Implication of Galectin-3 to regulate Graft vs. Host Disease (GvHD) and Graft vs. Tumor (GvT) Responses

Galectin-3 对调节移植物抗宿主病 (GvHD) 和移植物抗肿瘤 (GvT) 反应的影响

• 批准号: 10362542
• 负责人: Hemn Mohammadpour
• 金额: $ 11.79万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362542
• 关键词: Acute Graft Versus Host Disease; Advisory Committees; Affect; Allogenic; Anemia; Antigen-Presenting Cells; Aplastic Anemia; Biological Markers; Biology; Body Weight; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Clinical; Clinical Trials; Complication; Data; Development; Disease; Engraftment; FOXP3 gene; Family; Fibrosis; Galactose Binding Lectin; Galectin 3; Goals; Graft-Versus-Tumor Induction; HLA-A2 Antigen; Heart Diseases; Hematopoietic; Human; Immune; Immune System Diseases; Immunologic Deficiency Syndromes; Immunotherapy; Impairment; Incidence; Infection; Injections; Knowledge; Lead; Lectin; Malignant - descriptor; Malignant Neoplasms; Measures; Mentors; Methods; Modeling; Mus; Myeloid Cells; Natural Immunity; Non-Malignant; Normal tissue morphology; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Phase; Plasma; Play; Production; Prospective Studies; Reagent; Recombinants; Regulatory T-Lymphocyte; Relapse; Research; Research Personnel; Risk; Role; Severities; Severity of illness; Sickle Cell Anemia; Signal Transduction; Supervision; System; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissue Grafts; Tissues; Training; Work; Xenograft procedure; adaptive immunity; anti-PD1 therapy; base; cancer therapy; curative treatments; cytokine; effector T cell; experimental study; graft vs host disease; hematopoietic cell transplantation; immune reconstitution; improved; inhibitor; insight; leukemia/lymphoma; macrophage; mortality; mouse model; novel; novel strategies; novel therapeutics; overexpression; preservation; prevent; prognostic; reconstitution; response; side effect; skills; therapeutic target; tumor

Project Summary: Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective form of immunotherapy that is potentially curative for malignant (e.g. leukemia, lymphoma) and non-malignant conditions (e.g. anemia, immunodeficiencies). However, graft‐versus‐host disease (GvHD) remains a major deleterious side-effect for many patients. While studying GvHD in murine allo-HCT models, we surprisingly discovered an important role for Galectin-3 (Gal-3) in mitigating GvHD. Gal-3 is expressed by hematopoietic and non-hematopoietic cells and is known to influence innate and adaptive immunity. Interestingly, its contribution to GvHD is unknown. In murine allo-HCT experiments, recipient mice were reconstituted with T cell depleted bone marrow (TCD-BM) and T cells from wild type (WT) or Gal-3 deficient mice. I discovered that Gal-3 deficiency in donor T-cells significantly exacerbated the severity and mortality of GvHD and that Gal-3 is important for protecting recipient tissues from GvHD. Based on my preliminary data, the goal of this study is to explore a new paradigm regarding the role of Gal-3 in GvHD after allo-HCT. I hypothesize that Gal-3 is the key regulator of GvHD that modulates both donor and recipient hematopoietic and non-hematopoietic cell functions and decreases GvHD severity and mortality. Therefore, I will study murine models and human HCT patients to pursue three aims. Aim 1 will explore the cellular mechanism(s) by which Gal-3 signaling impacts GvHD. I will use Gal-3 deficient mice as donors to determine how Gal-3 signaling affects the functions of major T cell subsets known to dictate the onset and severity of GVHD, including CD4+, CD8+ and CD4+Foxp3+ regulatory T cells. Aim 2 will evaluate the therapeutic potential of manipulating Gal-3 signaling to modulate GvHD and the graft versus tumor (GvT) effect. To increase the translatability of this work, I established a xenotransplantation system using humanized NSG-HLA-A2 mice as HCT recipients to examine GvHD severity induced by human immune cells. Aim 3 will analyze the clinical association of Gal-3 with GvHD severity after allo-HCT. I will measure Gal-3 plasma levels in 200 de-identified allogeneic HCT patients and analyze the relationship between Gal-3 levels and clinical outcomes including GvHD incidence and severity, engraftment, and infection. In summary, this project will not only improve our understanding of the biology of allo-HCT, but my results may identify a new biomarker which will help identify patients at risk for developing severe GvHD after HCT. Moreover, this research may lead to a novel therapeutic rationale for modulating Gal-3 signaling to control GvHD. This project will be carried out under the supervision of the candidate's primary mentor Dr. Elizabeth Repasky, co-mentor Dr. Philip McCarthy, and advisory committee including Drs. Bruce Blazer, Pawel Kalinski, Theresa Hahn and Jonathan Bramson. By completing the training outlined in this application (K99), I will obtain the knowledge and skills required to take the initial steps toward scientific autonomy in the subsequent phase (R00), and successfully complete the transition from a postdoctoral trainee to an independent researcher.

异基因造血细胞移植(allo-HCT)是一种有效的治疗方法。 对恶性(如白血病、淋巴瘤)和非恶性有潜在疗效的免疫疗法 疾病(如贫血、免疫缺陷)。然而，移植物抗宿主病(GvHD)仍然是主要的 对许多患者来说都是有害的副作用。在研究小鼠allo-hct模型中的GvHD时，我们惊讶地发现 发现Galectin-3(Galectin-3，Gal-3)在缓解GvHD方面具有重要作用。GAL-3在造血细胞中的表达 和非造血细胞，已知会影响先天免疫和获得性免疫。有趣的是，它的 对GvHD的贡献尚不清楚。在小鼠allo-Hct实验中，受体小鼠用T细胞重建 野生型(WT)或Gal-3缺陷小鼠的去细胞骨髓(TCD-BM)和T细胞。我发现 供者T细胞Gal-3缺乏显著加剧了GvHD的严重程度和死亡率，Gal-3是 对于保护受体组织免受移植物抗宿主病非常重要。根据我的初步数据，这项研究的目标是 探索Gal-3在allo-HCT后GvHD中作用的新范式。我假设Gal-3是关键 GvHD调节剂，调节供受者的造血细胞和非造血细胞功能 并降低GvHD的严重程度和死亡率。因此，我将研究小鼠模型和人类HCT患者 追求三个目标。目的1探讨Gal-3信号影响移植物抗宿主病的细胞机制(S)。这就做 以Gal-3基因缺陷小鼠为供体研究Gal-3信号对主要T细胞功能的影响 已知的决定GVHD发病和严重程度的亚群，包括CD4+、CD8+和CD4+Foxp3+调节性T细胞 细胞。目的2将评估操纵Gal-3信号来调节GvHD和 移植物抗肿瘤(GVT)效应。为了增加这部作品的可译性，我建立了一个异种移植 利用人源化NSG-HLA-A2小鼠作为HCT受体检测人类GvHD严重程度的系统 免疫细胞。目的3将分析Gal-3与allo-HCT后GvHD严重程度的临床相关性。这就做 200例不明原因异基因血细胞移植患者血浆Gal-3水平测定及相关性分析 Gal-3水平与临床结果之间的关系，包括GvHD的发生率和严重程度、植入和感染。 总而言之，这个项目不仅将提高我们对allo-hct生物学的理解，而且我的结果可能 寻找一种新的生物标记物，有助于识别HCT后发生严重移植物抗宿主病的风险。 此外，这项研究可能导致调节Gal-3信号来控制的新的治疗原理 GVHD。该项目将在候选人的主要导师伊丽莎白博士的监督下进行 雷帕斯基，共同导师菲利普·麦卡锡博士，以及包括布鲁斯·布莱泽博士，帕维尔·卡林斯基博士在内的咨询委员会， 特里萨·哈恩和乔纳森·布拉姆森。通过完成本申请(K99)中概述的培训，我将获得 在后续阶段采取实现科学自主的初步步骤所需的知识和技能 (R00)，并顺利完成了从博士后实习生向独立研究员的过渡。