。我们会尽力 通过以下方式增强供体白细胞输注 (DLI) 的 GVL 效果： 颠覆移植宿主建立的机制 同种异体 BMT 后的耐受性。 虽然我们会检查 DLA 和 GVHD（急性、 对于 GVL，我们的主要重点是 T细胞激活和耐受之间的平衡控制 同种异体反应。我们将探讨抗原呈递的作用 我们假设的细胞发挥着关键作用（通过它们的存在或 缺乏）调节GVL。患者的免疫反应 DLI 试验将使用功能和流程来表征 细胞计数技术。最后，我们将确定最佳的IL-2 增强淋巴细胞耗尽骨髓后 GVL 效应的剂量 临床和实验室试验中的移植物。 IL-2将剂量 根据对 NK 和 T 细胞功能的影响而升级 实验室而不是传统的最大耐受剂量 升级研究。在这个项目结束时我们应该有一个 提高对 GVL 和尝试最大化 GVL 的方法的理解 GVL效应。