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.

项目概述：异基因造血细胞移植（allo-HCT）是一种有效的 可能治愈恶性肿瘤（如白血病、淋巴瘤）和非恶性肿瘤的免疫疗法 疾病（如贫血、免疫缺陷）。然而，移植物抗宿主病（GvHD）仍然是一个主要的 对许多患者有副作用。在研究小鼠allo-HCT模型中的GvHD时，我们惊讶地发现， 发现半乳糖凝集素-3（Gal-3）在减轻GvHD中的重要作用。Gal-3由造血细胞表达， 和非造血细胞，并且已知影响先天性和适应性免疫。有趣的是，其 对GVHD的贡献是未知的。在小鼠allo-HCT实验中，用T 细胞耗尽的骨髓（TCD-BM）和来自野生型（WT）或Gal-3缺陷小鼠的T细胞。我发现 供体T细胞中的Gal-3缺乏显著加剧了GvHD的严重性和死亡率，并且Gal-3是GvHD的一部分。 对于保护受体组织免受GvHD非常重要。根据我的初步数据，本研究的目标是 探索关于Gal-3在allo-HCT后GvHD中的作用的新范例。我假设Gal-3是 一种GvHD的调节物，调节供体和受体的造血和非造血细胞功能 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将探索Gal-3信号传导影响GvHD的细胞机制。我会 使用Gal-3缺陷小鼠作为供体以确定Gal-3信号传导如何影响主要T细胞的功能， 已知决定GVHD发作和严重程度的亚群，包括CD 4+、CD 8+和CD 4 + Foxp 3+调节性T细胞亚群。 细胞目的2将评估操纵Gal-3信号传导以调节GvHD和GvHD的治疗潜力。 移植物抗肿瘤（GVT）效应。为了增加这项工作的可翻译性，我建立了一个异种移植， 使用人源化NSG-HLA-A2小鼠作为HCT受体的系统来检查由人类诱导的GvHD严重性 免疫细胞。目的3分析Gal-3与allo-HCT后GvHD严重程度的临床相关性。我会 检测200例去身份异基因HCT患者血浆Gal-3水平，并分析其相关性。 Gal-3水平和临床结果之间的关系，包括GvHD发生率和严重程度、植入和感染。 总之，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 确定一种新的生物标志物，这将有助于识别HCT后有发生严重GvHD风险的患者。 此外，这项研究可能会导致一种新的治疗原理，调节Gal-3信号转导，以控制 移植物抗宿主病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 Repasky，共同导师Philip McCarthy博士和咨询委员会，包括布鲁斯布莱泽博士，Pawel Kalinski， 特蕾莎·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 在随后的阶段中采取科学自主的初步步骤所需的知识和技能 (R00)，并顺利完成从博士后见习生到独立研究员的转变。