MECHANISMS BY WHICH IFN-GAMMA SEPARATES GVHD AND GVL

在不减弱移植物抗白血病(GVL)效应的情况下选择性地预防GVHD的能力限制了 临床异基因造血细胞移植(allo-HCT)的成功，是治疗慢性粒细胞白血病的一种有效方法 治疗许多其他致命的血液系统恶性肿瘤。CD8 T细胞是主要的效应细胞 在allo-HCT后同时引起GVHD和GVL效应。我们之前的研究使用了抗干扰素-γ单抗和 干扰素-γ缺陷小鼠显示干扰素-γ通过以下途径限制供者CD8 T细胞的激活/扩增 诱导GVHD大鼠实质靶组织细胞凋亡及抑制单个核细胞侵袭 接受CD4耗尽的allo-HCT的受者，供者CD8T细胞会引起更严重的GVHD，但更少 在没有干扰素-γ的情况下，有效的抗淋巴造血GVH反应和GVL效应。的目标是 本项目旨在了解干扰素-γ调节供者CDS-T同种异体反应性的机制。 细胞作为开发方法的先决条件，可以在不严重的情况下诱导GVL效应 GVHD。在目标1中，我们将确定干扰素-γ是否限制两种受体抗原特异性的扩增 和-非特异性(内稳态增殖)供体CDS T细胞，并确定其机制 负责干扰素-γ诱导allo-HCT受者供者CDS T细胞的凋亡。在目标2中，我们将 验证干扰素-γ抑制供者迁移、原位增殖和/或存活的假说 CDS T细胞在实质GVHD靶组织中的作用，从而在保留GVL的同时抑制GVHD 效果。在目标3中，我们将确定干扰素-γ如何在不促进GVHD的情况下介导GVL效应。我们会： 1)建立干扰素-γ无反应性白血病模型，以确定干扰素-γ是否能增强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增敏来发挥作用；2) 干扰素-γ在不同细胞毒机制的同种异体反应性CTL分化中的作用 以及这些细胞毒机制在GVHD和GVL效应的诱导中的作用 3)确定NK细胞和NKT细胞在GVL诱导中的作用 效果。实现这些目标将有助于更好地理解全球变暖和 GVL相关CDS T细胞的同种异体反应并促进新方案的开发 人类白细胞抗原不全相合异基因红细胞移植的临床应用除了高度相关的假设外， 因此，PPG内的协作交互也可以基于模型来建立 在这个项目中开发的。

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.