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Single Cell Analysis of Alloreactive CD8+ T Cells in Kidney Transplant Rejection

肾移植排斥反应中同种异体 CD8 T 细胞的单细胞分析

基本信息

批准号：
10607410
负责人：
Tiffany Shi
金额：
$ 4.06万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2022-11-22 至 2026-07-21
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607410
关键词：
Acute Affect Alloantigen Allogenic Allograft Tolerance Allografting Alpha Cell Anti-CD40 Autoimmunity Automobile Driving Biology Biopsy Blood CD8-Positive T-Lymphocytes CTLA4-Ig Cell Therapy Cells Chronic Clonal Expansion Clone Cells Cross Reactions Cytomegalovirus Data Development Diabetes Mellitus Disease Effectiveness End stage renal failure Event Frequencies Gene Expression Goals Graft Rejection Hand Health Home Human Human Herpesvirus 4 Hypertension Immunity Immunobiology Immunosuppression Individual Infection Infection Control Infiltration Jurkat Cells Kidney Transplantation Knowledge Life Expectancy Link Literature Lymphocyte Lymphocytic choriomeningitis virus Malignant Neoplasms Mediating Memory Modeling Molecular Monoclonal Antibodies Mus Organ Organ Transplantation Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Persons Play Quality of life Reaction Risk Role Sampling Solid Specificity T cell infiltration T cell receptor repertoire sequencing T cell therapy T memory cell T-Lymphocyte Tacrolimus Testing Therapeutic Therapeutic immunosuppression Time Toxic effect Transplant Recipients Transplantation Urine Viral Viral Antigens Virus Diseases Work allograft rejection combat cross reactivity experimental study graft failure graft function heart allograft human disease insight kidney allograft mouse model new therapeutic target novel novel therapeutics peripheral blood post-transplant premature prevent response screening single cell analysis single-cell RNA sequencing standard of care transcriptomics transplant model

项目摘要

ABSTRACT Renal transplantation remains the only long-term solution to end-stage renal disease (ESRD), which affects approximately 2 million people worldwide. However, long term allograft acceptance requires lifelong immunosuppression, and current standard-of-care immunosuppressive therapies have a multitude of toxicities directly leading to decreased patient and allograft survival. Targeted anti-rejection therapies focusing on T cell co-stimulatory blockade, such as belatacept (CTLA4-Ig) or iscalimab (anti-CD40 mAb) have been developed to prevent T cell mediated rejection. Despite enhanced graft function, rejection episodes under these therapies are more frequent and difficult to treat.Current dogma suggests that these rejections are due to memory CD8+ T cell cross-reactivity from prior infections, which do not require co-stimulation. Here we will examine the cross- reactivity of expanded, graft-infiltrating CD8+ T cells in rejection biopsies from both humans and mice. Our novel preliminary data suggest that expanded CD8+ T cell clonotypes in the graft are alloreactive, and prior viral infection increases the alloresponse. These preliminary findings include: (a) a limited number of unique clonotypes are expanded in the rejecting allograft; (b) the same individual expanded CD8+ T cell clones are observed for months in persistent allograft rejection; (c) expanded clonotypes shift their gene expression to escape immunosuppression; and (d) subcloning of TCRs from expanded clonotypes into Jurkat cells confirmed their allospecificity. Further, we show that using established mouse models of viral infection and transplantation: (e) prior LCMV infection increases the response to alloantigen; and (f) mice without prior LCMV infection reject F1 heart allografts by day 14 post-transplant. Finally, we have samples from patients undergoing rejection after administration of viral-specific T cell therapy to treat infection. Together, our findings and existing literature support a highly novel hypothesis that a significant fraction of pre-existing viral-specific memory T cells home to the allograft shortly after transplant and their cross-reactivity to alloantigens drives rejection events. We propose to test this hypothesis by: (i) identifying alloreactive, viral-reactive, and cross-reactive graft- infiltrating CD8+ T cells in patients undergoing renal allograft rejection (Aim 1) and (ii) determining the impact of prior viral infection on CD8+ T cell infiltration into the allograft of a mouse model of transplantation (Aim 2). Our studies will enhance the knowledge of cross-reactive CD8+ T cells in renal allograft rejection and the characterization of alloreactive T cells on human disease. Given the organ shortage crisis and the limited life expectancies of transplant patients, defining the specificity of alloreactive CD8+ T cells in renal transplant rejection will enable discovery of novel therapeutic targets to directly target alloreactive cells while sparing bystander CD8+ T cells responsible for maintaining immunity to infections or cancers.

摘要