GENE TRANSFER IN ORGAN TRANSPLANTATION

器官移植中的基因转移

基本信息

批准号：
2003895
负责人：
Stuart Johnston Knechtle
金额：
$ 10.54万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-12-01 至 1997-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2003895
关键词：
MHC class I antigen T lymphocyte antibody formation antigen presentation artificial immunosuppression dosage drug administration routes enzyme linked immunosorbent assay gene expression heart transplantation in situ hybridization laboratory rat liver transplantation muscle cells tissue donors transfection transplantation immunology

项目摘要

Future improvements in immunosuppression for clinical organ transplantation will need to be based on a biological approach to donor- specific immunosuppression to increase the safety and success of organ transplants. Antigen specific immunosuppression directed at the major histocompatibility antigens of the transplant donor will need to be designed to suppress the action of the lymphocyte clones responsible for rejection of the particular graft the patient receives. To date, donor- specific immunosuppression has been achieved in certain animal models and partially achieved with donor-specific transfusions in human kidney transplant recipients. The application of specific immunosuppression has been limited by 1) availability of donor MHC antigens; 2) lack of a continuous supply of donor MHC antigen; 3) poor understanding of the optimal form of donor antigen (membrane bound versus secreted antigen, monomeric versus multimeric antigen); and 4) an incomplete understanding of the ideal microenvironment for antigen presentation to favor the induction of unresponsiveness. Due to recent developments in gene transfer techniques, MHC antigen availability has been dramatically increased in potential both by in vitro and in vivo MHC gene transfer to myocytes. A continuous in vivo supply of donor MHC antigen may be possible. By genetically altering the DNA encoding the MHC Class I antigen, it is possible to alter the form of MHC antigen. The aims of the current proposal are to evaluate the immune response to MHC Class I antigen expressed as a result of gene transfer into myocytes. The antibody and T cell response as well as hepatic and cardiac allograft survival following MHC gene transfer will be evaluated. The time course of MHC gene expression following in vivo transfer will be evaluated. The goal of this work will be to develop a means of inducing specific unresponsiveness using MHC gene transfer. Variables studied will include 1) the route of administration; 2) the dose administered; 3) the timing of administration; 4) the form of the gene injected; and 5) the organ transplanted, i.e., liver versus heart. The ultimate goal of this work is to apply gene transfer techniques to development of specific immunosuppression which is clinically applicable to increasing the safety and success of organ transplantation.

临床器官免疫抑制的未来改进移植需要基于捐赠者的生物学方法特异性免疫抑制可提高器官的安全性和成功率移植。针对主要抗原的特异性免疫抑制移植供体的组织相容性抗原需要旨在抑制淋巴细胞克隆的作用对患者接受的特定移植物的排斥。迄今为止，捐助者—— 在某些动物模型中已经实现了特异性免疫抑制通过人肾捐献者特异性输血部分实现移植受者。特异性免疫抑制剂的应用受到以下因素的限制：1) 供体 MHC 抗原的可用性； 2）缺乏一个持续供应供体MHC抗原； 3) 理解不够供体抗原的最佳形式（膜结合抗原与分泌抗原，单体抗原与多聚体抗原）； 4）不完整的理解抗原呈递的理想微环境有利于诱导无反应。由于基因转移技术的最新发展，MHC 抗原可用性的潜力已大大增加体外和体内 MHC 基因转移至肌细胞。体内连续供体 MHC 抗原的供应是可能的。通过基因改变编码 MHC I 类抗原的 DNA，可以改变形式 MHC 抗原。当前提案的目的是评估免疫反应 MHC I 类抗原因基因转移至肌细胞而表达。抗体和 T 细胞反应以及肝和心脏同种异体移植物将评估 MHC 基因转移后的存活率。时间历程将评估体内转移后MHC基因表达的情况。这这项工作的目标是开发一种方法来诱导特定的使用 MHC 基因转移治疗无反应。研究的变量将包括 1) 给药途径； 2) 给药剂量； 3）时机行政管理； 4) 注射基因的形式； 5）器官移植，即肝脏与心脏。这项工作的最终目标是将基因转移技术应用于开发适用于临床的特异性免疫抑制剂提高器官移植的安全性和成功率。