MECHANISMS BY WHICH IFN-GAMMA SEPARATES GVHD AND GVL

IFN-γ 分离 GVHD 和 GVL 的机制

基本信息

批准号：
7158088
负责人：
YONG-GUANG YANG
金额：
$ 17.75万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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

项目摘要

The inability to selectively prevent GVHD without diminishing graft-vs.-leukemia (GVL) effects limits the success of clinical allogeneic hematopoietic cell transplantation (allo-HCT), an effective therapy for the treatment of many otherwise fatal hematologic malignancies. CD8 T cells are major effector cells that induce both GVHD and GVL effects after allo-HCT. Our previous studies using anti-IFN-gamma mAb and IFN-gamma-deficient mice showed that IFN-gamma restricts donor CD8 T cell activation/expansion through induction of apoptosis and inhibits mononuclear cell infiltration in parenchymal GVHD target tissues in recipients of CD4-depleted allo-HCT, and that donor CD8 T cells induce more severe GVHD but less potent anti-lymphohematopoietic GVH reactions and GVL effects in the absence of IFN-gamma. The goal of this project is to understand the mechanisms by which IFN-gamma regulates the alloreactivity of donor CDS T cells as a prerequisite to the development of approaches that can induce GVL effects without severe GVHD. In Aim 1, we will determine whether or not IFN-gamma restricts expansion of both recipient antigen-specific and -nonspecific (homeostatic proliferation) donor CDS T cells, and identify the mechanisms responsible for IFN-gamma-induced apoptosis of donor CDS T cells in allo-HCT recipients. In Aim 2, we will test the hypothesis that IFN-gamma suppresses the migration, in-situ proliferation and/or survival of donor CDS T cells in parenchymal GVHD target tissues and thereby inhibits GVHD while preserving GVL effects. In Aim 3, we will determine how IFN-gamma mediates GVL effects without promoting GVHD. We will: 1) develop IFN-gamma-unresponsive leukemia models to determine whether or not IFN-gamma can enhance GVL effects by inhibiting tumor cell proliferation and/or sensitizing tumor cells to alloreactive CTLs; 2) assess the role of IFN-gamma in the differentiation of alloreactive CTLs with different cytotoxic mechanisms and the contribution of these cytotoxic mechanisms to the induction of GVHD vs. GVL effects in the presence and absence of IFN-gamma; and 3) determine the role of NK and NKT cells in the induction of GVL effects. Achieving these aims will lead to a better understanding of mechanisms involved in GVHDand GVL-associated alloreactivity of CDS T cells and facilitate the development of novel protocols for the performance of HLA-mismatched allo-HCT in the clinic. In addition to highly-relevant hypotheses to be addressed, collaborative interactions within the PPG can also be established based on the models developed in this project.

无法在不减弱移植物抗白血病（GVL）效应的情况下选择性预防 GVHD 限制了异基因造血细胞移植（allo-HCT）临床成功，是治疗造血干细胞移植的有效方法治疗许多其他致命的血液恶性肿瘤。 CD8 T 细胞是主要效应细胞 allo-HCT 后诱导 GVHD 和 GVL 效应。我们之前的研究使用抗 IFN-gamma mAb 和 IFN-gamma 缺陷小鼠表明，IFN-gamma 通过限制供体 CD8 T 细胞的激活/扩增诱导细胞凋亡并抑制实质 GVHD 靶组织中的单核细胞浸润 CD4 耗尽的同种异体 HCT 的受者，以及供体 CD8 T 细胞诱导更严重的 GVHD，但较少在没有 IFN-γ 的情况下，具有有效的抗淋巴造血 GVH 反应和 GVL 作用。目标是该项目旨在了解 IFN-gamma 调节供体 CDS T 的同种异体反应性的机制细胞作为开发可诱导 GVL 效应而无需严重的方法的先决条件移植物抗宿主病。在目标 1 中，我们将确定 IFN-gamma 是否限制受体抗原特异性的扩增 -非特异性（稳态增殖）供体 CDS T 细胞，并确定其机制负责同种异体 HCT 受者中 IFN-γ 诱导的供体 CDS T 细胞凋亡。在目标 2 中，我们将检验 IFN-γ 抑制供体的迁移、原位增殖和/或存活的假设 CDS T 细胞位于实质 GVHD 靶组织中，从而抑制 GVHD，同时保留 GVL 影响。在目标 3 中，我们将确定 IFN-γ 如何介导 GVL 效应而不促进 GVHD。我们将： 1）开发IFN-gamma无反应性白血病模型以确定IFN-gamma是否可以增强GVL 通过抑制肿瘤细胞增殖和/或使肿瘤细胞对同种异体反应性 CTL 敏感来发挥作用； 2）评估 IFN-γ 在具有不同细胞毒性机制的同种异体反应性 CTL 分化中的作用以及这些细胞毒性机制对诱导 GVHD 与 GVL 效应的贡献存在和不存在 IFN-γ； 3)确定NK和NKT细胞在诱导GVL中的作用影响。实现这些目标将有助于更好地理解 GVHD 所涉及的机制 CDS T 细胞的 GVL 相关同种异体反应性并促进新方案的开发 HLA不匹配的allo-HCT在临床中的表现。除了高度相关的假设之外待解决，PPG内部的协作交互也可以基于模型建立在这个项目中开发的。