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。包含在干细胞接种物中的供体T细胞识别受体同种异体抗原是GVHD的主要原因。当用于造血恶性肿瘤（如白血病）的免疫治疗时，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细胞是一种多潜能前体，具有明确的抗原识别特异性，但根据遇到的信号分化为不同的谱系具有很大的可塑性。幼稚T辅助细胞（Th）可以分化为四种不同的亚群：Th1、Th2、Th17和T调节细胞，但这些活化的T细胞亚群对GVHD的发展和GVL效应的贡献尚不清楚。缺乏这些知识使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的作用。本项目的目的是了解Th1/Th17分化、诱导t细胞分化的细胞因子以及Th1/Th17细胞产生的细胞因子对GVHD发展和GVL活性的贡献。核心假设是，Th1和Th17亚群都有助于GVHD的发展，但任何一个谱系单独都足以诱导GVHD，因此必须阻断这两个谱系以控制GVHD。该提案将通过靶向谱系特异性转录因子(s)进行概念验证，系统而严格地解决Th1和Th17分化在GVHD中的贡献（目的1）。与此同时，将开展更多的翻译研究，以了解Th17启动和效应细胞因子在GVHD中的作用，以及体内同种异体反应中Th1/Th17谱系的相互调节（Aim 2）。由于同种异体HCT主要用于治疗造血恶性肿瘤，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mhc错配和匹配的白血病或淋巴瘤BMT模型来评估Th1/Th17亚群在GVL效应和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Th1/Th17分化（目的3）。从该研究项目中获得的信息将为调节t细胞分化提供理论依据和方法，以实现我们在保持GVL活性的同时预防GVHD的最终目标。

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.