Mechanistic Evaluations of ILC2 Cells for the Treatment/Prevention of GVHD

ILC2 细胞治疗/预防 GVHD 的机制评估

• 批准号: 9403099
• 负责人: Jonathan S. Serody
• 金额: $ 54.38万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403099
• 关键词: Acute Graft Versus Host Disease; Address; Adrenal Cortex Hormones; Adverse effects; Allogenic; Amphiregulin; Behavior Therapy; Binding; Bone Marrow Cells; Bone Marrow Transplantation; Calcineurin inhibitor; Cause of Death; Cell Therapy; Cell physiology; Cells; Clinical Trials; Colon; Dendritic Cells; Development; Diagnosis; Diarrhea; Disease; Dose; Dysmyelopoietic Syndromes; Effector Cell; Environment; Epithelial; Epithelial Cells; Evaluation; Future; Gastrointestinal tract structure; Generations; Germ Lines; Goals; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematological Disease; Histocompatibility; Homeostasis; Human; Immune; Immune response; Immunosuppressive Agents; Individual; Inflammatory Response; Infusion procedures; Institution; Interleukin-13; Interleukin-4; Interleukin-5; Intestines; Lower Gastrointestinal Tract; Lymphoid Cell; Lymphoma; Maintenance; Malignant - descriptor; Mediating; Metabolic; Methotrexate; Minor; Mus; Myelogenous; Myeloid Cells; Myofibroblast; Organ; Parasitic infection; Pathogenesis; Patient-Focused Outcomes; Patients; Population; Prevention; Prevention approach; Process; Production; Radiation; Recruitment Activity; Recurrence; Refractory; Regulatory T-Lymphocyte; Relapse; Research Personnel; Role; STAT6 gene; Severities; Signal Transduction; Small Intestines; Stem cell transplant; Stem cells; Steroids; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; TC1 Cell; TSLP gene; Th2 Cells; Therapeutic Uses; Tissues; Translating; Transplantation; aggressive therapy; bone; bone marrow failure syndrome; chemotherapy; cytokine; graft vs host disease; high risk; improved; improved outcome; in vivo; interest; interleukin-13 receptor; killings; leukemia; novel strategies; nutrient absorption; polarized cell; prevent; receptor; reconstitution; repaired; response; standard care; targeted treatment; transcription factor; Acute Graft Versus Host Disease; Address; Adrenal Cortex Hormones; Adverse effects; Allogenic; Amphiregulin; Behavior Therapy; Binding; Bone Marrow Cells; Bone Marrow Transplantation; Calcineurin inhibitor; Cause of Death; Cell Therapy; Cell physiology; Cells; Clinical Trials; Colon; Dendritic Cells; Development; Diagnosis; Diarrhea; Disease; Dose; Dysmyelopoietic Syndromes; Effector Cell; Environment; Epithelial; Epithelial Cells; Evaluation; Future; Gastrointestinal tract structure; Generations; Germ Lines; Goals; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematological Disease; Histocompatibility; Homeostasis; Human; Immune; Immune response; Immunosuppressive Agents; Individual; Inflammatory Response; Infusion procedures; Institution; Interleukin-13; Interleukin-4; Interleukin-5; Intestines; Lower Gastrointestinal Tract; Lymphoid Cell; Lymphoma; Maintenance; Malignant - descriptor; Mediating; Metabolic; Methotrexate; Minor; Mus; Myelogenous; Myeloid Cells; Myofibroblast; Organ; Parasitic infection; Pathogenesis; Patient-Focused Outcomes; Patients; Population; Prevention; Prevention approach; Process; Production; Radiation; Recruitment Activity; Recurrence; Refractory; Regulatory T-Lymphocyte; Relapse; Research Personnel; Role; STAT6 gene; Severities; Signal Transduction; Small Intestines; Stem cell transplant; Stem cells; Steroids; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; TC1 Cell; TSLP gene; Th2 Cells; Therapeutic Uses; Tissues; Translating; Transplantation; aggressive therapy; bone; bone marrow failure syndrome; chemotherapy; cytokine; graft vs host disease; high risk; improved; improved outcome; in vivo; interest; interleukin-13 receptor; killings; leukemia; novel strategies; nutrient absorption; polarized cell; prevent; receptor; reconstitution; repaired; response; standard care; targeted treatment; transcription factor

Abstract: Graft-versus-host disease (GvHD) remains the predominant factor limiting the widespread utilization of allogeneic stem cell transplantation (allo-SCT) for the treatment of patients with high-risk or recurrent hematological malignancies. The primary approach to the prevention of acute GvHD is the use of calcineurin inhibitors (CNI) with methotrexate. With this approach, approximately, 30-80% of patients undergoing matched related or unrelated stem cell transplantation will develop acute GvHD. For patients that develop acute GvHD, therapy has not changed in over 30 years and consists of systemic corticosteroids. This approach has substantial side-effects leading to severe long-term complications. Treatment for patients with steroid-refractory acute GvHD is suboptimal with fewer than 15% of patients treated living more than a year after diagnosis. Thus, new forms of therapy are badly needed to improve the outcome of patients undergoing allo-SCT. Aggressive therapy targeting donor T cells in patients with steroid refractory acute GvHD of the lower GI tract, has not improved the long term outcome of patients refractory to corticosteroid therapy. This has led to increased interest in understanding how conditioning therapy and GvHD alter the homeostatic environment of the lower GI tract. Over the past 36 months, my group has evaluated the function of a relatively new population of innate lymphoid cells, termed type 2 innate lymphoid cells (ILC2). These cells are found in the GI tract and generate IL-4, IL-5 and IL-13. The cytokines IL-25 and IL-33 are critical to the generation of ILC2 cells. In the current proposal, we demonstrate that ILC2 cells are radiation and chemotherapy sensitive, and that they poorly reconstitute over a three month period from donor bone marrow cells. We demonstrate that infusion of donor ILC2 cells can prevent and more importantly TREAT ongoing acute GvHD of the lower GI tract. This was associated with significant decreases in donor Th1/Th17 and Tc1 cells in the colon and small bowel and improvement in colonic epithelial cell integrity. The activity of ILC2 cells required the generation of IL-13 and amphiregulin (AREG) by the ILC2 cells. Administration of ILC2 cells had no effect on the GvL response. The goals of the current proposal are to assess the use of ILC2 cells as a novel approach to the treatment of acute GvHD. We will investigate the mechanism by which ILC2 cells treat lower tract GvHD, the function of myeloid derived suppressor cells (MDSCs) and Tregs in this activity, and the roles that IL-13, AREG, dendritic cells and intestinal subepithelial myofibroblasts (ISEMFs) have in the activity of ILC2 cells. We will demonstrate that ILC2 cells function in mice receiving CNI and/or steroids, which will allow us to rapidly translate these findings to patients. Finally, we will evaluate the mechanism for activity of ILC2 cells focusing on signaling downstream of IL-13/IL-13 receptor and NOTCH. Understanding how ILC2 cells function is critical to future clinical trials that will use human ILC2 cells to treat patients with steroid-refractory GvHD of the lower GI tract.

抽象的： 移植物抗宿主病（GVHD）仍然是限制广泛利用的主要因素 同种异体干细胞移植（Allo-SCT），用于治疗高风险或经常性患者 血液学恶性肿瘤。预防急性GVHD的主要方法是使用钙调蛋白 甲氨蝶呤抑制剂（CNI）。使用这种方法，大约30-80％的患者正在接受匹配 相关或无关的干细胞移植将发展出急性GVHD。对于发展急性GVHD的患者， 30多年来，治疗没有改变，由全身性皮质类固醇组成。这种方法具有实质性 副作用导致严重的长期并发症。类固醇难治性急性GVHD患者的治疗 诊断后一年多以上的患者次数不到15％。因此，新形式 不需要治疗以改善接受Allo-SCT的患者的结果。 靶向供体T细胞类固醇耐用急性GVHD患者的侵袭性治疗 尚未改善患者对皮质类固醇治疗难治性的长期结局。这导致了增加 有兴趣了解条件疗法和GVHD如何改变较低GI的稳态环境 道。 在过去的36个月中，我的小组评估了相对较新的先天淋巴机的功能 细胞，称为2型先天淋巴样细胞（ILC2）。这些细胞在胃肠道中发现并产生IL-4，IL-5 和IL-13。细胞因子IL-25和IL-33对于产生ILC2细胞至关重要。在当前的提议中，我们 证明ILC2细胞是放射线和化学疗法敏感的，并且在A上重新构成不当 供体骨髓细胞的三个月。我们证明输注供体ILC2细胞可以防止 更重要的是处理下胃肠道的正在进行的急性GVHD。这与重要相关 结肠和小肠中的供体Th1/Th17和Tc1细胞的减少以及结肠上皮的改善 细胞完整性。 ILC2细胞的活性需要ILC2产生IL-13和两极的活性（AREG） 细胞。 ILC2细胞的给药对GVL反应没有影响。 当前建议的目标是评估使用ILC2细胞作为治疗方法的新方法 急性GVHD。我们将研究ILC2细胞处理较低道GVHD的机制， 髓样衍生的抑制细胞（MDSC）和Tregs在此活动中，以及IL-13，AREG，树突状的作用 细胞和肠上皮下肌纤维细胞（ISEMF）在ILC2细胞的活性中具有。我们将证明 ILC2细胞在接受CNI和/或类固醇的小鼠中起作用，这将使我们能够快速翻译这些发现 给患者。最后，我们将评估关注下游信号的ILC2细胞活性的机制 IL-13/IL-13受体和缺口。了解ILC2细胞的功能对于未来的临床试验至关重要 将使用人类ILC2细胞来治疗下胃肠道的类固醇难治性GVHD患者。