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; 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.

由供体淋巴细胞输注（DLI）介导的移植物 - 抗宿主（GVH）同种酶 已建立的鼠混合造血嵌合体消除了正常和恶性宿主造血细胞 而不会引起移植物抗宿主病（GVHD）。随后立即管理类似DLI 调理会导致严重的GVHD。从 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，扩展，产生细胞因子并采用“记忆” 表型用作DLI以建立的混合同种异体嵌合体。因此，缺乏 GVHD不能归因于调节细胞对同种异答响应的全局抑制。这个有效的GVH 反应在很大程度上局限于淋巴瘤系统，因为T细胞不积聚在GVHD靶标中 组织。我们将其称为淋巴瘤性GVH反应（LGVHR）。我们有证据 当将DLI给予混合嵌合的患者时，可以在临床上发生类似现象 建立具有非毛囊条件。在MHC上实现没有GVHD的LGVHR的能力 障碍提供了一种实现针对淋巴瘤性恶性肿瘤的强大GVT效应的方法 没有GVHD。为了确定GVHR局限于的机制 DLI之后，我们将：1）比较GVH反应性CD4和CD的动力学 接受DLI的小鼠的T细胞激活，增殖，分化，组织积累和死亡 辐照后立即建立混合的同种异体嵌合体后立即延迟；我们 将解决凋亡增加和混合中其他差异的重要性和机制 嵌合体与新鲜辐照的小鼠。 2）比较生存率，增殖，迁徙特性和GVHD 在非炎症环境中产生的效应子/记忆T细胞的效应函数（即DLI之后 对已建立的混合嵌合体进行管理与促炎环境（即DLI之后 给予新鲜辐照的小鼠）当细胞被传递到任何一种类型的细胞时 环境。这些研究将确定T细胞中心与外在环境的程度 因素决定给定效应子/记忆细胞群体诱导GVHD的能力； 3）检查 调节细胞群体和T细胞稳态增殖的作用在调节易感性中 GVHD。研究将与项目2和3中的研究协同作用，并将广泛使用核心A，B， 和C.对延迟DLI接收者中LGVHR机制的改进理解将推进 项目3中的研究，最终在这种方法中临床使用将GVHD和GVT效应分开 HLA不匹配的造血细胞移植。