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:
    10362542
  • 负责人:
  • 金额:
    $ 11.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

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.
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。

项目成果

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Hemn Mohammadpour其他文献

Hemn Mohammadpour的其他文献

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{{ truncateString('Hemn Mohammadpour', 18)}}的其他基金

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:
    10598800
  • 财政年份:
    2022
  • 资助金额:
    $ 11.79万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 11.79万
  • 项目类别:
Overcoming stress driven suppression of the anti-tumor immune response in cancer - understanding the MDSC piece of the puzzle
克服癌症中压力驱动的抗肿瘤免疫反应抑制——了解 MDSC 的难题
  • 批准号:
    9909548
  • 财政年份:
    2020
  • 资助金额:
    $ 11.79万
  • 项目类别:
Overcoming stress driven suppression of the anti-tumor immune response in cancer - understanding the MDSC piece of the puzzle
克服癌症中压力驱动的抗肿瘤免疫反应抑制——了解 MDSC 的难题
  • 批准号:
    10065427
  • 财政年份:
    2020
  • 资助金额:
    $ 11.79万
  • 项目类别:

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