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Core D: Antigen Receptor Identification and Tracking Core

核心 D：抗原受体识别和跟踪核心

基本信息

批准号：
10180874
负责人：
Nir Hacohen
金额：
$ 42.19万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-08 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180874
关键词：
Address Affect Alleles Antigen Receptors Antigen Targeting Antigens Antiviral Agents B-Lymphocytes B-cell receptor repertoire sequencing BCR gene Bar Codes Biological Biopsy Blood Blood Volume Blood specimen Cell Count Cells Chronic Clone Cells Complex Cytomegalovirus Data Data Set Development Differentiation Therapy Epitopes Evolution Exhibits Frequencies Gene Expression Genes HLA-A2 Antigen Hepatitis B Virus Hepatitis C virus Human Human Herpesvirus 4 IgK Immune Immune response Immunity Immunologic Memory Immunotherapy Individual Infection Influenza vaccination Infrastructure Label Leukapheresis Link Lymphocyte Lymphocyte Activation Lymphocyte Subset Messenger RNA Methods Monitor PD-1 blockade PD-1 pathway Pathway interactions Patients Peripheral Blood Mononuclear Cell Preventive vaccine Property Resolution Role Sampling Services Sorting - Cell Movement Specificity Stains Standardization T cell receptor repertoire sequencing T-Lymphocyte Technical Expertise Technology Testing Therapeutic Effect Time Tissue Sample Tissues Vaccination Vaccine Antigen Vaccines Viral Viral Antigens Virus Virus Receptors adaptive immune response anti-PD-1 anti-PD1 therapy antigen binding antigen-specific T cells base checkpoint therapy chronic infection cohort cost effective cytokine enzyme linked immunospot assay immune checkpoint blockade innovation insight liver biopsy pathogen receptor response scale up single-cell RNA sequencing tool transcriptome sequencing

项目摘要

Project Summary The overall objective of the U19 is to discover the role of the PD-1 pathway in human immunity by studying the effects of therapeutic PD-1 blockade on immune responses to chronic viruses (Project 1) and preventive vaccines (Project 2). To monitor adaptive immune responses in patients, we need to track the complex repertoire of T and B cells since clonotypes may behave differently over time and in response to infection and therapy. While there are several methods for tracking antigen-specific lymphocytes, large volumes of blood are needed for monitoring multiple antigens, biopsies have limited material for standard pipelines, and clonotypes with distinct antigen receptors are not distinguished. Standard bulk sequencing of TCRs and BCRs can provide quantitative clonotype frequencies; however, its utility is limited because the target antigens are not known for each TCR/BCR and the activation states of each clonotype cannot be determined. Core D provides an innovative service for tracking antigen-specific T and B cells in patient blood and tissues, allowing Projects 1 and 2 to quantify the frequency, antigen specificity and activation states of lymphocytes. Aim 1 provides an approach to match TCRs and BCRs to antigens by sequencing antigen receptors in patient T and B cells stimulated or tagged with viral or vaccine antigens. Aim 2 uses the more cost-effective bulk TCR- and BCR-seq to quantify the frequencies of clonotypes in serial samples of patients treated with anti-PD-1 therapy, but takes advantage of the results in Aim 1 to link antigen receptors from the repertoire with specific viral or vaccine antigens. Aim 3 uses leading-edge droplet-based RNA-seq to sequence paired antigen receptor chains (TCRα & β; IgH & IgK/L) along with thousands of mRNAs in single lymphocytes, linking functional pathways with antigen receptors. The resulting dataset from the three Aims will be integrated to provide the frequencies, antigen specificities and activation states of T and B cells, allowing us to test the hypothesis that anti-PD-1 therapy differentially impacts the proliferation and activation of each lymphocyte subset depending on its antigen specificity and pre-therapy differentiation state. In short, Core D enables the monitoring of antigen- specific lymphocytes at unprecedented resolution, and will help dissect changes in immune protection against chronic infections (including HBV, HCV, CMV, and EBV), and influenza vaccination as result of anti-PD-1 therapy. The establishment and refinement of these approaches and creation of a Core D infrastructure will enable interrogation of immune mechanisms and provide insights into development and durability of immunological memory in the context of checkpoint blockade or any other immunotherapies.

项目总结