Steroid-free Immunosuppressive Protocol Research Articles

Patient and Graft Survival Outcomes During 2 Eras of Immunosuppression Protocols in Kidney Transplantation: Indiana University Retrospective Cohort Experience

Since 1964 when Indiana University performed its first kidney transplant, immunosuppression protocol was steroid-based until 2004 when steroid-free immunosuppression protocol was adopted. We describe clinical outcomes on our patients administered early steroid withdrawal (ESW) protocol (5 days) compared with our historical cohort (HC), who were on chronic steroid-based immunosuppression. We performed a retrospective study evaluating kidney transplant recipients between 1993 and 2003 (HC, n=1689) and between 2005 and 2016 (ESW cohort, n=2097) at the Indiana University program, with a median follow-up of 10.5 years and 6.1 years, respectively. Primary outcomes were patient and death-censored graft survival at 1, 3, and 5 years in both study cohorts. Secondary outcomes were 1-year rates of biopsy-proven acute rejection; graft function at 1, 3, and 5 years; and risk of post-transplant infection (BK virus and cytomegalovirus) in the ESW cohort. Cox proportional model and Kaplan-Meier estimates were used to estimate survival probabilities. Fisher exact tests were used to compare episodes of acute rejection in the ESW cohort. No difference was observed in patient survival between the ESW and HC cohorts (P=.13). Compared with the ESW cohort, death-censored graft survival was significantly worse in the HC (5 year: 86.4% vs 90.6%, log-rank P < .001). One-year acute rejection reported in the ESW cohort alone was 15.7% and significantly worse in Black patients and younger patients (P < .05). In this sizeable single-center cohort study with significant ethnic diversity, ESW is a viable alternative to steroid-based immunosuppression protocol in kidney transplant recipients.

Short-term results of calcineurin-free and steroid-free immunosuppression protocol in live-donor renal allotransplantation: a prospective, randomized, controlled study

Short-term results of calcineurin-free and steroid-free immunosuppression protocol in live-donor renal allotransplantation: a prospective, randomized, controlled study

Cancer risk and mortality after kidney transplantation: a population-based study on differences between Danish centres using standard immunosuppression with and without glucocorticoids.

Kidney recipients receive immunosuppression to prevent graft rejection, and long-term outcomes such as post-transplant cancer and mortality may vary according to the different protocols of immunosuppression. A national register-based historical cohort study was conducted to examine whether post-transplant cancer and all-cause mortality differed between Danish renal transplantation centres using standard immunosuppressive protocols including steroids (Centres 2, 3, 4) or a steroid-free protocol (Centre 1). The Danish Nephrology Registry, the Danish Civil Registration System, the Danish National Cancer Registry and the Danish National Patient Register were used. A historical cohort of 1450 kidney recipients transplanted in 1995-2005 was followed up with respect to post-transplant cancer and death until 31 December 2011. Compared with Center 1 the adjusted post-transplant cancer risk was 6-39% lower in Centre 3 [hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.67-1.32], in Centre 2 (HR 0.72, 95% CI 0.52-0.98) and in Centre 4 (HR 0.61, 95% CI 0.44-0.83). Compared with Center 1, the adjusted post-transplant mortality was 21-55% higher in Centre 4 (HR 1.21, 95% CI 0.91-1.61), in Centre 3 (HR 1.35, 95% CI 0.98-1.86) and in Centre 2 (HR 1.55, 95% CI 1.17-2.05). On average, post-transplant cancer was associated with a 4-fold increase in the risk of death (HR 4.25, 95% CI 3.36-5.38). There was a tendency of a higher post-transplant cancer occurrence, but lower all-cause mortality, in the Danish transplantation centre that adhered to a standard steroid-free immunosuppressive protocol.

Steroid-free Liver Transplantation Using Rabbit Antithymocyte Globulin Induction in 500 Consecutive Patients.

We have previously documented the efficacy of a steroid-free immunosuppression protocol using rabbit antithymocyte globulin (RATG) induction in orthotopic liver transplantation (OLT) with tacrolimus minimization. The purpose of this report is to demonstrate the benefits of this protocol in a large cohort of patients. We evaluated outcomes of 500 consecutive OLT recipients who received RATG induction and a single dose of solumedrol given before the first dose of RATG. Mycophenolate mofetil was initiated postoperatively with delayed initiation of tacrolimus. Sirolimus replaced tacrolimus if serum creatinine remained above 2.0 mg/dL by day 7. Patients were weaned to tacrolimus or sirolimus monotherapy at 3 months. Mean model for end-stage liver disease (MELD) at transplantation was 22 ± 6. Forty-four percent of patients had hepatitis C. Posttransplant creatinine was highest at 1 month (1.43 ± 0.95 mg/dL) and improved to 1.26 ± 0.60 mg/dL (P < 0.05) at 2.5 years. Glomerular filtration rate was lowest at 1 month (65.6 ± 30.0) and improved by 1 year (72.7 ± 28.2, P < 0.01). Tacrolimus was initiated at 4.79 ± 13.3 days with a level of 4.95 ± 2.45 ng/mL at 1 year. One-year patient and graft survival were 92.8% and 89.6%, respectively, with a 3-year patient survival of 82.9%. Rejection occurred in 114 (22.8%) patients, 33 (6.6%) patients requiring steroids. Univariate and multivariate Cox proportional hazard analyses were performed to evaluate the effects of donor and recipient characteristics on patient and graft survivals. Pretransplant creatinine was consistently a statistically significant predictor for patient and graft survival. This is the largest reported series of OLT recipients using a steroid-free protocol with RATG induction demonstrating excellent outcomes, low complication rates, and preservation of renal function.

An in-progress, open-label, multi-centre study (SAILOR) evaluating whether a steroid-free immunosuppressive protocol, based on ATG induction and a low tacrolimus dose, reduces the incidence of new onset diabetes after transplantation.

BackgroundCorticosteroids and calcineurin inhibitors (CNIs) are included in renal transplantation immunosuppressive protocols around the world. Well-known side effects are associated with the use of these drugs, including new onset of diabetes after transplantation (NODAT). Long-term patient survival rates are lower among patients with NODAT. The optimal immunosuppressive protocol would therefore include not using corticosteroids and minimization of CNI use.Methods/DesignThis is a prospective, multi-centre, controlled, randomized, parallel group, open-label study involving kidney transplant patients. The study compares a steroid-free immunosuppressive protocol (study arm A), which is based on low-dose tacrolimus and mycophenolate mofetil (MMF) maintenance therapy together with antithymocyte globulin (ATG) induction, with the conventional immunosuppressive protocol (study arm B), being based on low-dose tacrolimus, MMF and steroids together with interleukin-2 receptor (IL2-R) induction. The study is designed to include most normal-risk patients. It will exclude patients seen as at a high risk of rejection. The primary objective of the study is to assess the cumulative incidence of NODAT in the two study arms 12 months after transplantation using the American Diabetes Association type 2 diabetes diagnostic criteria. The composite measure of freedom from acute rejection, graft survival and patient survival will be evaluated. Renal function and chronic changes in the transplanted kidney will be assessed.DiscussionIf this study confirms conceptual expectations, namely decreased incidence of NODAT, the steroid-free study protocol could be used with all patients. The regimen could be especially beneficial for patients at a high risk of diabetes mellitus.Trial registrationTrial registration: EudraCT 2012-000451-13.

Alemtuzumab Induction in Pediatric Kidney Transplantation

Introduction: Recipient parenchymal lymphatic cells are crucial for semidirect and indirect pathways of allorecognition and development of chronic rejection. We and others proposed that alemtuzumab, being infused several weeks pretransplant could eradicate peripheral lymphatic cells and promote donor-specific tolerance. Method: 107 children (54 boys, 53 girls; age 0,7 to 18 years) received living related kidney transplant in Russian Scientific Center of Surgery from September 2006 to January 2011. The major causes for recipients' ESRD were reflux nephropathy (29 %) and dysplasia (23%). Diseases that recur in the graft represented a small portion of our patients (5% primary FSGS). The average HLA mismatch was 2.5±1.0. Immunosupression (IS) protocol included two 30 mg doses of alemtuzumab: first given 12-29 days prior to transplantation and second on day of transplant. Maintenance IS was based on combination of low dose CNI and mycophenolate. Steroids were discontinued after achievement of target CNI level, usually by Day 5. IS was decreased in cases of BK viruria above 107 copies/ml, repeated BK or EBV viremia and recurrent CMV viremia. Patients were followed for 1192±470 days and protocol biopsies were taken 1 month, 1 and 3 year post transplant. Results: The Kaplan-Meier graft and patient survival was 95% and 97% for one year, 88% and 93% for three years, 84% and 90% for five years. Delayed graft function occurred in 7 patients. Biopsy proven acute rejection (BPAR) developed in 26% patients at one year and in 35% at two years, no rejections occurred behind 2 years. BANFF scores were borderline in 59%, 1a in 34%, 1b in 0.5%, 2a in 5% and 2b in 1% of all rejections. Among 93 patients with functioning grafts the decline of graft function by estimated GFR and degree of proteinuria between discharge and last control were not significant: 92±34 and 82±37 ml per min; 220±260 and 189±149 mg per day. Infections: All patients received prophylaxis with Valgancyclovir for 3 weeks after transplantation. CMV, EBV and BK viremia were monitored monthly during first post-transplant year, thereafter every 3 months. In case of detectable CMV-viremia preemptive therapy with Valgancyclovir was re-introduced. CMV and BKV viremia were noticed in 30% and 25% of all patients correspondingly during first 3 months and in less than 10 and 5% after first year. Prevalence of EBV viremia was reaching 20% at 2 years. We have not detected any cases of PTLD in our population; however 2 kids had lymphadenopathy associated with EBV-viremia that improved after discontinuation of CNI. At last follow up 53 patients was receiving combination of CNI+MMF, 15 MMF+PSI, 10 CNI+MMF+steroids, 6 mycophenolate alone, 3 CNI alone, 2 MMF+steroids, 2 CNI+steroids, 1 PSI+MMF+steroids and 1 CNI+Aza+steroids. Free of steroids remain 83% of patients. Conclusion: Alemtuzumab pretreatment prior to LRD kidney transplantation allows to reach satisfactory middle-term results and maintain steroid-free immunosuppressive protocol in the majority of pediatric patients.

Steroid‐free living donor liver transplantation for HCV – a multicenter prospective cohort study in Japan

This prospective, non-randomized, multicenter cohort study analyzed the safety and efficacy of a steroid-free immunosuppressive (IS) protocol for hepatitis C virus (HCV)-positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid-free IS protocol (Fr group) and 29 the traditional steroid-containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p=0.013). Preemptive anti-HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p=0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p=0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p=0.022, p<0.0001, p=0.012, respectively). The steroid-free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post-transplant period and HCV recurrence in HCV-positive LDLT recipients.

Impact of Islet Transplantation on Diabetes Complications and Quality of Life

Insulin represents a life-saving therapy for patients with type 1 diabetes but, despite appropriate treatment, it prevents only partially long-term diabetic complications, while generating fatal hypoglycemic episodes. Islet transplantation gained attention because of its safety, effectiveness, and minimal invasiveness; however it remains a procedure reserved for a selected group of patients. The introduction of the Edmonton Protocol in 2000, based on a newly designed steroid-free immunosuppressive protocol, revamped the course of islet transplantation. The main goal of islet transplantation remains insulin independence, although the effect of islet transplantation can be more comprehensively evaluated in terms of frequency of hypoglycemic episodes and impact on diabetic complications and quality of life. Islet transplantation was shown to have positive consequences on cardiovascular, renal, neurologic, and ocular diabetic complications. The proof of concept for cellular replacement therapy in diabetes has been established with islet transplantation, it only needs to be improved and rendered widely available.

Steroid-free maintenance of islet allografts using mycophenolate mofetil and cyclosporine in the non-human primate

Islet transplantation continues to be a promising treatment for type 1 diabetes, however, numerous limitations still prevent its widespread use. Many immunosuppressive medications used for islet transplantation are known to be diabetogenic. The goal of this study is to evaluate the short-term follow-up (90 day) of a steroid-free maintenance immunosuppression protocol of mycophenolate mofetil (MMF) and cyclosporine (CSA) in non-human primate islet allotransplantation. Diabetes was induced in the primate Macaca fascicularis via total pancreatectomy. Freshly isolated islets were autotransplanted (n=5) or allotransplanted (n=5) into the portal vein. Immunosuppression consisted of induction with rabbit anti-thymocyte globulin (ATG) and prednisone. CSA (25 mg/daily) and MMF (250 mg daily) were used for maintenance and given orally once daily throughout the 90 day study period. Fasting blood glucose measurements were used to monitor graft function. Intravenous glucose tolerance tests (IVGTT) were performed prior to pancreatectomy and at the study endpoint. Average fasting blood glucose levels were elevated in diabetic controls (313.6 mg/dl ±51.8) and untreated allograft recipients (257 mg/dl ±61.0) post-transplant. Auto-transplanted animals and allograft recipients treated with immunosuppression, on the other hand, maintained normoglycemia (74.5 mg/dl ±20.9, 62.3 mg/dl ±4.40) throughout the follow-up period. Additionally, beta cell function and first phase insulin secretion did not differ significantly between auto-graft and immunosuppressed allo-graft recipients post-transplant. We conclude that this steroid-free maintenance immunosuppression regimen is effective in maintaining islet allograft survival in the non-human primate and offers comparable graft function to that of autografts for up to 3 months post-transplant.

Islet cell transplantation

The transplantation of human islets has come a long way since the first diabetic person became insulin independent in 1989. The advent of a steroid-free immunosuppressive protocol in 2000 resulted in most recipients becoming insulin independent and remaining so for a year. However, beta-cell function declines thereafter. Strategies to enhance the islet mass transplanted and preserve beta-cell function are necessary. This review covers recent advances in determining the selection of appropriate enzymes for islet isolation, use of pancreases from heart-dead donors and techniques for predicting the functional capacity of isolated islets prior to transplantation. Changing the transplantation site away from the liver, where many islets are destroyed by an inflammatory process, is reviewed, and the possibility of seeding islets onto three-dimensional biodegradable scaffolds discussed. A method of preventing apoptosis of the beta cells prior to transplantation is detailed, as is the beneficial effect of using exenatide, after transplantation. Novel techniques to image islets are discussed, and this requires the labelling of the islets prior to implantation. Enhancing the vascularization of islets is shown to enhance functional outcomes. Encapsulation of the islets should obviate the need for using antirejection drugs, and it may be possible to expand beta cells in vitro. The above strategies are likely to enhance the outcomes of clinical islet transplants.

Steroid-Free Maintenance Immunosuppression With Rapamune and Low-Dose Neoral in Pancreas Transplant Recipients

Steroid-free immunosuppression is an attractive option because it avoids the many side effects of chronic corticosteroid use. It is especially attractive in pancreas recipients because it avoids the diabetogenic effects of steroids. We evaluated the outcome of a steroid-free maintenance immunosuppressive protocol in pancreas transplant recipients. Between August 2003 and May 2006, a total of 97 pancreas transplant recipients received steroid-free maintenance immunosuppression, consisting of induction with thymoglobulin and prednisone for the first 5 days. Patients were maintained on sirolimus adjusted to a target rapamycin trough level and reduced-dose cyclosporine adjusted to target C2 levels. All pancreas transplants (n=124) performed in the previous 3 years and maintained on a steroid-based immunosuppressive protocol with cyclosporine and mycophenolate mofetil were used for comparison. One-year patient and death censored pancreas graft survival were 93.8% and 94.8% for the steroid free group versus 95.2% and 87.9% for the comparator group, respectively. The incidence of acute rejection was 9.3% in the steroid-free group versus 28.3% in the comparator group (P<0.01). No pancreas loss in the steroid-free group was caused by acute rejection, whereas seven (5.6%) patients in the comparator group lost their pancreases because of acute rejection (P<0.05). At 1 year after transplant, the mean serum glucose and creatinine levels were not different between the two groups. We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of sirolimus and cyclosporine.

Excellent clinical outcomes in primary kidney transplant recipients treated with steroid‐free maintenance immunosuppression

Steroid-free maintenance immunosuppression is desirable to eliminate the side effects of chronic corticosteroid use. Complete steroid avoidance or rapid post-transplant steroid withdrawal has recently been used in renal transplant recipients with encouraging results. The present study evaluated the outcome of a steroid-free maintenance immunosuppressive protocol in kidney transplant recipients with at least one-yr follow up. Between April 2002 and October 2004, a total of 301 primary kidney transplant recipients received steroid-free maintenance immunosuppression. The regimen consisted of induction with thymogobulin and prednisone for the first five d. Patients were maintained on Sirolimus and Neoral. Neoral dose was adjusted to target C2 levels and the Sirolimus dose was adjusted to a target rapamycin trough level. All primary kidney transplants (n = 502) performed in the two yr (starting January 2000) prior to institution of the steroid-free regimen and thus maintained on a steroid-based immunosuppressive protocol were used for comparison. One-year patient and death censored graft survival were 93.1% and 98.1% for the steroid-free group vs. 95.2% and 95.2% for the comparator groups (p = ns). The incidence of biopsy-proven acute rejection was 4.9% in the steroid-free group vs. 9.4% in the comparator group (p < 0.01). Two (0.7%) of 301 patients in the steroid-free group lost their grafts because of acute rejection compared with nine (1.8%) patients in the comparator group (p < 0.05). At one-yr post-transplant the mean serum creatinine level was not different between the two groups. There were no significant differences in mean serum cholesterol and triglycerides levels as well as the percentage of patients on lipid lowering agents between the groups. White blood cell counts, daily doses of Neoral and weight gain were significantly lower in the steroid-free group vs. the comparator group. However, more patients in the steroid-free group required erythropoietin and iron therapy for anemia (p < 0.001). We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of Neoral and Sirolimus.

Corticosteroid-Free Immunosuppression in Pediatric Liver Transplantation: Safety and Efficacy After a Short-Term Follow-up

Background We report our results with the use of corticosteroid-free immunosuppression after pediatric liver transplantation, evaluating the efficiency and safety of this protocol in the early posttransplantation period. Patients and Methods From July 2003 to October 2005, 34 liver transplantations were performed in 32 pediatric patients (19 boys, 13 girls) at our institution. Recipient median age was 5 years (range, 0.2–14 years), and median body weight was 10 kg (range, 4–49 kg). Twenty-seven patients received a graft from in situ split liver transplantation, 5 a whole graft. Twenty-nine children (90%) received an immunosuppressive therapy based on methylprednisolone IV bolus at reperfusion (10 mg/kg) plus tacrolimus given at an initial dose of 0.08 mg/kg/d and then adjusted to obtain whole blood trough levels of 10 to 15 ng/mL during the first 3 months and 5 to 10 ng/mL after the 3rd month; basiliximab was given on postoperative days 0 and 4. Biopsy-proven acute rejection episodes were treated by methylprednisone IV boluses. Results After a median follow-up of 9 months (range, 1–27 months), the overall patient survival rate was 84% and graft survival rate was 79%. Three children (9%) died after their transplantations. Three (9%) experienced episodes of biopsy-proven acute rejection, always treated with IV steroid boluses. Mean RAI score was 4. One patient experienced PTLD that resolved with temporary reduction of immunosuppression. Cytomegalovirus infection rate was 14%. Sepsis occurred in 2 cases (6%). Conclusions Initial results with a steroid-free immunosuppressive protocol are encouraging, with low rates of acute rejection and infectious complications as in steroid-based protocols.

Sequential Kidney/Islet Transplantation: Efficacy and Safety Assessment of a Steroid-Free Immunosuppression Protocol

The aim of this study was to assess the efficiency and safety of the Edmonton immunosuppression protocol in recipients of islet-after-kidney (IAK) grafts. Fifteen islet infusions were administered to 8 patients with type 1 diabetes and a functioning kidney graft. Immunosuppression was switched on the day of transplantation to a regimen associating sirolimus-tacrolimus-daclizumab. Insulin-independence was achieved in all patients for at least 3 months, with an actual rate of 71% at 1 year after transplantation (5 of 7 patients). After 24-month mean follow-up, five have ongoing insulin independence, 11-34 months after transplantation, with normal HbA1c, fructosamine and mean amplitude of glycemic excursions (MAGE) values. Results of arginine-stimulation tests improved over time, mostly after the second islet infusion. Severe adverse events included bleeding after percutaneous portal access (n=2), severe pneumonia attributed to sirolimus toxicity (n=1), kidney graft loss after immunosuppression discontinuation (n=1), reversible humoral kidney rejection (n=1) and fever of unknown origin (n=1). These data indicate that the Edmonton approach can be successfully applied to the IAK setting. This procedure is associated with significant side effects and only patients with stable function of the kidney graft should be considered. The net harm versus benefit has not yet been established and will require further studies with larger numbers of enrolled subjects.

Steroid-free immunosuppression after renal transplantation—long-term experience from a single centre

A steroid-free immunosuppressive protocol may improve the general well-being of patients, but long-term renal graft survival has been a concern. In a retrospective clinical study, 329 consecutive transplantations with renal grafts at our centre during the period 1995-2004, were followed for up to 9.3 years. Patients mainly received steroid-free immunosuppression with an initial induction with antithymocyte globulin or basiliximab and maintenance therapy with ciclosporin and mycophenolate mofetil (MMF). Steroids were given after rejection, or if the physician judged it necessary, for instance because of primary kidney disease or when calcineurin inhibitor toxicity was suspected. About 71% of the patients did not take steroids at all. Nevertheless, graft survival rates at 1, 5 and 7 years were 95, 77 and 72% for all grafts, including 27% living donor transplants and 27% second or subsequent grafts. Ten patients (3.2%) died with functioning grafts. Within the first year of transplantation there were 69 acute rejections in 63 patients (19%). Four cases (1.3%) of post-transplant lymphoproliferative disorder (PTLD) occurred with one graft loss and no deaths. Owing to a high PTLD rate in a previous patient cohort, total immunosuppression was lessened after 1998. Steroid avoidance is possible with good results with respect to acute rejection and long-term graft survival. After introducing MMF, largely avoiding muromonab-CD3 mouse raised monoclonal antibody against CD (OKT3), and reducing doses of calcineurin inhibitor, the rates of PTLD did not differ from what is usually found. For the present, induction and use of MMF, together with a calcineurin inhibitor, is probably to be preferred.

Graft Loss from Recurrent Glomerulonephritis Is Not Increased with a Rapid Steroid Discontinuation Protocol

The risk of recurrence of glomerulonephritis in kidney transplant recipients on a steroid-free maintenance immunosuppression protocol is unknown. We studied the 4-year graft and patient survival in 105 adult kidney transplant recipients who received their transplant for glomerulonephritis (GN) and were treated with a protocol incorporating rapid discontinuation of prednisone for 5 days (group 1). We compared these outcomes to two control groups; 439 concurrent recipients who received a transplant for causes other than GN (group 2) and to 260 kidney transplant recipients who received an allograft for GN between 1994 and 1999 and were maintained on a steroid-based immunosuppressive protocol (group 3). The 4-year graft and patient survival were similar in the three groups. Acute rejection-free survival was also similar. Serial annual serum creatinine and estimated GFR were also comparable amongst the three groups. Two grafts were lost in group 1 from biopsy-proven recurrent GN and eight other subjects had evidence of histological recurrence at 11.2+/-11.9 months. Seven grafts were lost for recurrent disease in group 3 and 15 others had evidence of histological recurrence at 29.1+/-32.6 months. The mean time to graft loss from recurrence was 52+/-22 months. A regimen that utilizes rapid discontinuation of steroids conveys no added risk of graft loss from recurrent GN in the short term but longer follow-up is needed. A consideration should be made to discontinue corticosteroids in the potential recipients who are on them at the time of transplantation.

Immunosuppression and Procedure-Related Complications in 26 Patients with Type 1 Diabetes Mellitus Receiving Allogeneic Islet Cell Transplantation

The success of sirolimus and low-dose tacrolimus in islet cell transplantation has influenced many transplant centers to utilize this novel regimen. The long-term safety and tolerability of this steroid-free immunosuppressive protocol for allogeneic islet transplantation has yet to be determined. We transplanted 26 adult patients with long standing type 1 diabetes mellitus between April 2000 and June 2004. Immunosuppression consisted of induction with daclizumab and maintenance therapy with tacrolimus and sirolimus. Adverse events (AEs) in patients were followed and graded using the Common Terminology Criteria for Adverse Events, version 3.0 (National Cancer Institute). To date, the majority of patients were able to remain on the immunosuppression combination for up to 22+/-11 months. Four patients were successfully converted to Mycophenolate Mofetil due to tacrolimus-related toxicity. Withdrawal from immunosuppression was decided in four patients due to hypereosinophilic syndrome, parvovirus infection, aspiration pneumonia, and severe depression, respectively. Six patients required filgrastim therapy for neutropenia. Transient elevation of liver enzymes was observed in most patients early after islet infusion. Increased LDL in 20 patients required medical treatment. There was a varying range of AEs, most of them mild and self-limiting; however, some required urgent medical attention. The majority of patients were able to tolerate and remain on this effective regimen. To date, no deaths, cytomegalovirus disease, graft-versus-host disease, or posttransplant lymphoproliferative disease has been observed.

The Start of an Islet Transplantation Program in Japan

In Japan, pancreas donation had become possible from cadaveric donor sources, both heart-beating or non–heart-beating (NHB). Pancreas allografts have been distributed in the organ allocation system of the Japan Organ Transplant Network. Meanwhile, islet transplantation has been categorized as a tissue transplantation; it is free from legal restraints. Thus, pancreata for islet isolation must be obtained from NHB donors. Herein we report the starting program and preliminary results of islet transplantation in Japan. Selection and listing criteria for transplantation include regional priority, ABO blood type, previous islet transplant status with insulin independence, and a longer waiting time. Five institutes in Japan (Fukushima, Chiba, Kyoto, Kobe, and Fukuoka) are prepared to start programs. A two-layer cold storage method using perfluorocarbons and UW solution is recommended for pancreas preservation. Islet isolation and purification procedures are performed according to institute-specific protocol. Immunosuppression is based on sirolimus/tacrolimus combined with basiliximab induction. Two or three consecutive infusions of >5000 IE/kg are planned for each recipient until achieving insulin independence. Twenty-seven isolations and 14 transplants were performed in eight non–insulin-dependent diabetes mellitus (IDDM) recipients. Almost all (26 of 27) were NHB donors. All recipients are free from hypoglycemic episode after transplantation. One of these recipients is insulin independent; the others are currently on minimal doses of exogenous insulin. The feasibility of islet transplantation using NHB donors was confirmed using a two-layer cold storage method and a steroid-free immunosuppressive protocol, with a high rate of graft function.

A NOVEL IMMUNOSUPPRESSIVE FUNCTION OF ANTI-IL-2 RECEPTOR ANTIBODIES: IMPAIRMENT OF ANTIGEN UPTAKE AND T CELL STIMULATION OF HUMAN MYELOID DENDRITIC CELLS BY BASILIXIMAB IN VITRO AND IN VIVO

P1122 Aims: Anti-IL-2 receptor antibodies are part of many first line immunosuppressive treatment regimens after solid organ transplantation. While the importance of IL-2 for T cells has been demonstrated extensively, no data is available whether anti-IL2 receptor antibodies modulate also the function of dendritic cells. We here investigated the effects of basiliximab on phenotype and function of human dendritic cell (DC) subsets in vitro and in vivo. Methods: Myeloid and plasmacytoid DCs were isolated from the peripheral blood using magnetic bead-conjugated antibodies and incubated with different concentrations (0.1μg/ml to 10μg/ml) of basiliximab for 12 hours. Freshly isolated DCs were stained with fluorochrome-conjugated antibodies and analyzed on a fluorescence-activated cell sorter. We evaluated T cell stimulatory activity by a standard mixed lymphocyte reaction. A standard 51-chromium-release cytotoxicity assay was performed utilizing JY-EBV B cells s as target cells. Results: In vitro, basiliximab had no effect on surface expression of costimulatory molecules or maturation markers such as CD40, CD80, CD83 and CD86. However, basiliximab dramatically decreased in a dose dependent manner the ability of myeloid DCs to take up antigens as shown by BSA-FITC uptake assays. In contrast, the endocytotic function of another DC subtype, the plasmacytoid DC, was not affected by basiliximab. The ability of myeloid DCs to stimulate proliferation of allogenic PBMC was completely abolished by preincubation with basiliximab. Similarly, MHC-class I tetramer and cytotoxicity assays showed that recall-antigen-specific memory T cells could not be expanded in vitro by peptide-pulsed basiliximab treated DCs. Importantly, the impairment of myeloid DC endocytotic activity was confirmed also directly ex vivo in patients undergoing liver transplantation receiving basiliximab as part of a steroid-free immunosuppressive treatment protocol. Conclusions: We here describe for the first time that anti-IL-2 receptor antibodies impair not only T cell function but also antigen-uptake of myeloid dendritic cells and the ability of mDCs to stimulate allogenic PBMC and virus-specific memory T cells. These data give new insights in the immunosuppressive effects of basiliximab and might help to identify new drugs specifically targeting dendritic cells.

Steroid-free immunosuppression during and after liver transplantation--a 3-yr follow-up report.

Steroids are traditionally used in liver transplantation as a part of a triple or quadruple immunosuppressive regimen. Steroids act non-specifically and cause multiple side-effects. Most liver transplantation centers reduce the dosage of steroids and eventually withdraw them after various time intervals. A few steroid-free trials have been recently conducted after liver transplantation but long-term data are not yet available. In addition, in these trials steroids were usually given during surgery. We report the long-term (median = 40 months) follow-up data of a prospective pilot study designed to determine whether liver transplantation could be performed with no steroids at all (neither during nor after surgery). Twenty-one consecutive liver transplantations in 20 adult patients between August 1998 and July 1999 were prospectively included in an ab initio steroid-free immunosuppressive protocol. Mean age was 54 yr (40-67 yr). Tacrolimus (through levels, 8-10 ng/mL) and azathioprine (1-2 mg/kg) were started after liver transplantation. Patients were not given steroids during or after liver transplantation except in the event of rejection or in case of tacrolimus or azathioprine toxicity requiring significant dose reduction and/or withdrawal. There has been no case of primary graft dysfunction or non-function. Eleven of 21 liver transplantations (52%) received no steroids throughout the whole study. Rejection developed in five of 21 liver transplantations (23.5%). These rejections responded to standard i.v. steroids (plus ATG in one patient), followed by an oral steroid taper stopped 3 months after rejection. Steroids were transiently given in six liver transplantations for non-immune reasons: two with tacrolimus-induced neurotoxicity, three cases where azathioprine was discontinued, and one for an allergic reaction; four of these six patients are off steroids at last follow-up. The 3-yr graft and patient survival is 95 and 100%, respectively. Steroids are not necessary in more than 50% of liver transplantations. Steroids were transiently needed to treat acute rejection in 23.5% liver transplantations and for toxicity of calcineurin inhibitors or azathioprine or other reason in 28%. Of the patients who received steroids, the majority (70%) was eventually taken off steroids. This prospective single-center pilot study shows that liver transplantation without steroids is feasible and yields no penalty in terms of acute and chronic rejection, immune graft loss, graft function, patient and graft survival.