Intrarenal B cells in acute kidney allograft rejection
肾内 B 细胞在急性同种肾移植排斥反应中的作用
基本信息
- 批准号:10329990
- 负责人:
- 金额:$ 79.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-15 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcuteAddressAllogenicAntibodiesAntibody SpecificityAntigen PresentationAntigen-Presenting CellsAntigenic SpecificityAntigensArchitectureAutoimmune DiseasesAutomobile DrivingB-Cell Antigen ReceptorB-LymphocytesBiological MarkersBiopsyBloodCell CommunicationCell ShapeCellsCharacteristicsClinicClinicalCollaborationsComplementComplexCoupledDendritic CellsEnsureGenetic TranscriptionGlucocorticoidsGraft RejectionHelper-Inducer T-LymphocyteHeterogeneityHumanImmuneImmunityImmunoglobulin Variable RegionImmunosuppressionIn SituInflammationInflammatoryInvestigationKidneyKidney TransplantationMeasuresMediatingMethodsMonoclonal AntibodiesMusOutcomeOutputPaperPathogenicityPeripheralPhenotypePlayPopulationPositioning AttributeProcessPropertyReportingResistanceRoleSeminalSensitivity and SpecificityShapesSpecificitySteroid ResistanceT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTechniquesTestingTherapeutic InterventionTissue Sampleadaptive immunityallograft rejectionantibody-mediated rejectioncell typeconvolutional neural networkdonor-specific antibodyeffector T cellexperimental studygenetic signaturehigh throughput technologyhuman diseasehuman tissueimmune functioninnovationkidney allograftkidney biopsymolecular targeted therapiesmouse modelneural networknew therapeutic targetnovelnovel strategiesperipheral bloodprogrammed cell death protein 1responsesecondary lymphoid organsingle-cell RNA sequencingstandard of caretherapeutically effectivetransplant modeltwo photon microscopy
项目摘要
ABSTRACT
In a seminal paper, Sarwal et al.1 reported that the presence of a B cell gene signature and dense clusters
of B cells in the renal biopsies was strongly associated with glucocorticoid-resistant T cell-mediated graft
rejection (TCMR) and kidney allograft loss. They proposed a hypothesis that, despite standard of care
immunosuppression, infiltrating B cells play a pivotal role in a subset of acute cellular rejection of kidney
allografts in the clinic. While some subsequent studies supported this hypothesis, others reported opposite
outcomes. As a result, the role of intrarenal B cells in clinical TCMR is currently unclear, and an understanding
of their role is urgently required to allow clinicians to rationally decide if B cell depletion might be useful for
reversing steroid-resistant TCMR. We hypothesize that the identification of additional features of intrarenal B
cells or of the rejecting biopsy are required to more accurately predict poor graft outcome and the need for B
cell depletion to treat TCMR. These features include an understanding the specificity of intrarenal B cells and
their functional properties, as well as the inflammation architecture of the biopsy. To this end, we have
developed two innovative approaches to understand in situ adaptive T and B cell immunity in human biopsies
from rejecting kidney allografts. First, we are able to pair the transcriptional state in single B cells with the
antigenic specificity of the antibody they secrete. Sorted B cells from renal biopsies are subjected to single cell
(sc) RNA-Seq, and the immunoglobulin variable regions are cloned from these same cells and expressed
corresponding antibodies. Second, we have developed a novel approach to characterize the spatial
architecture between different immune cell populations in human tissue and identify functional relationships2,3.
Using a novel deep convolutional neural network (DCNN), coupled to a tuned neural network (TNN), we can
accurately capture T cell shape change upon recognition of antigen presented by dendritic cells (DCs) in
multicolor confocal micrographs. Therefore, this analytic pipeline (Cell Distance Mapping, CDM) can identify
and quantify antigen presentation in fixed tissue samples from both mice and humans. We will use CDM to
study T cell interactions with B cells or dendritic cells (DCs) in rejecting kidney biopsies. Third, we developed a
mouse model of kidney transplantation to address mechanistic questions raised by observations made from
the human renal biopsies. We will apply these three approaches to test our project hypothesis in two Aims:
Aim 1. Test the hypothesis that the different transcriptional and functional states of intrarenal B cells during
rejection are associated with B cell receptor (BCR) specificity and rejection type.
Aim 2: Test the hypothesis that the type of cellular rejection (T cell mediated rejection vs. mixed T cell- and
antibody-mediated rejection) is defined by characteristic in situ cellular interactions between T cells and B cells
or DCs that are amenable to specific therapeutic intervention.
摘要
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 }}
Anita S Chong其他文献
Anita S Chong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('Anita S Chong', 18)}}的其他基金
Intrarenal B cells in acute kidney allograft rejection
肾内 B 细胞在急性同种肾移植排斥反应中的作用
- 批准号:
10543172 - 财政年份:2020
- 资助金额:
$ 79.13万 - 项目类别:
Intrarenal B cells in acute kidney allograft rejection
肾内 B 细胞在急性同种肾移植排斥反应中的作用
- 批准号:
9980656 - 财政年份:2020
- 资助金额:
$ 79.13万 - 项目类别:
Impact of Infections on the Stability of Established Tolerance
感染对既定耐受稳定性的影响
- 批准号:
8512661 - 财政年份:2013
- 资助金额:
$ 79.13万 - 项目类别:
Infections and The Stability of Transplantation Tolerance
感染和移植耐受的稳定性
- 批准号:
8512659 - 财政年份:2012
- 资助金额:
$ 79.13万 - 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:
$ 79.13万 - 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:
$ 79.13万 - 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:
$ 79.13万 - 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:
$ 79.13万 - 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:
$ 79.13万 - 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:
$ 79.13万 - 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:
$ 79.13万 - 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:
$ 79.13万 - 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:
$ 79.13万 - 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:
$ 79.13万 - 项目类别:
Standard Grant