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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：同种异体造血细胞移植（allo-HCT）是造血干细胞移植的有效形式。对恶性（例如白血病、淋巴瘤）和非恶性具有潜在治愈作用的免疫疗法然而，移植物抗宿主病（GvHD）仍然是一个主要疾病。在研究小鼠同种异体 HCT 模型中的 GvHD 时，我们感到惊讶。发现半乳糖凝集素 3 (Gal-3) 在减轻 GvHD 中发挥重要作用，Gal-3 由造血细胞表达。和非造血细胞，已知会影响先天性和适应性免疫。在小鼠同种异体 HCT 实验中，受体小鼠用 T 进行重建。我发现，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。供体 T 细胞中的 Gal-3 缺陷显着加剧了 GvHD 的严重程度和死亡率，并且 Gal-3 是对于保护受体组织免受 GvHD 的影响非常重要根据我的初步数据，本研究的目标是探索关于异基因 HCT 后 Gal-3 在 GvHD 中的作用的新范例我敢说 Gal-3 是关键。 GvHD 调节剂，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。目标 1 将探索 Gal-3 信号传导影响 GvHD 的细胞机制。使用 Gal-3 缺陷小鼠作为供体以确定 Gal-3 信号如何影响主要 T 细胞的功能已知决定 GVHD 发作和严重程度的子集，包括 CD4+、CD8+ 和 CD4+Foxp3+ 调节性 T 目标 2 将评估操纵 Gal-3 信号传导来调节 GvHD 和 GvHD 的治疗潜力。为了提高这项工作的可翻译性，我建立了异种移植。使用人源化 NSG-HLA-A2 小鼠作为 HCT 受体的系统来检查人类诱导的 GvHD 严重程度目标 3 将分析 Gal-3 与异基因 HCT 后 GvHD 严重程度的临床关联。测量200名未鉴定的同种异体HCT患者的血浆Gal-3水平并分析其关系 Gal-3 水平与临床结果（包括 GvHD 发生率和严重程度、植入和感染）之间的关系。总之，这个项目不仅会提高我们对allo-HCT生物学的理解，而且我的结果可能会确定一种新的生物标志物，有助于识别 HCT 后有发生严重 GvHD 风险的患者。此外，这项研究可能会产生一种新的治疗原理，用于调节 Gal-3 信号传导以控制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 博士以及包括 Bruce Blazer 博士、Pawel Kalinski 博士在内的顾问委员会，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初步步骤实现科学自主所需的知识和技能（R00），并顺利完成从博士后实习生到独立研究员的转变。