Th1/Th17 Cell Differentiation in GVHD and GVL

描述（由申请人提供）：造血细胞移植（HCT）为治疗各种恶性和非恶性造血系统疾病提供了巨大的希望，但移植物抗宿主病（GVHD）仍然是HCT成功的主要障碍，因为它导致高发病率和死亡率。包括在干细胞接种物中并识别受体同种异体抗原的供体T细胞是GVHD的主要原因。当用作造血系统恶性肿瘤（例如白血病）的免疫疗法时，同种异体HCT的治疗潜力依赖于移植物抗白血病（GVL）效应，通过免疫机制根除残留的肿瘤细胞。T细胞是一种多潜能的前体细胞，具有明确的抗原识别特异性，但根据遇到的信号分化成不同谱系的可塑性很大。初始辅助性T细胞（Th）可分化为Th 1、Th 2、Th 17和调节性T细胞，但这些活化的T细胞亚群在GVHD发生和GVL效应中的作用尚不清楚。由于缺乏这些知识，我们无法选择性地靶向致病亚群或其相关细胞因子来控制GVHD，同时维持GVL效应。该项目的目标是了解Th 1/Th 17分化、诱导T细胞分化的细胞因子以及Th 1/Th 17细胞产生的细胞因子对GVHD发展和GVL活性的贡献。中心假设是Th 1和Th 17亚群都有助于GVHD的发展，但单独的任一谱系足以诱导GVHD，因此必须阻断这两种谱系以控制GVHD。该提案将通过靶向谱系特异性转录因子以进行概念验证（目的1），系统地和严格地解决Th 1和Th 17分化在GVHD中的贡献。与此同时，将进行更多的翻译研究，以了解Th 17引发和效应细胞因子在GVHD中的作用，以及Th 1/Th 17谱系在体内同种异体反应中的相互调节（目的2）。由于异基因HCT主要用于治疗造血系统恶性肿瘤，因此评估不同T细胞亚群对GVL效应的贡献至关重要。我们将通过使用白血病或淋巴瘤的MHC不匹配和匹配的BMT模型来评估Th 1/Th 17亚群在GVL效应沿着GVHD发展中的作用。此外，在这些研究中，临床适用的干预措施将用于阻断Th 1/Th 17分化（目标3）。从这项研究项目中获得的信息将提供调节T细胞分化的原理和方法，以实现我们预防GVHD同时保留GVL活性的最终目标。 公共卫生相关性：造血细胞移植（HCT）为治疗包括癌症在内的各种疾病提供了巨大的希望。然而，这种治疗过程有一个主要的并发症，称为移植物抗宿主病（GVHD），这是由供体T细胞诱导的，这些T细胞识别不同的抗原并导致受体的组织损伤。另一方面，供体T细胞也可以为患者带来有益的效果，包括抗肿瘤和抗感染。在当前的研究中，我们将研究供体T细胞如何对受体正常组织和肿瘤细胞中的抗原做出反应。这些结果可能提供了调节T细胞活化的原理和方法，以达到我们预防GVHD的最终目标，同时保留供体T细胞介导的有益作用。

DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) offers great promise for the treatment of a variety of malignant and non-malignant hematopoietic diseases, but graft-versus-host disease (GVHD) remains the major obstacle for success of HCT as it leads to high incidence of morbidity and mortality. Donor T cells that are included in the stem cell inoculum and recognize recipient alloantigens are the major cause of GVHD. When used as immunotherapy for hematopoietic malignances (e.g. leukemia), the therapeutic potential of allogeneic HCT relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. T cell is a multi-potential precursor with defined antigen recognition specificity but substantial plasticity for differentiation into distinct lineages according to the signals encountered. Naive T helper cells (Th) can differentiate into four different subsets: Th1, Th2, Th17 and T regulatory cells, but the contributions of these activated T cell subsets to GVHD development and GVL effect remains unclear. Lacking the knowledge precludes us from selectively targeting the pathogenic subset or its associated cytokines for controlling GVHD while maintaining GVL effect. The goal of this project is to understand the contribution of Th1/Th17 differentiation, the cytokines that induce T-cell differentiation, and the cytokines produced by Th1/Th17 cells to GVHD development and GVL activity. The central hypothesis is that both the Th1 and Th17 subsets contribute to GVHD development but either lineage alone is sufficient to induce GVHD, and thus both lineages must to be blocked in order to control GVHD. This proposal will systematically and stringently addresses the contribution of Th1 and Th17 differentiation in GVHD by targeting lineage-specific transcription factor(s) for proof-of-concept (Aim 1). In parallel, more translational studies will be conducted to understand the role of Th17 priming and effector cytokine in GVHD and the reciprocal regulation of Th1/Th17 lineages in alloresponse in vivo (Aim 2). Because allogeneic HCT is primarily utilized to treat hematopoietic malignances, it is critically important to evaluate the contribution of different subset of T cells to GVL effect. We will evaluate the role of Th1/Th17 subsets in GVL effect along with GVHD development by using MHC-mismatched and -matched BMT models with leukemia or lymphoma. Furthermore, clinically applicable interventions will be used to block Th1/Th17 differentiation in these studies (Aim 3). The information learned from this research project will provide the rationale and means to regulate T-cell differentiation toward our ultimate goal of preventing GVHD while sparing GVL activity. PUBLIC HEALTH RELEVANCE: Hematopoietic cell transplantation (HCT) offers great promise for the treatment of a variety of diseases, including cancer. However, this therapeutic procedure has a major complication, termed graft-versus-host disease (GVHD), which is induced by donor T cells that recognize disparate antigens and cause tissue injuries in the recipient. Donor T cells, on the other hand, can also bring beneficial effects to the patient, including anti- tumor and anti-infection. In the current research, we will study how donor T cells respond to antigens in recipient normal tissues and in tumor cells. Results may provide the rationale and means to regulate T-cell activation toward our ultimate goal of preventing GVHD while sparing those beneficial effects mediated by donor T cells.