权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Study of tolerance mechanism in a functional tolreance modrl of rat lung transplant

大鼠肺移植功能耐受模型耐受机制研究

基本信息

批准号：
08457341
负责人：
FUJIMURA Shigefumi
金额：
$ 5.5万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Our previous studies have shown that a spontaneous functional tolerance develops in a rat model of lung transplantation. The tolerance observed in this model may be due to the minor histocompatible differences. To further examine this model, the effect of pre-transplant donor-specific spleen cell transfusions (DSTs) was examined on the functional tolerance state in this model.F344 rats received WKY spleen cells on days-45 and-30 before transplantations. Control F344 rats received lung grafts without DSTs. Recipients in both groups were euthanized on day 7,14,21 and 49 post-transplant, and allograft rejection (AR) was graded stage 0-IV.Intragraft cytokine gene transcripts were examined using RT-PCR techniques. In addition, allogeneic and third party skin grafts were placed on recipients at day 35 to evaluate the development of systemic tolerance. Control animals showed stage II-III AR in the first 3 weeks followed by spontenous recovery with stage I-II AR on day 49. In contrast, DST animals showed stage Ill-IV AR by day14-21, without any evidence of recovery on day 49. WKY skin grafts showed prolonged survival in control animals, but were promptly rejected in DST animals. Intragraft cytokine gene expression in control animals was characterized by weak expression of IL-2 and high IL-10, while DST animals showed high levels of IL-2 transcripts.Conclusions : 1) Pre-transplant DSTs did not enhance allograft survival, but induced AR and ablated tolerance in the WKY*F344 lung transplant model. 2) The DST-induced AR was associated with a deviation of cytokine immune responses from a predominant Th2 to Th1.3) Factors other than histocompatibility, such as route of alloantigen exposure, amount or nature of alloantigens associated specifically with lung allografts, are involved in deviating native immune responses toward acceptance in this model.

我们之前的研究表明，在大鼠肺移植模型中产生了自发的功能耐受性。在该模型中观察到的耐受性可能是由于较小的组织相容性差异。为了进一步验证该模型，我们检测了移植前供体特异性脾细胞输注（DSTs）对该模型功能耐受状态的影响。F344大鼠在移植前第45天和30天接受WKY脾细胞。对照组F344大鼠接受无DSTs肺移植。两组受者分别于移植后第7、14、21和49天实施安乐死，并将同种异体移植排斥反应（AR）分级为0-IV期。采用RT-PCR技术检测细胞因子基因转录物。此外，在第35天将异体和第三方皮肤移植物置于受者身上，以评估全身耐受性的发展。对照动物在前3周出现II-III期AR，随后在第49天自发恢复，出现I-II期AR。相比之下，DST动物在第14-21天出现了ii - iv期AR，在第49天没有任何恢复的迹象。WKY皮肤移植物在对照组动物中显示出较长的存活时间，但在DST动物中迅速出现排斥反应。对照组动物的细胞因子基因表达表现为IL-2低表达和IL-10高表达，而DST动物的IL-2转录物水平较高。结论：1)在WKY*F344肺移植模型中，移植前DSTs并没有提高同种异体移植物的存活率，但诱导了AR和消融耐受。2) dst诱导的AR与细胞因子免疫反应从主要的Th2向Th1.3偏离有关)组织相容性以外的因素，如同种异体抗原暴露途径、与肺同种异体移植物特异性相关的同种异体抗原的数量或性质，在该模型中参与了使天然免疫反应偏离接受的过程。