Th1/Th17 Cell Differentiation in GVHD and GVL

GVHD 和 GVL 中的 Th1/Th17 细胞分化

• 批准号: 8458597
• 负责人: Xue-Zhong Yu
• 金额: $ 29.37万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458597
• 关键词: Address; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Antigens; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cells; Clinical; Complication; Development; Disease; Genes; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Hematopoietic; Immunologics; Immunotherapy; In Vitro; Incidence; Infection; Injury; Interleukin-17; Interleukin-4; Interleukin-6; Intervention; Knowledge; Learning; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mediating; Minor Histocompatibility Antigens; Modeling; Morbidity - disease rate; Mus; Non-Malignant; Normal tissue morphology; Pathology; Patients; Play; Regulation; Regulatory T-Lymphocyte; Research; Research Project Grants; Residual Tumors; Role; Severity of illness; Signal Transduction; Specificity; Stem cells; T cell differentiation; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic procedure; Tissues; base; clinically relevant; cytokine; defined contribution; graft function; graft versus host disease induction; graft vs host disease; hematopoietic cell transplantation; in vivo; leukemia; mortality; neoplastic cell; neutralizing antibody; prevent; public health relevance; receptor; success; transcription factor; translational study; tumor

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.

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，但是移植物抗旋转疾病（GVHD）仍然是HCT成功的主要障碍，因为它导致了较高的发病率和死亡率和死亡率。供体T细胞包含在干细胞接种物中并识别受体同种剂的供体T细胞是GVHD的主要原因。当用作造血恶性肿瘤的免疫疗法（例如白血病）时，同种异体HCT的治疗潜力取决于移植物 - 白细胞（GVL）的效应，可以通过免疫学机制消除残留的肿瘤细胞。 T细胞是一种具有定义的抗原识别特异性的多电势前体，但可根据遇到的信号分化为不同的谱系的可塑性。幼稚的T辅助细胞（Th）可以分为四个不同的子集：TH1，TH2，TH17和T调节细胞，但是这些激活的T细胞子集对GVHD发育的贡献和GVL效应尚不清楚。缺乏知识使我们无法选择性地靶向致病性子集或其相关的细胞因子来控制GVHD，同时保持GVL效应。该项目的目的是了解Th1/Th17分化的贡献，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发育和GVL活性的贡献。中心假设是Th1和Th17子集都有助于GVHD的发展，但单独的谱系都足以诱导GVHD，因此必须阻止两个谱系以控制GVHD。该提案将通过靶向特定于谱系的转录因子（AIM 1）来系统，严格地解决GVHD中Th1和Th17分化的贡献。同时，将进行更多的翻译研究，以了解Th17启动和效应子细胞因子在GVHD中的作用以及Th1/Th17谱系在体内的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T细胞不同子集对GVL效应的贡献至关重要。我们将通过使用白血病或淋巴瘤使用MHC不匹配和匹配的BMT模型来评估TH1/TH17亚集在GVL效应中的作用以及GVHD的发展。此外，在这些研究中，将使用临床适用的干预措施来阻止Th1/Th17的分化（AIM 3）。从该研究项目中汲取的信息将提供基本原理和手段，以规范T细胞分化，以防止GVHD在避免GVL活动时进行防止GVHD。

项目成果

Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice.

• DOI: 10.1371/journal.pone.0137641
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Schutt SD;Fu J;Nguyen H;Bastian D;Heinrichs J;Wu Y;Liu C;McDonald DG;Pidala J;Yu XZ
• 通讯作者: Yu XZ