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
- 来源:
- 关键词:Acute Graft Versus Host DiseaseAdvisory CommitteesAffectAllogenicAnemiaAntigen-Presenting CellsAplastic AnemiaBiological MarkersBiologyBody WeightBone MarrowCD4 Positive T LymphocytesCD8B1 geneCell physiologyCellsClinicalClinical TrialsComplicationDataDevelopmentDiseaseEngraftmentFOXP3 geneFamilyFibrosisGalactose Binding LectinGalectin 3GoalsGraft-Versus-Tumor InductionHLA-A2 AntigenHeart DiseasesHematopoieticHumanImmuneImmune System DiseasesImmunologic Deficiency SyndromesImmunotherapyImpairmentIncidenceInfectionInjectionsKnowledgeLeadLectinMalignant - descriptorMalignant NeoplasmsMeasuresMentorsMethodsModelingMusMyeloid CellsNatural ImmunityNon-MalignantNormal tissue morphologyOutcomePathogenesisPathologicPathway interactionsPatientsPhasePlasmaPlayProductionProspective StudiesReagentRecombinantsRegulatory T-LymphocyteRelapseResearchResearch PersonnelRiskRoleSeveritiesSeverity of illnessSickle Cell AnemiaSignal TransductionSupervisionSystemT memory cellT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticTissue GraftsTissuesTrainingWorkXenograft procedureadaptive immunityanti-PD1 therapybasecancer therapycurative treatmentscytokineeffector T cellexperimental studygraft vs host diseasehematopoietic cell transplantationimmune reconstitutionimprovedinhibitorinsightleukemia/lymphomamacrophagemortalitymouse modelnovelnovel strategiesnovel therapeuticsoverexpressionpreservationpreventprognosticreconstitutionresponseside effectskillstherapeutic targettumor
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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