IMMUNOBIOLOGY OF LYMPHOHEMATOPOIETIC GVH REACTIONS

供者淋巴细胞输注(DLI)介导的移植物抗宿主(GVH)异体反应 已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 而不会引起移植物抗宿主病(GVHD)。紧随其后实施类似的DLI 条件反射导致严重的移植物抗宿主病。更强大的移植物抗肿瘤(GVT)效果是通过 混合造血嵌合体的延迟DLI比完全同种异体嵌合体的延迟DLI要好。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” 对已建立的混合同种异体嵌合体给予DLI时的表型。因此，缺乏 GVHD不能归因于全球抑制调节细胞的同种异体反应。这个强大的GVH 反应主要局限于淋巴造血系统，因为T细胞不会在GVHD靶区积聚 纸巾。我们称之为淋巴造血性GVH反应(LGVHR)。我们已经获得了证据 当给混合嵌合体患者进行DLI时，临床上也会发生类似的现象 建立在非清髓性条件作用下。跨MHC实现无GVHD的LGVHR的能力 BALECTS提供了一种获得针对淋巴造血系统恶性肿瘤的强大GVT效应的方法 没有GVHD。为了确定GVHR被限制在 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 DLI小鼠T细胞活化、增殖、分化、组织蓄积和死亡 在照射后立即或在混合同种异体嵌合体建立后延迟； 将阐述细胞凋亡增加的意义和机制与其他混合疾病的差异 嵌合体与新照射的小鼠。2)比较GVHD和GVHD的存活、增殖、迁移特性 非炎症性环境中产生的效应器/记忆T细胞的效应器功能(即DLI 已建立的混合嵌合体的给药)与促炎环境(即遵循DLI 给新照射的小鼠)当细胞过继转移到 环境。这些研究将确定T细胞内在与外在环境之间的关系 决定特定效应/记忆细胞群体诱发移植物抗宿主病的能力的因素；3)检查 调节性细胞群体和T细胞稳态增殖在调节易感性中的作用 GVHD。这些研究将与项目2和项目3中的研究协同进行，并将广泛使用A、B、 以及C.对延迟DLI受者LGVHR机制的更好理解将促进 项目3中的研究，并最终临床使用这种方法来分离GVHD和GVT的影响 血型不合的造血细胞移植。

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.