Acute Cellular Rejection

Acute cellular rejection can be defined as an acute inflammation of the allograft primarily affecting interlobular bile ducts and vascular endothelia, including portal and hepatic veins and occasionally the hepatic artery and its branches.
It usually occurs between 5 to 30 days after transplantation. Clinical findings include fever as well as swelling, cyanosis and tenderness of the allograft. Bile often become pale and its flow decreases. Occasionally, ascites develops because of liver swelling with increased intrahepatic pressure.
Liver dysfunction manifests as concomitant nonselective increases in some or all of the standard liver injury tests: early increase of GT and alkaline phosphatase, followed by total bilirubin, AST, ALT. Leukocytosis and eosinophilia are also frequently present. Unfortunately, all clinical and laboratory findings lack sensitivity or specificity. The diagnosis is considered on clinical grounds and confirmed by examination of a core needle biopsy specimen of the allograft.
Histological findings of acute rejection are:
(1)	mixed but predominantly mononuclear portal inflammation, containing blastic, activated lymphocytes, neutrophils and frequently eosinophils;
(2)	bile duct inflammation and/or damage;
(3)	subendothelial inflammation of portal or terminal hepatic veins.
At least two of these three features are required for the diagnosis.
Grading systems for the evaluation of acute rejection have been proposed.
A verbal grading of acute rejection is based on the overall appearance of the biopsy. After the global assessment, three specific features: portal inflammation, bile duct inflammation/damage, and venular inflammation, can be more critically evaluated and semiquantitatively scored on a 0 to 3 (mild, moderate and severe) scale. The three scores are then added together to obtain a final Rejection Activity Index (RAI). 
Acute cellular rejection is a common complication after orthotopic liver transplantation, recognized as a risk factor for graft survival and patient morbidity. Reported incidence of acute cellular rejection ranges between 24% and 80% &. Therefore the necessity to maintain liver allograft recipients on continuos immunosuppressive therapy.
Immunosuppressive protocols are mainly based upon combination of cyclosporine  or tacrolimus with steroids and in some cases with a third drug like azathioprine or mycophenolate mofetil &. Induction therapy with antilymphocyte serum or OKT3 has been widely used with different result &. No consensus on the best immunosuppressive protocol currently exists. Moreover, all the proposed regimens are far from ideal because of the still high incidence of acute rejection and because the treatment of rejection episodes increases the risk of infection, of development of post-transplant lymphoproliferative disease and of other immunosuppression-related complications &.
Recently, interleukin IL-2 receptor monoclonal antibodies have been used to prevent acute rejection after kidney transplantation, significantly reducing the incidence of rejection episodes, without clinically relevant safety or tolerability problem &.
At the beginning of our program recipients immunosuppression consisted of oral cyclosporine and steroids. The target cyclosporine plasma level was 350-250 ng/ml during the first 2 weeks after transplantation, 200-300 ng/ml from week 3 to week 12, and 50-150 ng/ml thereafter. Steroid therapy was with 2 mg/kg/day i.v. methylprednisolone during the first week and with oral prednisone from the second postoperative week, starting at the dose of 1 mg/kg/day and than tapering the dose in order to stop steroid administration 3 months after transplantation.
Forty-one children were immunusuppressed according to this protocol. Six patients died in the early postoperative period. After a median follow up time of 28 months (range 10-36), 28 of the remaining 35 recipients (80%) experienced at least on episode of biopsy proven acute cellular rejection. Rejection developed after a median time from transplantation of 19 days (range 6-305) and was treated with steroid boluses, with maximal dose of 45 mg/kg administered in 3-6 days. If no improvement in biochemistry was observed and the liver biopsy taken after steroid treatment was still positive for rejection, patients were converted to tacrolimus with the diagnosis of steroid-resistant rejection. According to these criteria, 16 children (57%) experienced steroid-resistant rejection and were switched to tacrolimus. A total of 53 rejection episodes developed in this group, corresponding to 1.9 episodes per patient. Overall one-year actuarial patient and grafts survival rates were 80% and 74%, respectively. No patients or grafts were lost for acute rejection. One child, with an history of early acute rejection, steroid boluses and conversion to tacrolimus immunosuppression, developed chronic rejection and underwent successfull retransplantation.
Due to the high incidence of acute rejection and conversion to tacrolimus, we decided to add basiliximab, a chimeric interleukin IL-2 receptor monoclonal antibody, to the baseline dual-immunosuppressive therapy. A total of 20 mg basiliximab (40 mg in recipients weighting more than 40 kg) was given in two doses of 10 mg each by i.v. infusion, on day 0 and 4 after transplantation. A total of 11 pediatric patients were treated according to this protocol. Two children died in the early postoperative period. After a median follow up time of 16 months (range 10-23), the incidence of acute rejection in this group was 56%, corresponding to 5 patients who developed at least one episode of rejection.Rejection developed after a median time from transplantation of 26 days (range 8-105) and required conversion to tacrolimus in 3 children (60%).A total of 8 rejection episodes developed in this group, corresponding to 1.6 episodes per patient. Overall one-year actuarial patient and grafts survival rates were 82% and 69%, respectively. We did not observe acute or chronic rejection-related death or graft failure.
When tacrolimus was approved in our country as primary immunosuppressive drug, we introduced the drug in our immunosuppressive protocol, in combination with steroids, maintaining the whole blood trough level between 15 and 10 ng/ml during the first month after transplantation and between 5 and 10 ng/ml thereafter. Steroids administration was the same as with cyclosporine. Thirty-three children in our series received dual tacrolimus-based baseline immunosuppression. After a median follow up time of 6 months (range 1-28), 8 patients experienced biopsy-proven acute rejection (24%), after a median time from transplantation of 26 days (range 9-372). Total number of rejection episodes observed in this group was 8, corresponding to 1 episodes per patient. Overall one-year actuarial patient and grafts survival rates were 86% and 82%, respectively. In this group of patients no grafts were lost due to acute or chronic rejection.
Ten pediatric recipients in our series were not analyzed: 7 received a triple regimen immusosuppression with cyclosporine, steroids and azathiprine, and 3 were the first children treated with basiliximab at a dosage calculated from the recipients body surface area. Pharmacokinetic study on liver pediatric recipient demonstrated that these dosages were not enough in order to saturate IL-2 receptor (8).