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: 9528655
• 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/9528655
• 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; Myeloid Cells; Myeloid-derived suppressor cells; Myofibroblast; Organ; Parasitic infection; Pathogenesis; Patient-Focused Outcomes; Patients; Population; Prevention; Prevention approach; Process; Production; Radiation; Recurrence; Refractory; Regulatory T-Lymphocyte; Relapse; Research Personnel; Role; STAT6 gene; Severities; Signal Transduction; Small Intestines; Stem cell transplant; Stem cells; Steroids; 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; leukemia; novel strategies; nutrient absorption; polarized cell; prevent; receptor; reconstitution; recruit; 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）仍然是限制广泛使用的主要因素 同种异体干细胞移植（allo-SCT）用于治疗高危或复发患者 血液系统恶性肿瘤。预防急性 GvHD 的主要方法是使用钙调神经磷酸酶 抑制剂（CNI）与甲氨蝶呤。通过这种方法，大约 30-80% 的患者接受匹配的治疗 相关或不相关的干细胞移植都会发生急性GvHD。对于发生急性 GvHD 的患者， 治疗方法 30 多年来没有改变，由全身性皮质类固醇组成。这种做法具有实质性 导致严重的长期并发症的副作用。类固醇难治性急性 GvHD 患者的治疗 情况不佳，只有不到 15% 的接受治疗的患者在诊断后存活超过一年。因此，新的形式 迫切需要大量的治疗来改善接受同种异体干细胞移植的患者的预后。 针对类固醇难治性下胃肠道急性 GvHD 患者的针对供体 T 细胞的积极治疗， 并没有改善皮质类固醇治疗难治性患者的长期结果。这导致了增加 有兴趣了解调理疗法和 GvHD 如何改变下消化道的稳态环境 道。 在过去 36 个月里，我的团队评估了相对较新的先天淋巴群体的功能 细胞，称为 2 型先天淋巴细胞 (ILC2)。这些细胞存在于胃肠道中并产生 IL-4、IL-5 和IL-13。细胞因子 IL-25 和 IL-33 对于 ILC2 细胞的产生至关重要。在当前的提案中，我们 证明 ILC2 细胞对放射和化疗敏感，并且它们在一段时间内很难重建 来自供体骨髓细胞的三个月期。我们证明，输注供体 ILC2 细胞可以预防 更重要的是治疗下胃肠道持续的急性 GvHD。这与重大 结肠和小肠中供体 Th1/Th17 和 Tc1 细胞减少，结肠上皮细胞改善 细胞完整性。 ILC2 细胞的活性需要 ILC2 产生 IL-13 和双调蛋白 (AREG) 细胞。 ILC2细胞的施用对GvL反应没有影响。 当前提案的目标是评估 ILC2 细胞作为治疗以下疾病的新方法的用途： 急性GvHD。我们将研究ILC2细胞治疗下消化道GvHD的机制， 骨髓源性抑制细胞 (MDSC) 和 Tregs 在此活动中的作用，以及 IL-13、AREG、树突状细胞的作用 细胞和肠上皮下肌成纤维细胞（ISEMF）具有ILC2细胞的活性。我们将展示 ILC2 细胞在接受 CNI 和/或类固醇的小鼠中发挥作用，这将使我们能够快速转化这些发现 给患者。最后，我们将评估 ILC2 细胞的活性机制，重点关注下游信号传导 IL-13/IL-13 受体和 NOTCH。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类固醇难治性 GvHD 患者。