Reseach of Xenogeneic hepatic transplantction

首先，我们建立了大鼠到小鼠的异种移植模型。通过这些模型，我们阐明了粘附分子在异种排斥反应中起重要作用。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单克隆抗体在心脏移植小鼠模型中协同诱导耐受。目前的研究是通过阻断细胞粘附来识别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，只有用单克隆抗体暂时阻断细胞粘附分子才能有效延长异种移植物的存活时间。抗粘附单抗和次优剂量的FK506联合可协同延长异种移植物的存活时间。到目前为止，这种协同作用的机制尚不清楚。我们发现，在体外和体内抗icam -1和抗lfa -1耐受的小鼠中，IL-2的产生受到抑制。抑制IL-2的产生被认为导致t细胞克隆失活，从而导致特异性耐受。因此，FK506和单抗同时作用于ICAM-1和LFA-1可能会增强对辅助性T细胞因子如IL-2和IFN-g的抑制作用。我们在临床阶段进行活体相关肝移植，但我们无法完全抑制移植排斥反应。进一步细致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正性质以及如何解决它。

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.