Enhancing Innate Immune Reconstitution Post Allogeneic HSCT.

增强同种异体 HSCT 后的先天免疫重建。

• 批准号: 10653130
• 负责人: Jonathan S. Serody
• 金额: $ 69.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653130
• 关键词: Acute leukemia; Address; Adult; Allogenic; Autologous Stem Cell Transplantation; B-Lymphocytes; Behavior Therapy; Biology; Blood; Blood Circulation; Bone Diseases; Bone Marrow; Bone Marrow Cells; Bone Marrow Diseases; Bone Marrow Stem Cell; Bone Marrow Transplantation; Bronchiolitis Obliterans; Categories; Cells; Collaborations; Complication; Cues; Development; Dysmyelopoietic Syndromes; Epigenetic Process; Fetal Liver; GATA3 gene; Gastrointestinal tract structure; Generations; Genetic; Genetic Transcription; Goals; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hepatocyte; Human; IL17 gene; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-1 beta; Interleukin-12; Knowledge; Laboratories; Langerhans cell; Lead; Leukocytes; Lung; Lung infections; Lymphocyte; Lymphoid Cell; Lysine; Maintenance; Malignant - descriptor; Mediating; Methods; Molecular; Morbidity - disease rate; Mus; Myeloproliferative disease; Natural regeneration; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Process; Relapse; Resources; Risk Factors; Role; Stem cell transplant; Syndrome; T-Lymphocyte; Time; Transplantation; Viral Bronchiolitis; Virus Diseases; Work; bone marrow failure syndrome; congenital bone marrow failure; cytokine; drug discovery; fetus cell; graft vs host disease; graft vs leukemia effect; high risk; immune reconstitution; in vivo; interleukin-22; interleukin-23; mortality; mucosal site; novel strategies; novel therapeutics; pathogen; pharmacologic; post-transplant; precursor cell; prevent; receptor; reconstitution; response; tissue repair; transcription factor; tumor

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.

抽象的 异基因造血干细胞移植（allo-HSCT）是治疗以下疾病的首选方法 患有恶性骨髓疾病和先天性骨髓衰竭综合征的患者。功效 allo-HSCT 的抗肿瘤活性取决于预处理治疗和供体移植物的抗肿瘤活性。这 allo-HSCT的功效取决于供体骨髓/干细胞替代宿主免疫的能力 系统。然而，很明显并非所有免疫细胞都是由成体骨髓细胞产生的。 B1b 淋巴细胞和朗格汉斯细胞是由胎儿细胞产生的，而不是由供体骨髓重建的。 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细胞（ILC） 与 T 淋巴细胞相似，但不表达种系编码受体，在 干细胞移植。 同种异体造血干细胞移植后胃肠道中缺乏 ILC2 细胞的机制尚不清楚，因为这些细胞通常 存在于患者的血液中，并在自体干细胞移植后重建。我们的 研究小组在小鼠中发现，胎肝来源的 ILC2 前体细胞可以重建胃肠道，这表明 该生态位可以支持ILC2细胞。这使我们推测，在 来自 GvH 反应的异基因 HSCT 限制了 ILC2 细胞的发育。 ILC2 细胞具有显着的可塑性，由关键谱系特异性基因座的表观遗传变化介导，从而导致 ex-ILC2 细胞的发育，其功能与 ILC1 或 ILC3 细胞相似。我们组发现了 产生 IFN-γ 的 ILC1 细胞会加剧胃肠道 GvHD。此外，促炎细胞因子， IL-12 和 IL-1β 在异基因 HSCT 后增加，特别是在存在 GvH 反应的情况下，转化为 ILC2 至 ILC1 细胞。我们课题组在ILC2细胞中发现H3K9me1/2标记，其维持基因 gata3、cmaf 和 rora 的转录对 ILC2 的维持和功能至关重要，可通过抑制来增强 赖氨酸特异性去甲基化酶。第一个具体目标是增强体内ILC2细胞的功能 通过抑制含有 Jumonji 的赖氨酸特异性去甲基酶来治疗 GvHD。 闭塞性细支气管炎综合征（BOS）是异基因造血干细胞移植的一个重要并发症。产生IL-的T细胞 17A，Th17 细胞，对于 BOS 的发病机制至关重要。 BOS 的一个危险因素是先前存在的病毒 肺部感染，尽管其机制尚不清楚。最近我们的团队发现病毒 肺部感染将肺 ILC2 细胞转化为 ILC3 样细胞，产生 IL-23，这对肺的扩张至关重要 Th17 细胞。该提案的第二个具体目标集中于使用 ILC2 细胞给予的去甲基酶 预防和/或治疗病毒后 BOS。 完成该项目的目标将大大增强我们对重要机制的理解 移植后 ILC2 细胞的损失，并提供利用 ILC 治疗 GvHD 的新方法。