P. Reggiani

Pharmacokinetics of FK506 and mycophenolic acid in experimental and clinical intestinal transplantation.

Abstract Rejection control remains the crucial problem of intestinal transplantation. Currently, this type of transplantation requires prolonged administration of high-dose immunosuppressive treatment via parenteral route, resulting in a high incidence of toxicity.1−3 The aim of our study is to investigate the pharmacokinetics of both FK506 and mycophenolic acid (MPA) after oral administration in swine and human intestinal transplantation and to verify whether administration via oral route only is sufficient to reach and subsequently to maintain target drug levels.

Small bowel transplantation under oral immunosuppression: experimental study in the pig.

Abstract Despite recent improvements, clinical intestinal transplantation remains an experimental procedure for the treatment of irreversible failure of the intestine. Depending on the extent of additional failures, the transplant of the bowel can also be performed as a part of a multivisceral graft. Although these procedures have been performed preclinically for many years and have also been reported to have a successful outcome in the clinical setting, they have not yet become routine, unlike the transplant of other organs. With the aim of improving clinical results, many groups are studying on experimental models. Experimental studies are predominantly performed in rats, with fewer studies conducted in large animals. In 1992, the authors began an experimental program of orthotopic liver-small bowel transplantation (OLSBTx) and surgical technique. Results in the pig have been described for the first time by our group. Despite an acceptable control of rejection, results of intestinal function were poor. The OLSBTx is a high-risk procedure, and in animals an aggressive postoperative treatment is impossible. We therefore decided to continue with the transplant of the small bowel alone (SBTx) because it is a less demanding procedure.

Serotonin (5-HT): An enteroendocrine marker of reperfusion injury after liver-small bowel allotransplantation in the pig

Abstract HISTOMORPHOLOGIC and functional aspects of preservation/reperfusion injury, after small bowel transplantation, have been well investigated after different modalities and types of perfusion solutions. Experimental and clinical studies on bowel preservation damage have well defined the modifications of enteric and Goblet cells, vascular structures, myoenteric nerves, and ganglia. The enteroendocrine system is not so well studied. In recent studies of Lai et al, 1 on auxiliary small bowel allotransplantation in the dog without immunosuppression, biopsies of the small bowel were done daily and at time of death; specimens were stained with immunohistochemical methods for chromogranin A and somatostatin. Also, in animals with severe rejection, this type of enteroendocrine cell did not present any evident modification. Kaihara et al 2 suggested serotonin as a good marker of ischemia/reperfusion injury after allotransplantation of the small bowel in the rat. In their experience, the release of serotonin in the lumen bowel after reperfusion inversely correlated with the number and quality of serotonin cells. Our previous experiences with normothermic preservation in Ringer lactate solution, up to 20 hours in the pig, showed good preservation of argentaffin and serotonin cells up to 6 hours with a progressive marked reduction in the following hours. 3 The bowel perfused and preserved ipothermically with 4°C Wisconsin solution up to 36 hours, showed normal argentaffin cells up to 20 hours, after which time these cells were numerically reduced and degranulated. On the basis of these previous observations, we decided to analyze the modifications of enteroendocrine cells in a pig model of orthotopic liver-small bowel allotransplantation with different preservation/reperfusion times.

Serotonin (5-HT): An enteroendocrine marker of rejection after small bowel allotransplantation in the pig

Abstract The histopathologic findings of mucosal epithelial cell injury in acute and chronic rejection in small bowel transplantation are well known. Several studies have been done on the pig either as autotransplantation, allotrans-plantation, orthotopic, or enterotopic transplantation, with or without immunosuppression. Very few investigations on the enteroendocrine system have been done. In particular, none have been done on rejection in pigs after intestinal transplantation. On the other hand, changes in the enteroendocrine markers (somatostatin and chromogranin A) have been examined in detail after auxiliary small bowel transplantation in dogs without immunosuppression, showing no apparent changes on the 7th postoperative day, even if in a severe rejection status. Recent studies on rats have evaluated the presence of serotonin after small bowel allotransplantation with different times of preservation, and after reperfusion. The authors concluded that the number of serotonin-positive cells decreased with a preservation time of more than 1 hour in Ringer lactate at 4°C. We too have examined the modifications of argentaffin as well as serotonin-positive cells in the harvested small bowel of pigs perfused with Belzer solution (4°C) and preserved in Ringer lactate at 4°C, after preservation and reperfusion in the combined liver-small bowel allotransplantation. We noticed that the argentaffin and serotonin cells were preserved up to 20 hours and that after reperfusion the most important injury was due to the disappearance of these cells from the crypts. In this study, we studied the modifications of the intestinal enterochromaffin cells after combined liver-small bowel and small bowel alone allotransplantation in pigs, with the aim of evaluating a correlation with rejection.

Reduced acute rejection after liver transplantation with neoral-based double immunosuppression

CCYCLOSPORINE (CyA) is unequivocally a milestone in the development of organ transplantation. However, the wide interand intrapatient variability in gut absorption and the subsequent different bioavailability limited the exploitation of CyA in inducing immunosuppression without frequent blood monitoring. The clinical use of CyA in liver transplantation is further complicated by its bile-dependent absorption. These characteristics lead to fluctuations in the blood levels and to a potential higher incidence of acute rejection mainly in the early postoperative period. Recently, a new microemulsion formulation (Neoral) of CyA has been introduced in the clinical arena. The new formulation is better absorbed by the gastrointestinal tract, even in liver transplant patients with open external biliary drainage. Few open and randomized trials confirm the possibility of inducing immunosuppression by oral administration of CyA with a lower incidence of rejection in the Neoral arms. In this open, nonrandomized, retrospective study, we compare the incidence of acute rejection and nephrotoxicity during the first postoperative month and graft and patient survival rates at 1 year in 33 consecutive liver transplant adult patients: 17 patients treated with a Sandimmune-based double therapy and 16 patients treated with Neoral-based double therapy.

Transplantation of small bowel alone or with the liver in pigs : Use of peripheral blood lymphocytes in monitoring rejection

Abstract The small bowel is an organ with a large lymphoid component. In addition to the organized structures of the Peyers patches and mesenteric lymph nodes, the lamina propria also contains a vast mass of mobile lymphocytes. The transplantation of the small bowel has thus been associated with significant rejection phenomena and the possibility of graft-versus-host disease (GVHD) in the recipient, despite the immunosuppressive treatment. In a swine model, we have compared by mixed lymphocyte reaction (MLR) the immunological events occurring during orthotopic liver-small bowel transplantation (OLSBTx) and small bowel transplantation alone (SBTx) to evaluate a possible immunological advantage of combined liver-small bowel transplantation in order to prevent intestinal rejection.