Novel GvHD-Specific Gene Identification for Optimal Control of GvHD
用于最佳控制 GvHD 的新型 GvHD 特异性基因鉴定
基本信息
- 批准号:10302150
- 负责人:
- 金额:$ 19.69万
- 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:2021-05-21 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AllogenicAnimal ModelAplastic AnemiaB-Cell LymphomasCRISPR libraryCRISPR/Cas technologyCell TransplantationClinicalComplicationDataDiseaseDysmyelopoietic SyndromesFGFR3 geneFailureGene TargetingGenesGeneticGoalsGraft-Versus-Tumor InductionGuide RNAHLA AntigensHematologic NeoplasmsHumanImmunologicsImmunosuppressionInbred BALB C MiceInflammatoryInflammatory Bowel DiseasesIntestinesLinkLiverLymphoma cellMarrowMature T-LymphocyteMediatingModelingMolecular TargetMusNoduleOrganPathway interactionsPatientsPeripheral Blood Mononuclear CellPharmacologyPreventionPsoriatic ArthritisRNA libraryRefractoryRelapseRheumatoid ArthritisRiskSkinSolidSpleenT-LymphocyteTestingTherapeuticTimeTransplant RecipientsTransplantationcancer immunotherapeuticscancer therapycell mediated immune responsechimeric antigen receptorcurative treatmentseffective therapygenome-widegraft vs host diseasegraft vs leukemia effecthematopoietic cell transplantationimmunoreactionimmunoregulationimprovedimproved outcomeinsightleukemialymph nodesmouse modelnegative affectnew therapeutic targetnext generation sequencingnovelnovel therapeuticsorgan transplant rejectionpreservationpreventsubcutaneoussuccesstherapeutic developmenttumor
项目摘要
ABSTRACT
Graft-versus-host disease (GvHD) is one of the most significant barriers to success for allogeneic hematopoietic
cell transplantation (allo-HCT). The goal of this project is to identify novel genes whose genetic/pharmacologic
blockade may selectively prevent GvHD while maintaining or enhancing anti-leukemia activities (aka graft-
versus-leukemia or GvL effect). Allo-HCT remains the most effective treatment for patients with hematologic
malignancies, as the therapeutic benefit of allo-HCT is primarily derived from GvL. However, allo-HCT also
carries the risk that the donor T cells in the transplant (graft) will become overzealous and begin to attack not
only the leukemia but also the patient's skin, intestines and liver, resulting in GvHD. Because of a strong
association between the two donor T cell-mediated immune responses, specifically limiting GvHD remains the
goal of allo-HCT. Managing the threat of GvHD would broaden the scope and benefit of allo-HCT. Several
groups, including ours, have proposed therapeutic strategies to reduce GvHD without abrogating the beneficial
GvL effect in animal models and human patients. However, the mechanisms by which allogeneic donor T cells
differentially modulate GvHD and GvL remain largely unknown. This gap in our mechanistic understanding
hinders our ability to specifically prevent/treat GvHD. We hypothesize that the genes we identify as being
differentially associated with donor T cells that infiltrate tumors versus GvHD organs will be critical targets for
the prevention of GvHD without negatively affecting GvL. To this end, we performed an unbiased genome-wide
CRISPR/Cas9 library screen. As a result, we have for the first time identified 487 novel GvHD-associated genes
that could potentially serve as molecular targets in GvHD, as the guide RNAs for these genes were enriched
only in T cells obtained from tumor nodules but not from any GvHD target organs. We found that five sets of
genes that are involved in known pathways are most significantly enriched in these 487 genes. All of these five
pathways are closely linked to the RELN-RAP1-FGFR3 axis that has not been actively investigated in the allo-
HCT field. Thus, we will determine if genetic/pharmacologic inhibition of the RELN-RAP1-FGFR3 axis results in
GvHD-specific immune modulation while maintaining or enhancing GvL in our mouse models of murine
GvHD/GvL and human PBMC/T cell-mediated xeno-GvHD/GvL. If successful, our findings of novel therapeutic
targets to selectively and optimally control GvHD will be potential game-changers. Our proposed studies will
provide significant mechanistic insights into GvHD and its prevention, which may have transformative
implications for therapeutic development not only for solid organ transplant rejection but also inflammatory
diseases such as inflammatory bowel disease, psoriasis and rheumatoid arthritis. In addition, our studies may
also help improve the efficacies of anti-cancer therapies and immunotherapeutic approaches
.
摘要
移植物抗宿主病(GvHD)是同种异体造血干细胞移植成功的最重要障碍之一。
细胞移植(allo-HCT)。该项目的目标是确定新的基因,其遗传/药理学
阻断可以选择性地预防GvHD,同时维持或增强抗白血病活性(aka graft-
抗白血病或GvL效应)。Allo-HCT仍然是血液病患者最有效的治疗方法。
在恶性肿瘤中,因为allo-HCT的治疗益处主要来源于GvL。然而,allo-HCT也
存在移植物中的供体T细胞变得过度活跃并开始攻击非供体T细胞的风险。
不仅白血病,而且患者的皮肤,肠道和肝脏,导致GvHD。因为一个强大的
两种供体T细胞介导的免疫应答之间的关联,特别是限制GvHD仍然是一个问题。
allo-HCT的目标。管理GvHD的威胁将扩大allo-HCT的范围和益处。几
包括我们在内的研究小组已经提出了治疗策略,以减少GvHD,而不废除有益的
动物模型和人类患者中的GvL效应。然而,同种异体供体T细胞
差异调节GvHD和GvL的基因在很大程度上仍然未知。我们对机械论的理解
阻碍了我们特异性预防/治疗GvHD的能力。我们假设我们认为是
与浸润肿瘤的供体T细胞相对于GvHD器官的供体T细胞的差异相关将是免疫治疗的关键靶点。
预防GvHD而不负面影响GvL。为此,我们进行了一个无偏的全基因组
CRISPR/Cas9文库筛选。因此,我们首次鉴定了487个新的GvHD相关基因。
这些基因的指导RNA被富集,
仅在得自肿瘤结节而非得自任何GvHD靶器官的T细胞中。我们发现五组
参与已知途径的基因在这487个基因中最显著地富集。该五项
通路与在同种异体移植中尚未积极研究的JN-RAP 1-FGFR3轴密切相关,
HCT字段。因此,我们将确定是否遗传/药理学抑制的JN-RAP 1-FGFR3轴导致,
GvHD特异性免疫调节,同时维持或增强我们的小鼠模型中的GvL。
GvHD/GvL和人PBMC/T细胞介导的异种-GvHD/GvL。如果成功的话,我们的新疗法
选择性和最佳控制GvHD的目标将是潜在的游戏规则改变者。我们建议的研究将
为GvHD及其预防提供了重要的机制见解,这可能具有变革性意义。
不仅对实体器官移植排斥反应而且对炎症性排斥反应的治疗发展的意义
炎症性肠病、牛皮癣和类风湿性关节炎等疾病。此外,我们的研究可能
也有助于提高抗癌疗法和免疫疗法的功效,
.
项目成果
期刊论文数量(0)
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Jaebok Choi其他文献
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{{ truncateString('Jaebok Choi', 18)}}的其他基金
Novel GvHD-Specific Gene Identification for Optimal Control of GvHD
用于最佳控制 GvHD 的新型 GvHD 特异性基因鉴定
- 批准号:
10408858 - 财政年份:2021
- 资助金额:
$ 19.69万 - 项目类别:
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