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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：
9980656
负责人：
Anita S Chong
金额：
$ 79.13万
依托单位：
UNIVERSITY OF CHICAGO
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：
https://reporter.nih.gov/project-details/9980656
关键词：
Ablation Acute Address Allogenic Antibodies Antibody Specificity Antigen Presentation Antigen-Presenting Cells Antigenic Specificity Antigens Architecture Autoimmune Diseases Automobile Driving B-Lymphocytes Biological Markers Biopsy Blood Cell Communication Cell Shape Cells Characteristics Clinic Clinical Collaborations Complement Complex Coupled Dendritic Cells Ensure Genetic Transcription Glucocorticoids Graft Rejection Helper-Inducer T-Lymphocyte Heterogeneity Human Immune Immunity Immunoglobulin Variable Region Immunosuppression In Situ Inflammation Inflammatory Investigation Kidney Kidney Transplantation Measures Mediating Methods Monoclonal Antibodies Mus Outcome Output Paper Pathogenicity Peripheral Phenotype Play Population Positioning Attribute Process Property Receptors, Antigen, B-Cell Reporting Resistance Role Seminal Sensitivity and Specificity Shapes Specificity Steroid Resistance T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Therapeutic Intervention Tissue Sample Treatment Efficacy adaptive immunity allograft rejection cell type convolutional neural network effector T cell experimental study genetic signature high throughput technology human disease human tissue immune function innovation kidney allograft kidney biopsy molecular targeted therapies mouse model neural network new therapeutic target novel novel strategies peripheral blood programmed cell death protein 1 response secondary lymphoid organ single-cell RNA sequencing standard of care transplant model two 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