Research about mechanism of delayd xenograft rejection (DXR).

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Purpose : Delayd xenograft rejection (DXR) takes place in discordant xenotransplantation, even complement activation, natural antibody and blood coagulation are inhibited by drugs such as CVF (cobra venom factor). Although pathology of the heart underlying DXR shows infiltration of NK (natural killer) cells and macrophages, the mechanism of how these cells can induce DXR is unknown. In this study, we addressed the contribution of NK cells to DXR using congenitally NK activity deficient rat, Beige rat (Bg) that is derived from DA rat (DA).Materials and methods :1. NK activity (^<51>Cr release assay) was measured using Yac-1 cells as targets and splenocytes of DA and Bg as effector cells.2. Expression of cell surface antigens in DA and Bg splenocytes was compared by flowcytemetry.3. Using RT-PCR,the expression of effector molecules such as perforin, granzyme A and granzyme B was detected in DA and Bg splenocytes.4. Under complement inhibition by CVF (-1,0 day. 30U/kg. iv.), guinea pig hearts were transplanted into DA and Bg, and their grafts survival time were compared.Result :1. NK activity in BG was severely impaired in comparison with that in DA.(DA : 62.8%, BG : 18.2% at E/T=100)2. There was no difference in NK cells number between DA and BG,whereas cell numbers of CD8 positive and IL2R positive cells were decreased in Bg as compared with those in DA.3. The expressions of perforin, granzyme A and granzyme B mRNA were inhibited in Bg as compared with those in DA.4. Grafts mean survival time in Bg (28(]SY.+-。[)1.5hr, n=9) was significantly longer than that in DA (20(]SY.+-。[)2.1hr, n=9).Conclusion : NK cells and CD8 positive cells play an important role in the process of DXR.Therefore, the inhibition of these cells function would lead to longer xenografts survival.