Enhancing Innate Immune Reconstitution Post Allogeneic HSCT.

摘要 异基因造血干细胞移植(allo-HSCT)是治疗急性髓系白血病的首选方法。 患有恶性骨髓疾病(BM)和先天性骨髓衰竭综合征的患者。药效 异基因造血干细胞移植的疗效取决于条件化治疗和供体移植物的抗肿瘤活性。这个 异基因造血干细胞移植的疗效取决于供者骨髓/干细胞替代宿主免疫的能力 系统。然而，很明显，并不是所有的免疫细胞都来自成人骨髓细胞。B1B 淋巴细胞和朗格汉斯细胞是从胎儿细胞中产生的，并不是由捐赠者的骨髓重建的。 此外，我们的团队和其他人已经证明，产生细胞因子的先天淋巴样细胞(ILC) 类似于T淋巴细胞，但不表达生殖系编码的受体，在 干细胞移植。 异基因造血干细胞移植后胃肠道中没有ILC2细胞的机制尚不清楚，因为这些细胞通常是 在患者的血流中发现，并在自体干细胞移植后重建。我们的 研究小组在小鼠身上发现，胎肝来源的ILC2前体细胞可以重建胃肠道，表明 该利基可以支持ILC2细胞。这导致我们假设，炎症反应在 GVH反应产生的Allo-HSCT限制了ILC2细胞的发育。 ILC2细胞具有显著的可塑性，由关键谱系特异性基因座的表观遗传变化介导，导致 EX-ILC2细胞的发育，其功能类似于ILC1或ILC3细胞。我们小组已经找到了 产生干扰素-γ的ILc1细胞会加重胃肠道移植物抗宿主病。此外，促炎细胞因子， IL-12和IL-1β在异基因造血干细胞移植后升高，特别是在GVH反应存在的情况下，转化为 ILC2至ILC1细胞。我们的团队已经在ILC2细胞中发现了H3K9me1/2标记，它保持了基因 对ILC2的维持和功能至关重要的GATA3、cmaf和RORA的转录通过抑制而增强 赖氨酸专一性脱甲基酶。第一个具体目标是增强体内ILC2细胞的功能，以 通过抑制含有Jumonji的脱甲基酶和赖氨酸特异性脱甲基酶来治疗GvHD。 闭塞性细支气管炎综合征(BOS)是allo-HSCT的重要并发症。产生IL-2的T细胞 17A、Th17细胞在BOS的发病机制中起关键作用。BOS的一个危险因素是先前的病毒 肺部感染，尽管其机制尚不清楚。就在最近，我们团队发现病毒 肺部感染可将肺ILC2细胞转化为ILC3样细胞，产生IL-23，IL-23对肺泡癌的扩张至关重要 Th17细胞。这项建议的第二个具体目标是使用ILC2细胞给予的去甲基酶 预防和/或治疗病毒感染后的BOS。 完成这一项目的目标将大大加强我们对以下机制的理解 ILC2细胞移植后的丢失，为利用ILC治疗移植物抗宿主病提供了新的途径。

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the preferred approach for the treatment of patients with malignant diseases of the bone marrow (BM) and congenital BM failure syndromes. The efficacy of allo-HSCT is dependent on the anti-tumor activity of the conditioning therapy and the donor graft. The efficacy of allo-HSCT is dependent on the ability of donor bone marrow/stem cells to replace the host immune system. However, it is clear that not all immune cells are generated from adult bone marrow cells. B1b lymphocytes and Langerhans cells are generated from fetal cells and not reconstituted by donor bone marrow. Additionally, our group and others have shown that innate lymphoid cells (ILC), which generate cytokines similar to T lymphocytes but don’t express germ-line encoded receptors, are not completely reconstituted after stem cell transplantation. The mechanism for the absence of ILC2 cells in the GI tract post allo-HSCT is not clear as these cells routinely are found in the bloodstream of patients and are reconstituted after autologous stem cell transplantation. Our group has found in mice that fetal liver derived ILC2 precursor cells can reconstitute the GI tract indicating that the niche can support ILC2 cells. This has led us to hypothesize that the inflammatory response found after allo-HSCT from the GvH response limits the development of ILC2 cells. ILC2 cells have significant plasticity, mediated by epigenetic changes in critical lineage-specific loci that leads to the development of ex-ILC2 cells, which are functionally similar to ILC1 or ILC3 cells. Our group has found that ILC1 cells, which generate IFN-γ, exacerbate GI tract GvHD. Furthermore, the pro-inflammatory cytokines, IL-12 and IL-1β, which are increased post allo-HSCT especially in the presence of the GvH response, convert ILC2 to ILC1 cells. Our group has found in ILC2 cells that H3K9me1/2 marks, which maintain gene transcription of gata3, cmaf and rora, critical for ILC2 maintenance and function, are enhanced by inhibiting lysine specific demethylases. The first specific aim focuses on enhancing the function of ILC2 cells in vivo to treat GvHD by inhibiting Jumonji containing and lysine-specific demethylases. Bronchiolitis obliterans syndrome (BOS) is a significant complication of allo-HSCT. T cells that generate IL- 17A, Th17 cells, are critical to the pathogenesis of BOS. One risk factor for BOS is an antecedent viral infection of the lung, although the mechanism for this is not clear. Quite recently our group has found that viral infection in the lung converts lung ILC2 cells to ILC3-like cells that generate IL-23 critical for the expansion of Th17 cells. The second specific aim of this proposal focuses on the use of demethylases given with ILC2 cells to prevent and/or treat post-viral BOS. Completion of the goals of this project will greatly enhance our understanding of the mechanisms important for the loss of ILC2 cells post-transplant, and provide new approaches to utilize ILCs to treat GvHD.