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: 10619457
• 负责人: Hemn Mohammadpour
• 金额: $ 24.9万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619457
• 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; Cytoprotection; 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; Lectin; Lymphoma; Macrophage; 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; Postdoctoral Fellow; 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-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissue Grafts; Tissues; Training; Transplant Recipients; Work; Xenograft procedure; adaptive immunity; anti-PD1 therapy; cancer therapy; curative treatments; cytokine; effector T cell; experimental study; graft vs host disease; hematopoietic cell transplantation; immune reconstitution; improved; inhibitor; insight; leukemia; mortality; mouse model; novel; novel strategies; novel therapeutics; overexpression; preservation; prevent; prognostic; reconstitution; response; side effect; skills; therapeutic target; transplant model; 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.

项目摘要：同种异体造血细胞移植（Allo-HCT）是一种有效形式 免疫疗法可能治愈恶性肿瘤（例如白血病，淋巴瘤）和非恶性肿瘤 条件（例如贫血，免疫缺陷）。但是，移植物与宿主病（GVHD）仍然是主要的 许多患者的有害副作用。在研究Murine Allo-HCT模型中的GVHD时，我们令人惊讶 在缓解GVHD中发现了Galectin-3（GAL-3）的重要作用。 gal-3由造血表达 和非造成山摩托细胞，众所周知会影响先天和适应性的免疫史。有趣的是，它的 对GVHD的贡献尚不清楚。在鼠类Allo-HCT实验中，将受体小鼠与T重构 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。我发现了 供体T细胞中的GAL-3缺乏显着加剧了GVHD的严重程度和死亡率，而GAL-3为 对于保护受体组织免受GVHD的影响很重要。根据我的初步数据，这项研究的目的是 探索有关GAL-3在Allo-HCT之后的GAL-3在GVHD中的作用的新范式。我假设gal-3是关键 GVHD的调节剂调节供体和受体造血和非杂型细胞功能 并增加了GVHD的严重性和死亡率。因此，我将研究鼠模型和人类HCT患者 追求三个目标。 AIM 1将探索GAL-3信号传递GVHD的细胞机制。我会 使用Gal-3缺乏小鼠作为供体来确定GAL-3信号如何影响主要T细胞的功能 已知可以决定GVHD的发作和严重性的子集，包括CD4+，CD8+和CD4+ FOXP3+调节t 细胞。 AIM 2将评估操纵GAL-3信号调节GVHD和的治疗潜力 移植物与肿瘤（GVT）效应。为了增加这项工作的可翻译性，我建立了异种移植 使用人源化的NSG-HLA-A2小鼠作为HCT接受者检查人类引起的GVHD严重程度 免疫细胞。 AIM 3将分析Allo-HCT后GAL-3与GVHD严重程度的临床关联。我会 测量200个去识别的同种异体HCT患者的GAL-3等离子体水平并分析关系 在GAL-3水平和临床结果之间，包括GVHD的发生率和严重程度，植入和感染。 总而言之，该项目不仅会改善我们对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，该标志物将有助于确定HCT之后患有严重GVHD风险的患者。 此外，这项研究可能导致一种新型的热原理，用于调节GAL-3信号传导 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。 Repasky，Co-Mentor Philip McCarthy博士和包括博士在内的咨询委员会。布鲁斯·布拉泽（Bruce Blazer），帕维尔·卡林斯基（Pawel Kalinski）， 特蕾莎·哈恩（Theresa Hahn）和乔纳森·布兰森（Jonathan Bramson）。通过完成此应用程序中概述的培训（K99），我将获得 在随后的阶段采取初步迈向科学自治的初步步骤所需的知识和技能 （R00），并成功完成了从博士后学员到独立研究人员的过渡。