Enhancing Innate Immune Reconstitution Post Allogeneic HSCT.

摘要 异基因造血干细胞移植（allo-HSCT）是治疗造血干细胞移植的首选方法。 患有骨髓（BM）恶性疾病和先天性BM衰竭综合征的患者。疗效 allo-HSCT的效果取决于预处理疗法和供体移植物的抗肿瘤活性。的 allo-HSCT的疗效取决于供体骨髓/干细胞替代宿主免疫的能力。 系统然而，很明显，并非所有的免疫细胞都是由成人骨髓细胞产生的。B1b 淋巴细胞和朗格汉斯细胞由胎儿细胞产生，而不是由供体骨髓重建。 此外，我们的研究小组和其他人已经表明，产生细胞因子的先天淋巴细胞（ILC） 类似于T淋巴细胞，但不表达生殖系编码受体， 干细胞移植 allo-HSCT后胃肠道中缺乏ILC 2细胞的机制尚不清楚，因为这些细胞通常 在患者的血流中发现，并在自体干细胞移植后重建。我们 研究小组在小鼠中发现，胎肝来源的ILC 2前体细胞可以重建胃肠道，这表明， 小生境可以支持ILC 2细胞。这使我们假设，在感染后发现的炎症反应 来自GvH应答的allo-HSCT限制了ILC 2细胞的发育。 ILC 2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， 与ILC 1或ILC 3细胞功能相似的ex-ILC 2细胞的发育。我们小组发现 产生IFN-γ的ILC 1细胞会加剧胃肠道GvHD。此外，促炎细胞因子， IL-12和IL-1β在allo-HSCT后增加，特别是在存在GvH应答的情况下， ILC 2至ILC 1细胞。我们小组在ILC 2细胞中发现了H3 K9 me 1/2标记，该标记维持基因 通过抑制ILC 2的维持和功能，增强gata 3、cmaf和rora的转录， 赖氨酸特异性脱甲基酶。第一个具体目标集中于增强ILC 2细胞在体内的功能， 通过抑制含Jumonji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。T细胞产生IL- 17 A，Th 17细胞，在BOS的发病机制中至关重要。BOS的一个危险因素是前驱病毒 肺部感染，尽管其机制尚不清楚。最近，我们的研究小组发现， 肺中的感染将肺ILC 2细胞转化为ILC 3样细胞，所述ILC 3样细胞产生对肺ILC 2细胞的扩增至关重要的IL-23。 Th 17细胞该建议的第二个具体目的集中于使用ILC 2细胞给予的脱甲基酶 以预防和/或治疗病毒感染后的BOS。 该项目目标的完成将大大提高我们对以下方面重要机制的理解： ILC 2细胞在移植后的损失，并提供了新的方法来利用ILC治疗GvHD。

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.