IMMUNOBIOLOGY OF LYMPHOHEMATOPOIETIC GVH REACTIONS

供体淋巴细胞输注（DLI）介导的移植物抗宿主（GVH）同种异体反应， 建立的鼠混合造血嵌合体消除正常和恶性宿主造血细胞 而不引起移植物抗宿主病（GVHD）。类似DLI给药后立即 调理导致严重的GVHD。更有效的移植物抗肿瘤（GVT）效果是从 与完全同种异体嵌合体相比，对混合造血嵌合体给予延迟的DLI。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施用至建立的混合同种异体嵌合体时，表型。因此，缺乏 GVHD不能归因于调节细胞对同种异体反应的全面抑制。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靶细胞中积累。 组织中我们称之为淋巴造血GVH反应（LGVHR）。我们有证据表明 当对混合嵌合体的患者给予DLI时，临床上可能发生类似的现象， 建立了非清髓性条件反射。在整个MHC中实现LGVHR而不发生GVHD的能力 屏障提供了一种方法，以实现强大的GVT效应，对淋巴造血系统恶性肿瘤 没有GVHD。为了确定GVHR局限于 DLI后淋巴造血系统，我们将：1）比较GVH反应性CD 4和CDS的动力学 接受DLI的小鼠中的T细胞活化、增殖、分化、组织积聚和死亡 照射后立即或延迟建立混合异基因嵌合体;我们 将解决的意义和机制，增加细胞凋亡和其他差异，在混合 嵌合体与新鲜照射的小鼠。2)比较移植物的存活、增殖、迁移特性和GVHD 在非炎性环境（即DLI后）中产生的效应/记忆T细胞的效应功能 给予建立的混合嵌合体）与促炎环境（即DLI后 当细胞过继转移到任一类型的细胞中时， 环境这些研究将确定T细胞-内在与外在环境 决定给定效应/记忆细胞群诱导GVHD的能力的因素; 3）检查 调节细胞群和T细胞稳态增殖在调节对 GVHD。这些研究将与项目2和项目3的研究产生协同作用，并将广泛利用核心A、B、 和C.对延迟DLI受者中LGVHR机制的更好理解将促进 项目3中的研究，并最终在临床上使用这种方法来分离GVHD和GVT的影响， HLA错配造血细胞移植

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.