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After the introduction of cyclosporine into liver transplantation in 1983, 1-year patient survival more than doubled. Later, with the improved microemulsified formulation of cyclosporine (Neoral) more stable pharmacokinetics were achieved. Today, C(2) monitoring of cyclosporine blood levels allows a more accurate estimation of the area under the concentration-versus-time curve as the single best indicator of cyclosporine exposure. As a consequence, with better control of side effects as well as desired effects the results of cyclosporine in liver transplantation have been further improved. The introduction of mycophenolate mofetil and basiliximab/daclizumab combination therapy has provided new options for the prevention of allograft rejection. The safety profile of individual immunosuppressive regimens comes more into focus since acute allograft rejection may be controlled successfully with competing strategies. As the focus in liver transplantation is shifting toward greatly improved long-term results, late posttransplant mortality with a functioning graft is a major concern. Prevention of long-term complications associated with highly effective immunosuppressants--posttransplant lymphoproliferative disease, cytomegalovirus infection, diabetes, hypertension, and hyperlipidemia-gains importance. Technical advances in living-related and cadaveric split-liver transplantation have lead to increasing use of segmental liver transplantation with the need to consider the effects of immunosuppression on liver regeneration and metabolism. The individualized orchestration of immunosuppression taking into account the underlying liver disease as well as other individual predispositions remains a future challenge.

Aim The pattern of rejection of vascularized pancreas allografts in presensitized recipients was studied among congeneic and recombinant rat strains in order to establish the time frame of rejection. Donors and recipients differed either in their entire MHC or in class I or class II MHC antigens. Material and methods Streptozotocin diabetic (55 mg/kg bone weight) recipients underwent an intra-abdominal heterotopic pancreas whole organ transplantation. The exocrine secretion of the pancreas was suppressed by ligation of the duct. Rejection was defined as recurrence of diabetic hyperglycemia exceeding 14 mmol/L, which was subsequently confirmed by histologic examination. The pancreas recipients were presensitized by repetitive donor-specific skin transplants performed 12, 8, and 4 weeks prior to pancreas grafting. Results The results shown accelerated rejection in all instances. Animals with incompatibility for the entire MHC showed a median rejection time in naive recipients of 12.5 days and in presensitized recipients of 8 days. Class I MHC incompatible native recipients rejected the allografts after 16.5 days (median) and presensitized recipients after 9 days (median). Concerning class II MHC incompatibility rejection appeared in naive recipients after 16 days (median) and in presensitized recipients after 7 days (median). Hyperacute rejection, however, was not observed. Discussion These results show an accelerated pattern of rejection in all instances caused by donor MHC antigens. Hyperacute rejection, however, was not observed. The effect is slightly pronounced in class II MHC incompatibility. Acceleration of rejection may be caused by stimulation of the humoral as well as the cellular pathway of the immune response. The underlying mechanisms concerning the different MHC incompatibilities, however, remains speculative.

Introduction In a substantial proportion of patients, recurrent hepatitis C after liver transplantation (OLT) rapidly progresses to graft cirrhosis. The role of different immunosuppressive schemes is not well evaluated. Patients and methods The clinical course of 130 patients with recurrent hepatitis C after OLT was retrospectively analyzed. Mean trough levels of calcineurin inhibitors and cumulative doses of the remaining immunosuppressants were calculated. The results were compared with liver function tests, histological fibrosis progression, and survival. Results Survival and fibrosis progression were similar in patients with tacrolimus and cyclosporine and did not correlate with mean trough levels. In contrast, the application of azathioprine (mean dose of more than 25 mg/d during the first 3 months after OLT) was associated with significantly less progression of fibrosis (P = .01). Administration of azathioprine after the early postoperative phase was not related to the long-term outcome. The dose of prednisolone in the long-term course after OLT significantly correlated with the rate of fibrosis progression (P = .008). Conclusions The clinical course of recurrent hepatitis C was variable. Survival and fibrosis progression did not correlate with the type or trough level of calcineurin inhibitors. Azathioprine early in the course after OLT and prolonged administration of prednisolone were associated with less fibrosis progression.

Cyclosporine is widely used as an immunosuppressive agent after solid organ transplantation. Limited data are available on the modulation of human dendritic cells by cyclosporine. We investigated the effects of cyclosporine on the phenotype and function of human dendritic cell (DC) subsets. DCs were isolated from peripheral blood using magnetic bead-conjugated antibodies. Cyclosporine did not alter the ability of myeloid and plasmacytoid dendritic cells to take up antigens. Expression of the co-stimulatory molecule CD80 but not CD86 increased on both DC subsets when stimulated with cyclosporine. The ability of cyclosporine treated myeloid DCs to stimulate proliferation of allogenic PBMC was significantly reduced. Similarly, stimulation of memory CD8+ T cells by dendritic cells was impaired by cyclosporine pretreatment. In conclusion, cyclosporine differentially alters function and phenotype of myeloid dendritic cells leading to a partially impaired capacity to stimulate allogenic and autologous T cells.

KIDNEYS from pigs transgenic for human decay accelerating factor (h-DAF) have been shown not to be hyperacutely rejected when transplanted into nonhuman primates. In the initial reports on the use of h-DAF kidneys profound anemia was the reason for termination of the experiments in most of the monkeys. This was probably due to either species incompatibility of the porcine erythropoietin in the recipient cynomolgus monkeys, the induction of neutralizing anti-pig erythropoietin antibodies, or cyclophosphamide bone marrow toxicity. We have developed a life-supporting kidney xenotransplantation model with bilateral ligature of the recipients’ native ureters but preservation of the native kidneys, thus allowing ongoing recipient erythropoietin production.

Little is known about hearing impairment in patients after organ transplantation. Few cases of hearing loss associated with different immunosuppressants have been published. To evaluate severe hearing impairment in patients after liver transplantation (OLT), all living adult patients in need of a hearing aid were analyzed. Out of 521 transplanted patients, 25 (5%) were identified with hearing aids. Nine (36%) of these patients either suffered from hearing loss prior to OLT or experienced risk factors such as ototoxic drugs. Of the remaining 16 patients who developed severe hearing loss after OLT (64%), half were men. Mean age was 42 +/- 18 years at OLT, which took place 8 +/- 4 years ago. Main transplantation indication was virus-induced cirrhosis (44%). In 14/16 (88%) patients, the hearing aid was bilateral. In 50% of patients, the hearing aid was necessary within 2 years post-OLT. Additional tinnitus was present in 9/16 patients (56%), otalgia in three patients (19%). Four patients (25%) reported a history of sudden deafness. In three of them, an association with high levels of calcineurin inhibitors was found. The proportion of patients receiving tacrolimus (50%) was relatively higher than those receiving cyclosporine (50%) compared to control patients (28% respectively 64%, P < .05). In conclusion, a high incidence of severe hearing loss was found in patients after liver transplantation. In most patients, onset of hearing loss is early and bilateral, suggesting a dose-dependent toxicity. The pathogenetic role of different immunosuppressants remains to be evaluated.

It is well established that small bowel transplants can induce graft-vs-host (GVH) reactions which are potentially lethal for the graft recipients. Using a model of MHC congenic and recombinant rat strains, we have characterized the genetic control of GVH reactions after parental to F1 hybrid small bowel transplantation. Lethal graft-vs-host disease (GVHD) in the rat is primarily mediated by class II MHC incompatibility, while class I MHC and non-MHC antigens do not induce a symptomatic GVH reactivity. Following small bowel transplantation, not only may GVH reactions occur, but the transplant is also a potential victim of rejection. In our rat model, we have now analyzed the genetic control of host-vs-graft (HVG) reactions after F1 hybrid to parental small bowel transplantation and compared the results after heterotopic and orthotopic placement.