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

摘要： 移植物抗宿主病(GvHD)仍然是限制其广泛应用的主要因素。 异基因干细胞移植治疗高危或复发患者 恶性血液病。预防急性移植物抗宿主病的主要方法是使用钙调神经磷酸酶 甲氨蝶呤的抑制剂(CNI)。使用这种方法，大约30%-80%的患者接受了匹配 相关或不相关的干细胞移植将发展为急性移植物抗宿主病。对于患有急性移植物抗宿主病的患者， 治疗方法30多年来没有改变，由全身皮质类固醇组成。这种方法有很大的 副作用导致严重的长期并发症。激素难治性急性移植物抗宿主病的治疗 是次优的，只有不到15%的接受治疗的患者在确诊后存活超过一年。因此，新的形式 为了改善接受异基因干细胞移植的患者的预后，迫切需要进行大量的治疗。 下消化道激素难治性急性移植物抗宿主病患者的供体T细胞靶向治疗 并没有改善对皮质类固醇治疗无效的患者的长期结果。这导致增加了 有兴趣了解条件疗法和GvHD如何改变下消化道的动态平衡环境 一条小路。 在过去的36个月里，我的团队评估了一种相对较新的先天淋巴系统的功能 细胞，称为2型先天淋巴样细胞(ILC2)。这些细胞位于胃肠道中，产生IL-4、IL-5 和IL-13。细胞因子IL-25和IL-33对ILC2细胞的产生起关键作用。在目前的提案中，我们 证明ILC2细胞对放射和化疗敏感，并且在一年多的时间内它们的重建能力很差 三个月内从供者的骨髓细胞。我们证明，输注供体ILC2细胞可以防止 更重要的是治疗持续的急性下消化道移植物抗宿主病。这与显著的 供者结肠和小肠中Th1/Th17和Tc1细胞减少和结肠上皮细胞改善 细胞完整性。ILC2细胞的活性需要ILC2细胞产生IL-13和双调节蛋白(AREG) 细胞。ILC2细胞给药对GVL反应无影响。 目前建议的目标是评估ILC2细胞作为一种新的治疗方法的使用。 急性GvHD。我们将探讨ILC2细胞治疗下尿路移植物抗宿主病的机制。 髓源性抑制细胞和树突状细胞在这一活动中的作用以及IL-13、AREG、树突状细胞 细胞和肠道上皮下肌成纤维细胞(ISEMF)具有ILC2细胞的活性。我们将演示 ILC2细胞在接受CNI和/或类固醇治疗的小鼠中起作用，这将使我们能够快速转化这些发现 对病人来说。最后，我们将评估ILC2细胞的活动机制，重点是下游信号 IL-13/IL-13受体和缺口的表达。了解ILC2细胞的功能对未来的临床试验至关重要 将使用人类ILC2细胞治疗下胃肠道激素难治性GvHD患者。

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.