MECHANISMS BY WHICH IFN-GAMMA SEPARATES GVHD AND GVL

IFN-γ 分离 GVHD 和 GVL 的机制

• 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
• 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/7158088
• 关键词: antigen antibody reaction; antineoplastics; apoptosis; cell migration; cell proliferation; clinical research; cytotoxic T lymphocyte; disease /disorder model; graft versus host disease; hematopoietic tissue transplantation; homologous transplantation; interferon gamma; intravital microscopy; laboratory mouse; leukemia; leukocyte activation /transformation; model design /development; molecular dynamics; monoclonal antibody; natural killer cells; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; stem cell transplantation; tissue donors; transfection

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.

不能选择性地预防GVHD而不减少移植物-vs.白血病（GVL）的影响限制了 临床上异基因造血细胞移植（allo-HCT）的成功， 治疗许多其他致命的血液恶性肿瘤。CD 8 T细胞是主要的效应细胞， 在allo-HCT后诱导GVHD和GVL效应。我们以前的研究使用抗IFN-γ mAb和 IFN-γ缺陷小鼠显示IFN-γ通过以下途径限制供体CD 8 T细胞活化/扩增： 诱导细胞凋亡和抑制单核细胞浸润的实质GVHD靶组织中， 供体CD 8 T细胞诱导更严重的GVHD，而供体CD 8 T细胞诱导更严重的GVHD， 在没有IFN-γ的情况下，有效的抗淋巴造血GVH反应和GVL作用。的目标 本项目旨在了解IFN-γ调节供体CDS-T同种异体反应性的机制 细胞作为开发可以诱导GVL效应而没有严重的GVL效应的方法的先决条件。 GVHD。在目标1中，我们将确定IFN-γ是否限制受体抗原特异性 和非特异性（稳态增殖）供体CDS T细胞，并确定机制 负责IFN-γ诱导的同种异体HCT受体中供体CD 8 T细胞的凋亡。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 实质GVHD靶组织中的CD 8 T细胞，从而抑制GVHD，同时保留GVL 方面的影响.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-γ无反应性白血病模型，以确定IFN-γ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敏感的作用; 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。 IFN-γ的存在和不存在;和3）确定NK和NKT细胞在GVL诱导中的作用 方面的影响.实现这些目标将有助于更好地理解GVHD的相关机制， GVL相关的CDS T细胞的同种异体反应性，并促进新方案的开发， HLA不匹配的allo-HCT在临床上的表现。除了高度相关的假设， 在这些模型的基础上，还可以建立PPG内部的协作交互 在这个项目中开发的。