Type 2 Innate Cell Regulation of Th1 Activity in Acute GvHD

急性 GvHD 中 Th1 活性的 2 型先天细胞调节

• 批准号: 8835686
• 负责人: Danny Bruce
• 金额: $ 5.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-02 至 2016-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835686
• 关键词: Accounting; Acute; Acute Graft Versus Host Disease; Acute leukemia; Adverse effects; Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Behavior Therapy; Bone Marrow; Bone Marrow Transplantation; Cell physiology; Cells; Clinical; Clinical Data; Data; Development; Disease; Dysmyelopoietic Syndromes; Effectiveness; Effector Cell; Environment; Explosion; Gastrointestinal tract structure; Generations; Goals; Graft-Versus-Tumor Induction; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Immune; Immunologics; Individual; Inflammatory; Infusion procedures; Interferons; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Investigation; Laboratories; Lead; Lower Gastrointestinal Tract; Lung; Lymphoid Cell; MPP2 gene; Malignant - descriptor; Malignant lymphoid neoplasm; Manuscripts; Mediating; Minor; Modeling; Multipotent Stem Cells; Mus; Myelogenous; Myeloid Cells; Organ; Outcome; Pancytopenia; Pathogenesis; Pathology; Patients; Phenotype; Play; Population; Process; Radiation; Regulation; Regulatory T-Lymphocyte; Research; Role; Skin; Stem cell transplant; Suppressor-Effector T-Lymphocytes; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells; Time; Transplantation; Tropism; chemotherapy; cytokine; effective therapy; graft vs host disease; high risk; improved; leukemia; macrophage; mortality; neoplastic cell; pre-clinical; prevent; public health relevance; receptor; response; tumor

 DESCRIPTION (provided by applicant): Allogeneic stem cell transplantation (allo-SCT) remains the most effective therapy for patients with high risk acute leukemia, specific low-grade lymphoid malignancies, and other malignant diseases. Widespread use is limited by the immunological consequence of allo-SCT, graft-versus-host disease (GvHD), which accounts for 15-30% of mortality in recipients. As a result, only 25-30% of patients who could benefit from allo-SCT receive this treatment. The effectiveness of allo-SCT is dependent upon elimination of tumor cells via conditioning therapy and the immunologic targeting of tumor cells by donor immune cells termed the graft-versus-leukemia (GvL) response. The desired effect, GvL and the unwanted side effect, acute GvHD (aGvHD) are mediated in part by donor T cells that recognize minor or major MHC disparities between donor and recipient/tumor. This leads to an immunological cascade in which T cells and other immune effector cells migrate and expand in host GvHD target organs leading to the unfortunate clinical consequence of a GvHD. The particular subset of T cells that mediates aGvHD is not clear. Several studies have implicated Th1 and/or Th17 T cells in the pathogenesis of aGvHD. Pre-clinical data suggest that IFN- producing Th1 cells are perhaps more important for GI tract aGvHD whereas IL-17 producing Th17 cells are more important for skin and lung pathology. However, both murine models and clinical data indicate that suppression of Th1 and Th17 responses by shifting to a Th2 T cell phenotype limits aGvHD. One potential mechanism for the enhanced Th1 tropism of the lower GI tract is the role of conditioning therapy on the release of cytokines and bacterial products tha may polarize naïve T cells toward a Th1. Our laboratory has shown that co-infusion of Tregs cells, reduces aGvHD by suppressing Th1 responses. The recent explosion of data surrounding innate immune cells, such as type 2 innate lymphoid cells (ILC2) and type 2 multipotent progenitors (MPP2) has increased the possibility of discovering additional candidate suppressive cells. Type 2 ILCs express significant quantities of Th2 cytokines, as well as regulatory receptors that are constitutively expressed on Tregs. The goal of this proposal is to evaluate the ability of type 2 innate cells to suppress allo-activated inflammatory Th1/Th17 cells, increase Th2 cell activation and enhance the development of anti-inflammatory M2 macrophages and myeloid-dervied suppressor cells (MDSC), suppressing aGvHD. For the first aim of this proposal we will investigate the hypothesis that the absence of host ILC2/MPP2 cells is critically important in the Th1 response in the GI tract and that infusion of ILC2/MPP2 cells wil alter the host cytokine profile, suppress Th1/Th17 cells and expand the Th2 population reducing GvHD without altering the GvL response. In addition, our second aim will investigate the mechanism(s) by which these cells function to prevent aGvHD and the hypothesis that co-transplantation of activated ILC2 and MPP2 cells alters the development of M2 macrophages and MDSCs as a result of the generation of a type 2 micro-environment.

 描述（由申请人提供）：同种异体干细胞移植（allo-SCT）仍然是治疗高危急性白血病、特定低度淋巴恶性肿瘤和其他恶性疾病的最有效疗法，其广泛使用受到免疫学后果的限制。 allo-SCT，即移植物抗宿主病 (GvHD)，仅占受者死亡率的 15-30%。 25-30% 可以从异基因 SCT 中受益的患者接受这种治疗。异基因 SCT 的有效性取决于通过调理治疗消除肿瘤细胞以及供体免疫细胞对肿瘤细胞的免疫靶向（称为移植物抗-）。白血病 (GvL) 反应所需的效果、GvL 和不需要的副作用、急性 GvHD (aGvHD) 部分是由供体 T 细胞介导的，这些 T 细胞识别供体和供体之间轻微或主要的 MHC 差异。这会导致免疫级联反应，其中 T 细胞和其他免疫效应细胞在宿主 GvHD 靶器官中迁移和扩增，导致 GvHD 的不幸临床后果。介导 aGvHD 的特定 T 细胞亚群尚不清楚。多项研究表明 Th1 和/或 Th17 T 细胞与 aGvHD 的发病机制有关。临床前数据表明，产生 IFN-γ 的 Th1 细胞可能对胃肠道更为重要。 aGvHD 而产生 IL-17 的 Th17 细胞对皮肤和肺部病理学更重要，然而，小鼠模型和临床数据表明，通过转变为 Th2 T 细胞表型来抑制 Th1 和 Th17 反应限制了 aGvHD 增强的一种潜在机制。下胃肠道的 Th1 向性是调理治疗对细胞因子和细菌产物释放的作用，这些细胞因子和细菌产物可能使幼稚 T 细胞极化为 Th1。最近有关先天免疫细胞（例如 2 型先天淋巴细胞 (ILC2) 和 2 型多能祖细胞 (MPP2)）的数据激增，增加了发现其他候选抑制性细胞的可能性。 ILC 表达大量的 Th2 细胞因子以及在 Tregs 上组成型表达的调节受体。本提案的目标是评估 2 型先天性的能力。细胞抑制同种异体激活的炎症 Th1/Th17 细胞， 增加 Th2 细胞活化并增强抗炎 M2 巨噬细胞和骨髓来源抑制细胞 (MDSC) 的发育，抑制 aGvHD 对于本提案的第一个目标，我们将研究宿主 ILC2/MPP2 细胞的缺失至关重要的假设。在胃肠道的 Th1 反应中很重要，ILC2/MPP2 细胞的输注将改变宿主细胞因子谱，抑制 Th1/Th17 细胞并扩大 Th2 细胞群，从而减少此外，我们的第二个目标是研究这些细胞预防 aGvHD 的机制，以及活化的 ILC2 和 MPP2 细胞的共移植会改变 M2 巨噬细胞和 MDSC 发育的假设。 2 型微环境生成的结果。