A Tandin

Tacrolimus enhances the immunosuppressive effect of cyclophosphamide but not that of leflunomide or mycophenolate mofetil in a model of discordant liver xenotransplantation.

Leflunomide (LEF), which suppresses both T and B cells, prolongs survival of heart xenografts in the concordant hamster to rat animal model.1 However, xenotransplantation across discordant barriers is the most likely approach to solve the problem of organ shortage. By perfusing guinea pig livers with University of Wisconsin solution containing sodium nitroprusside, we have solved the problem of poor reperfusion of this organ when transplanted into rats.2 Accordingly, we tested the effect of LEF alone or in combination with tacrolimus (FK) on survival of guinea pig to rat liver xenografts. Results were compared with those obtained following the use of cyclophosphamide (CyP) and mycophenolate mofetil (MMF).

Role of UW solution and sodium nitroprusside in reperfusion of liver xenografts from guinea-pig to rat

Guinea‐pig livers are poorly reperfused when transplanted into rats. We have observed that, in contrast to that of the rat, the guinea‐pig intrahepatic portal vein (PV) has a thick layer of smooth muscle. It is possible that, after perfusion of the liver with ice‐cold saline, this could go into spasm, resulting in poor reperfusion. To test this hypothesis, guinea‐pig livers were perfused with different solutions stored at varying temperatures and transplanted into LEW rats. To prevent xenograft hyperacute rejection, all xenograft recipients were treated with 80 U/kg cobra venom factor (CVF) i.v. on days –1 and 0. In addition to the percentage reperfusion, PV resistance and recipient survival were also monitored. In group I, liver xenografts perfused with ice‐cold saline (4°C) reperfused poorly (20–30%), resulting in the development of portal hypertension (16.5 cmH2O vs. 12 cmH2O in naive LEW rats) and shortened mean survival time (11.7 ± 4.2 h). In contrast, group II livers perfused with saline at room temperature (23°C) underwent homogeneous reperfusion (98–100%) with no increase in portal vein resistance, indicating that low temperature was the main trigger for the spasm of the PV. Moreover, recipient survival in this group was significantly prolonged to a mean of 22 ± 2.6 h (P < 0.01). Although UW solution (group III) and the vasodilator sodium nitroprusside (NP) (group IV) when used alone improved the degree of hepatic reperfusion, it was still not optimal. The supplementation, however, of UW solution with NP in group V animals resulted in homogeneous reperfusion (98%) with no portal hypertension and consistent prolonged graft survival of 21.0 ± 1.7 h. Therefore, this study has determined that the riddle of the abnormal reperfusion of guinea‐pig liver xenografts by rat blood is non‐immune mediated and is due to the spasm of the strong smooth muscle in the PV tree produced by cold perfusates.

Hamster-to-rat bone marrow xenotransplantation and humoral graft vs. host disease

Abstract: Bone marrow transplantation (BMT) may induce tolerance across xenogeneic barriers. We have established a xenogeneic BMT model where hamster BM is transplanted into splenectomized LEW rat recipients resulting in high levels of engraftment. Unfortunately, graft vs. host disease (GVHD) with severe dermatitis developed in all rat recipients. We were successful in treating or preventing the dermatitis of this xenogeneic GVHD by the use of the T‐cell suppressant tacrolimus. However, this compound did not prevent the development of a fatal liver injury in the rat recipients. This study was designed to elucidate the pathogenesis of this liver injury appearing in T‐cell suppressed rat recipients of hamster BM.

Concordant hamster-to-rat liver xenotransplantation leads to hyperlipidemia

Different species have adapted in different ways to their environment through the variation of specific metabolic parameters. For example, hamsters, unlike rats, are able to adjust their metabolism when they are subjected to extreme temperatures, modifying the mobilization of fat and regulating its storage.1 Knowing that the liver plays a primary role in lipid metabolism, we performed liver transplantation between hamsters and rats to determine what effects this might have in recipient cholesterol and trygliceride levels.

Xenogeneic Humoral Graft-Vs-Host Disease Following Hamster-to-Rat Bone Marrow Transplantation

Bone marrow transplantation (BMT) is an effective strategy to induce tolerance across xenogeneic barriers.1 This approach has been used in the hamster-to-rat BMT model.2 However, all animals suffered from graft-vs-host disease (GVHD). Although xenogeneic GVHD has been observed in other studies, it is not yet well characterized.3 Because xenograft rejection is primarily mediated by humoral mechanisms, we tested the hypothesis that, unlike allogeneic GVHD in which cellular mechanisms predominate, xenogeneic GVHD could also be humorally mediated.

Loss of Serum Bicarbonate After Discordant Liver Xenotransplantation

It is a concern in liver xenotransplantation (XTx) that discordant combinations might not be sufficiently compatible for physiologic functioning in the recipient. Closer examination of the guinea pig- (GP) to-rat liver XTx model uncovered potential incompatibilities in bile production between these species. GP (along with rabbits) have the greatest bile flow rate of all species studied.1 Additionally, there is a fundamental difference between the two species in the rate of bile excretion. Bile flow in rats is bile acid dependent, whereas the rate in GP is independent of bile acid; the latter is believed to be driven osmotically by bicarbonate.2 Because bile flow is 4 times greater in GP than in rats, we tested whether the different excretion mechanisms would affect HCO3− blood levels and pH in rat recipients of GP liver xenografts (Xeno).