| Research Abstract |
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.
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