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

Reseach of Xenogeneic hepatic transplantction

异种肝移植的研究

基本信息

批准号：
06454362
负责人：
KAWASAKI Seiji
金额：
$ 2.82万
依托单位：
Shinshu University School of medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

First, we established a rat-to mouse xenograft model. Using these models, we elucidated that adhesion molecules play some important roles in xenogeneic rejection. We showed that blockade of the both sides of adhesion pairs is critical for effective immune suppression. Anti-ICAM-1 and anti-LFA-1 mAbs synergistically induced tolerance in our mouse model of cardiac transplantation. The present study was performed to identify, by blocking cell adhesion the molecules that are essential in immune suppression. The result showed that simultaneous blockade of donor ICAM-1 and recipient LFA-1 is most effective in xenograft survival prolongation. Also, it is of interest that only temporal blockade of cell adhesion molecules with mAbs effectively prolongs concordant xenograft survival. A combination of anti-adhesion mAbs and a suboptimal dose of FK506 synergistically prolonged xenograft survival. The mechanism of this synergism is, as yet, unclear. We showed that IL-2 production is inhibited in mice rendered tolerant by anti-ICAM-1 and anti-LFA-1 both in vitro and in vivo. Suppression of IL-2 production is thought to lead to T-cell clonal inactivation, which results in specific tolerance. Therefore, inhibition of T helper 1 cytokines, such as IL-2 and IFN-g is possibly enhanced by the simultaneous administration of FK506 and mAbs to ICAM-1 and LFA-1. We are performing living related liver transplantation in the clinical stage but we are unable to completely inhibit transplant rejection. Further careful pathophysiologic work should enable us to understand more about the true nature of this problem and how to solve it.

首先，我们建立了大鼠-小鼠异种移植模型。利用这些模型，我们阐明了粘附分子在异种排斥反应中的重要作用。我们发现，阻断粘附对的两侧对于有效的免疫抑制至关重要。抗ICAM-1和抗LFA-1单克隆抗体在我们的小鼠心脏移植模型中协同诱导耐受。进行本研究以通过阻断细胞粘附来鉴定在免疫抑制中必不可少的分子。结果表明，同时阻断供体ICAM-1和受体LFA-1对延长异种移植物存活最有效。此外，令人感兴趣的是，只有用mAb暂时阻断细胞粘附分子才能有效地抑制异种移植物的存活。抗粘附mAb和次优剂量FK 506的组合协同延长异种移植物存活。这种协同作用的机制尚不清楚。我们表明，IL-2的产生被抑制在小鼠中呈现耐受性的抗ICAM-1和抗LFA-1在体外和体内。IL-2产生的抑制被认为导致T细胞克隆失活，这导致特异性耐受。因此，FK 506和ICAM-1和LFA-1单克隆抗体同时给药可能会增强对T辅助细胞因子1（如IL-2和IFN-g）的抑制。我们在临床阶段进行活体肝移植，但我们无法完全抑制移植排斥反应。进一步仔细的病理生理学工作应该使我们能够更多地了解这个问题的真实性质以及如何解决它。