Role of antigen-specific T cells in immunotherapy-associated acute interstitial nephritis and kidney allograft rejection
抗原特异性 T 细胞在免疫治疗相关急性间质性肾炎和肾同种异体移植排斥中的作用
基本信息
- 批准号:10351987
- 负责人:
- 金额:$ 13.43万
- 依托单位:
- 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:2022-01-07 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:ANCA vasculitisAcuteAcute Renal Failure with Renal Papillary NecrosisAddressAffectAllograftingAnimal ModelAnimalsAntigensArchivesAutoantigensAutoimmuneAutoimmunityBiologyBiopsyBiopsy SpecimenBlood specimenCTLA4 geneCancer PatientCellsChronicClinicalClinical DataClinical ResearchClinical TrialsDataData AnalysesDialysis procedureDiseaseEnd stage renal failureEvolutionFibrosisFundingFutureGenetic TranscriptionGenomicsGoalsGraft RejectionHaptensHospitalsHumanHypersensitivityImmuneImmune ToleranceImmune checkpoint inhibitorImmune responseImmunooncologyImmunotherapyInfectionInfiltrationInflammationInflammatoryInjury to KidneyInstitutesInterstitial NephritisInvestigationKidneyKidney DiseasesKidney TransplantationLeadLymphocyteMalignant NeoplasmsMembranous GlomerulonephritisMolecularMulti-site clinical studyMultiomic DataObservational StudyOrganPatient-Focused OutcomesPatientsPeptidesPeripheral Blood Mononuclear CellPharmaceutical PreparationsPhenotypePilot ProjectsPlayProliferatingProton Pump InhibitorsProximal Kidney TubulesPublic HealthRenal Replacement TherapyResearchRiskRisk FactorsRoleSamplingSignal TransductionSpecificityStainsT cell receptor repertoire sequencingT cell responseT-Cell ActivationT-Cell ReceptorT-LymphocyteT-cell receptor repertoireTechniquesTherapeuticTissue SampleTransplant RecipientsTransplantationTumor-infiltrating immune cellsUp-RegulationWomanallograft rejectionanti-CTLA4anti-PD-1antigen-specific T cellsautoreactivitybasecancer immunotherapycheckpoint therapycomplementarity-determining region 3designdimensional analysisexperiencefeasibility testinghigh dimensionalityhuman diseasehuman tissueimmune checkpointimprovedischemic injurykidney allograftkidney biopsymortalitymultiple omicsneoantigensnephrogenesisnext generation sequencingnovelperipheral bloodpreventprogrammed cell death protein 1prospectiveresponsesingle-cell RNA sequencingtherapy developmenttumor
项目摘要
Project Summary
Cancer immunotherapy has become a standard therapy for many cancers. However, it’s associated with acute
kidney injury, resulting in significantly increased mortality. Acute interstitial nephritis is the most common acute
kidney injury, affecting 2-3% of the patients receiving immune checkpoint inhibitors (ICIs). In addition, 40% of
the kidney transplant patients receiving ICIs suffer from acute rejection, and once rejection occurs, 65% lose
allograft and require renal replacement therapy. Thus, understanding the mechanisms of ICI-associated acute
kidney injury and finding therapies is critical. My K08 project aims to understand the roles of immune
checkpoint molecules (PD-1 and CTLA-4) in kidney inflammation, by using the novel animal models that
express neoantigen peptides specifically in kidney proximal tubules and tracking antigen-specific T cell
response in the animals by tetramer staining technique. The results showed that the presence of antigen-
specific T cells and ICIs trigger the immune cell infiltration to the kidneys, mimicking acute interstitial nephritis
seen in the cancer patients treated with ICIs. While animal models are ideal to address the precise molecular
mechanisms of the disease, there’s a limitation in the applicability of the findings to the human disease. The
largest multicenter clinical study that I led recently found that the ICI-associated kidney injury occurs much
faster and more robust in kidney transplant recipients compared to non-kidney transplant patients. The findings
led to my central hypothesis that pre-existing donor antigen-specific T cells in the kidney transplant recipients
are quickly activated, proliferated in the presence of ICIs, and cause direct kidney injury. In this pilot study, I
propose to perform high dimensional analyses using human tissue samples to track antigen-specific T cells by
single cell RNA sequencing and T cell receptor (TCR) repertoire analysis. We will analyze the TCR clonotype
and phenotype of antigen-specific T cells, using the archived peripheral blood mononuclear cells, tumor and
kidney biopsy samples, obtained from the patients who had acute graft rejection after cancer ICI therapy, by
collaborating with Center of Immuno-Oncology at Dana Faber Cancer Institute and single cell genomics core at
Brigham and Women’s Hospital. This pilot project tests the feasibility of the high dimensional analysis of the
patient samples for a future prospective clinical trial in the patients with ICI-associated kidney injury. If feasible,
we will incorporate these analyses in the prospective clinical trial, which will eventually help understand the
mechanism of acute interstitial nephritis and acute graft rejection in the patients treated with cancer
immunotherapy.
项目摘要
癌症免疫疗法已成为许多癌症的标准疗法。然而,它与急性
肾损伤,导致死亡率显著增加。急性间质性肾炎是最常见的急性
肾损伤,影响2-3%接受免疫检查点抑制剂(ICI)的患者。此外,40%的
接受ICIs的肾移植患者发生急性排斥反应,一旦发生排斥反应,
同种异体移植并需要肾脏替代治疗。因此,了解ICI相关急性
肾损伤和寻找治疗方法至关重要。我的K 08项目旨在了解免疫的作用,
检查点分子(PD-1和CTLA-4)在肾脏炎症中的作用,
在肾近曲小管特异性表达新抗原肽,并追踪抗原特异性T细胞
通过四聚体染色技术观察动物中的反应。结果表明,抗原的存在-
特异性T细胞和ICI触发免疫细胞浸润肾脏,模拟急性间质性肾炎
在接受ICIs治疗的癌症患者中观察到。虽然动物模型是解决精确分子问题的理想模型,
由于该疾病的发病机制不同,这些发现对人类疾病的适用性存在局限性。的
我最近领导的一项最大的多中心临床研究发现,ICI相关的肾损伤
与非肾移植患者相比,在肾移植受者中更快、更稳健。这些发现
我的核心假设是,肾移植受者体内预先存在的供体抗原特异性T细胞
在ICI存在时被迅速激活、增殖并导致直接肾损伤。在这项试点研究中,我
建议使用人体组织样本进行高维分析,以跟踪抗原特异性T细胞,
单细胞RNA测序和T细胞受体(TCR)库分析。我们将分析TCR克隆型
和抗原特异性T细胞的表型,使用存档的外周血单核细胞、肿瘤和
肾活检样本,从癌症ICI治疗后发生急性移植物排斥反应的患者中获得,
与Dana Faber癌症研究所免疫肿瘤学中心和单细胞基因组学核心合作,
布莱根妇女医院该试验项目测试了高维分析的可行性,
患者样本,用于ICI相关肾损伤患者的未来前瞻性临床试验。如果可行,
我们将在前瞻性临床试验中纳入这些分析,这将最终有助于了解
恶性肿瘤患者急性间质性肾炎和急性移植排斥反应的发生机制
免疫疗法。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Naoka Murakami其他文献
Naoka Murakami的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Naoka Murakami', 18)}}的其他基金
Role of antigen-specific T cells in immunotherapy-associated acute interstitial nephritis and kidney allograft rejection
抗原特异性 T 细胞在免疫治疗相关急性间质性肾炎和肾同种异体移植排斥中的作用
- 批准号:
10548204 - 财政年份:2022
- 资助金额:
$ 13.43万 - 项目类别:
Protection of kidney from autoimmunity by modulating co-stimlatory signaling
通过调节共刺激信号来保护肾脏免受自身免疫的影响
- 批准号:
9908074 - 财政年份:2019
- 资助金额:
$ 13.43万 - 项目类别:
Protection of kidney from autoimmunity by modulating co-stimlatory signaling
通过调节共刺激信号来保护肾脏免受自身免疫的影响
- 批准号:
10886997 - 财政年份:2019
- 资助金额:
$ 13.43万 - 项目类别:
Protection of kidney from autoimmunity by modulating co-stimlatory signaling
通过调节共刺激信号来保护肾脏免受自身免疫的影响
- 批准号:
10397065 - 财政年份:2019
- 资助金额:
$ 13.43万 - 项目类别:
Protection of kidney from autoimmunity by modulating co-stimlatory signaling
通过调节共刺激信号来保护肾脏免受自身免疫的影响
- 批准号:
10614441 - 财政年份:2019
- 资助金额:
$ 13.43万 - 项目类别:
相似海外基金
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 13.43万 - 项目类别:
Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 13.43万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 13.43万 - 项目类别:
Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 13.43万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 13.43万 - 项目类别:
Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 13.43万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 13.43万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 13.43万 - 项目类别:
Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 13.43万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
- 批准号:
2244994 - 财政年份:2023
- 资助金额:
$ 13.43万 - 项目类别:
Standard Grant