IMMUNOBIOLOGY OF LYMPHOHEMATOPOIETIC GVH REACTIONS

淋巴造血 GVH 反应的免疫生物学

• 批准号: 7158084
• 负责人: Megan Sykes
• 金额: $ 17.53万
• 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/7158084
• 关键词: antineoplastics; antitumor antibody; cell migration; cell proliferation; clinical research; cytotoxic T lymphocyte; graft versus host disease; helper T lymphocyte; hematopoietic tissue transplantation; homologous transplantation; hybrid antibody; inflammation; injection /infusion; laboratory mouse; leukemia; leukocyte activation /transformation; lymphatic system; lymphocyte; lymphoma; molecular dynamics; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; stem cell transplantation; tissue donors; transfection

Graft-versus-host (GVH) alloresponses mediated by donor lymphocyte infusions (DLI) administered to established murine mixed hematopoietic chimeras eliminate normal and malignant host hematopoietic cells without causing graft-versus-host disease (GVHD). Administration of similar DLI immediately following conditioning leads to severe GVHD. More potent graft-versus-tumor (GVT) effects are achieved from delayed DLI given to mixed hematopoietic chimeras than are achieved in fully allogeneic chimeras. We have observed that GVH-reactive T cells are activated, expand, produce cytokines and adopt the "memory" phenotype when administered as DLI to established mixed allogeneic chimeras. Therefore, the lack of GVHD cannot be attributed to global suppression of the alloresponse by regulatory cells. This potent GVH reaction is largely confined to the lymphohematopoietic system, as T cells do not accumulate in GVHD target tissues. We refer to this as a lymphohematopoietic GVH reaction (LGVHR). We have obtained evidence that a similar phenomenon can occur clinically when DLI are given to patients in whom mixed chimerism is established with non-myeloablative conditioning. The ability to achieve LGVHR without GVHD across MHC barriers provides an approach to achieving powerful GVT effects against lymphohematopoietic malignancies without GVHD. In order to identify the mechanisms whereby GVHR are confined to the lymphohematopoietic system following DLI, we will: 1) Compare the kinetics of GVH-reactive CD4 and CDS T cell activation, proliferation, differentiation, tissue accumulation and death in mice receiving DLI immediately following irradiation or with a delay following establishment of mixed allogeneic chimerism; we will address the significance and mechanisms of increased apoptosis and other differences in mixed chimeras vs freshly irradiated mice. 2) Compare the survival, proliferation, migratory properties and GVHD effector function of effector/memory T cells generated in a non-inflammatory environment (i.e. following DLI administration to established mixed chimeras) versus a pro-inflammatory environment (i.e. following DLI administration to freshly irradiated mice) when the cells are adoptively transferred to either type of environment. These studies will determine the extent to which T cell-intrinsic versus extrinsic environmental factors determine the capacity of a given effector/memory cell population to induce GVHD; 3) Examine the role of regulatory cell populations and of T cell homeostatic proliferation in modulating susceptibility to GVHD. The studies will synergize with those in Projects 2 and 3, and will make extensive use of Cores A, B, and C. An improved understanding of the mechanisms of LGVHR in delayed DLI recipients will advance the studies in Project 3 and ultimately the clinical use of this approach to separating GVHD and GVT effects in HLA-mismatched hematopoietic cell transplantation.

由供者淋巴细胞输注（DLI）介导的移植物抗宿主（GVH）同种异体反应 建立的小鼠混合造血嵌合体消除正常和恶性宿主造血细胞 不会引起移植物抗宿主病（GVHD）。随后立即进行类似的 DLI 调理会导致严重的GVHD。更有效的移植物抗肿瘤（GVT）效果是通过 与完全同种异体嵌合体相比，混合造血嵌合体的 DLI 延迟。我们有 观察到 GVH 反应性 T 细胞被激活、扩增、产生细胞因子并采用“记忆” 当作为 DLI 施用以建立混合同种异体嵌合体时的表型。因此，缺乏 GVHD 不能归因于调节细胞对同种异体反应的整体抑制。这种有效的 GVH 反应主要局限于淋巴造血系统，因为 T 细胞不会在 GVHD 靶标中积累 组织。我们将此称为淋巴造血 GVH 反应 (LGVHR)。我们已取得证据 当 DLI 给予混合嵌合体患者时，临床上也会出现类似的现象 通过非清髓性调理建立。跨 MHC 无需 GVHD 即可实现 LGVHR 的能力 屏障提供了一种针对淋巴造血系统恶性肿瘤实现强大 GVT 效应的方法 没有GVHD。为了确定 GVHR 仅限于 DLI 后的淋巴造血系统，我们将： 1) 比较 GVH 反应性 CD4 和 CDS 的动力学 接受 DLI 的小鼠中 T 细胞激活、增殖、分化、组织积累和死亡 辐射后立即或在混合同种异体嵌合体建立后延迟；我们 将解决细胞凋亡增加的意义和机制以及混合细胞中的其他差异 嵌合体与刚受辐射的小鼠。 2) 比较存活、增殖、迁移特性和GVHD 在非炎症环境中（即 DLI 之后）生成的效应/记忆 T 细胞的效应功能 给予已建立的混合嵌合体）与促炎环境（即 DLI 之后 当细胞过继转移到任一类型的 环境。这些研究将确定 T 细胞内在与外在环境的影响程度 因素决定给定效应/记忆细胞群诱导 GVHD 的能力； 3) 检查 调节细胞群和 T 细胞稳态增殖在调节易感性中的作用 移植物抗宿主病。这些研究将与项目 2 和 3 中的研究相协同，并将广泛使用核心 A、B、 C. 更好地了解延迟 DLI 接受者的 LGVHR 机制将促进 项目 3 中的研究以及最终在临床中使用这种方法来分离 GVHD 和 GVT 效应 HLA 不匹配的造血细胞移植。