Chronic Rejection Process Research Articles

Dimethylarginine metabolism during acute and chronic rejection of rat renal allografts

Background. Dimethylarginines are inhibitors of NO synthesis and are involved in the pathogenesis of vascular diseases. In this study, we ask the question if asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels change during fatal and reversible acute rejection, and contribute to the pathogenesis of chronic vasculopathy.Methods. The Dark Agouti to Lewis rat strain combination was used to investigate fatal acute rejection. Fischer 344 kidneys were transplanted to Lewis rats to study reversible acute rejection episode and the process of chronic rejection. Isograft recipients and untreated Lewis rats were used as controls. l-arginine derivatives were determined by HPLC, and ADMA-metabolizing enzymes were studied by quantitative RT–PCR and western blotting.Results. Renal transplantation transiently increased dimethylarginine levels independent of acute rejection. ADMA plasma levels did not importantly differ between recipients undergoing fatal or reversible acute rejection, whereas SDMA was even lower in recipients of Fisher 344 grafts. In comparison to isograft recipients, ADMA and SDMA levels were slightly elevated during reversible, but not during the process of chronic rejection. Increased dimethylarginine levels, however, did not block NO synthesis. Interestingly, protein methylation, but not ADMA degradation, was increased in allografts.Conclusions. Our data do not support the concept that renal allografts are protected from fatal rejection by dimethylarginines. Dimethylarginines may play a role in triggering chronic rejection, but a contribution to vascular remodelling itself is improbable. In contrast, differential arginine methylation of yet unknown proteins by PRMT1 may be involved in the pathogenesis of acute and chronic rejection.

Vascular deposition of complement C4d is increased in liver allografts with chronic rejection

Background Complement protein C4d has been used as a marker of antibody mediated rejection in kidney allografts. C4d has been shown to be deposited also in chronic kidney allograft rejection, and frequently in acute liver allograft rejection. In chronic liver allograft rejection there is limited data of C4d positivity. Methods 7 liver allografts explanted at retransplantation due to chronic rejection were examined for expression of C4d. Immunoperoxidase technique on frozen sections was used. The “zero” biopsies of the same livers at the first transplantation served as controls. Results Expression of C4d was significantly increased in portal and central veins as well as in the portal stroma of the grafts with chronic rejection when compared to the expression at implantation of the graft. Conclusion The complement system and anti-donor antibodies may contribute to the process of chronic allograft rejection in the liver.

Regulatory Allospecific T Cell Clones Abrogate Chronic Allograft Rejection

True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar rat donors, Lewis rat recipients). We generated and subcloned T cell lines from lymphocytes derived from either acutely rejecting grafts or from the grafts of CTLA4-Ig-treated tolerant rats. Pretransplantation adoptive transfer of T cell clones generated from rejected grafts (Th1 clones) accelerated acute rejection or promoted development of chronic rejection, whereas transfer of T cell clones generated from tolerized grafts (Th2 clones) protected rats from acute rejection and progressive organ dysfunction. When Th1 and Th2 clones were injected simultaneously, Th2 clones specifically regulated activation of Th1 clones. Rats that received injections of Th2 clones accepted long-term donor-specific skin grafts but acutely rejected third-party skin grafts. Tolerant rats treated with Th2 clones demonstrated an increased number of regulatory CD4+CD25+Foxp3+ cells and strong mononuclear cell staining for IL-10 but negligible IFN-gamma, IL-17, and IL-23 compared with untreated rats or those treated with Th1 clones. In summary, these results demonstrate the regulatory functions of Th2 cells in a clinically relevant allogeneic transplant model and provide new insight into the functional role of Th2 cells in preventing the process of chronic rejection.

Features of chronic allograft rejection on rat small intestine transplantation

The aim of this study was to develop a model of chronic rejection of the entire small intestine transplantation and to analyze the features of chronic rejection. Allogenic small bowel transplantation was performed in a rat combination of Lewis to F344. Intestines were procured at the 60th and the 90th day after operation. We compared the semiquantitative score of histological parameters. The immunological components involved in the chronic rejection process were evaluated by immunohistochemical staining and the cytokine levels in grafts. The significant characteristics of the allograft on histology were changes of villous architecture, interstitial fibrosis, leukocyte infiltration, and obliterative arteriopathy. Allografts on the 60th day post-transplantation had more score in inflammatory events, while the grafts on the 90th day after operation had more values in ischemia/fibrotic events. The number of infiltrating CD4, CD8 and macrophage cells in allografts progressively decreased over time. The level of intragraft cytokines such as IL-6, TNF-alpha and IL-10 in the 90th day after transplantation also decreased compared with that in the 60th day. These data suggested that in the early stage (POD 60), there were more active and intense inflammatory events; later (POD 90) allografts manifested less inflammation and more arterial obliteration and fibrosis.

Donor-Specific Tolerance Is Induced after Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation and May Persist after Graft Rejection.

The association between stable hematopoietic chimerism and donor specific tolerance (DST) for solid organ grafts was demonstrated clinically and in different experimental models. However, the existing data also demonstrate that the establishment of hematopoietic chimerism does not always correlate with the development of DST, especially for skin grafts. As these issues could have major implications for organ transplantation in general, the present study was undertaken to assess DST in recipients with transient or stable hematopoietic cell (HC) chimerism established after nonmyeloablative conditioning regimens. In a canine model of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning, DST to skin grafts was evaluated in DLA-identical recipients with stable mixed hematopoietic chimerism (MC) (n=11), or following transient HC engraftment (n=22). There was a significant improvement in the survival of DLA-identical HC donor-derived skin grafts in recipients with stable MC compared to normal recipients (n=7; P<0.0001). However, HC donor-derived skin grafts in 4 recipients with MC developed an inflammatory reaction without skin graft loss consistent with a chronic rejection process. Survival of DLA-identical HC donor-derived skin grafts was also significantly prolonged in recipients after transient HC engraftment compared to normal recipients (P=0.002). However, a chronic inflammatory process without graft loss developed in all of the HC donor-derived skin grafts from this group. An increased time to rejection of the hematopoietic graft was significantly associated with an improved survival of the subsequent skin graft (P=0.02). The time to rejection of third-party (DLA-nonidentical) skin grafts (n=40) was the same in recipients with stable MC and previous HC graft as well as normals (median- 8 days). Autologous skin grafts (n=40) survived for the duration of follow-up without developing chronic inflammation. Extended HC donor-specific skin graft survival (>15 days) was predictive of subsequent stable engraftment at second HCT in recipients with previous graft rejection after first HCT. Five of 6 dogs with extended survival of the skin graft beyond day 15 became stable MC after second HCT compared to 0/9 dogs with skin grafts surviving less than 11 days (P=0.0008). In this model, DST to skin grafts in recipients with stable MC after nonmyeloablative HCT may not be complete, and chronic inflammation may develop without loss of that graft. Partial DST may persist after rejection of HC grafts established with nonmyeloablative conditioning. Further investigations are required to understand the mechanisms responsible for DST after allogeneic HCT.

Humoral immune response after kidney transplantation is enhanced by acute rejection and urological obstruction and is down-regulated by mycophenolate mofetil treatment

The anti-allograft immune response may have a cellular and a humoral component. Lymphocytotoxic antibodies (Ab) and anti-human leucocyte antigen (HLA) Ab present before kidney transplantation carry an enhanced risk of acute rejection. Current immunosuppressive drugs act predominantly upon the cellular immune pathway which may leave unopposed the humoral mechanisms of anti-allograft response. We studied the production of lymphocytotoxic Ab and anti-HLA Ab after kidney transplantation under different drug therapies. Two hundred and sixty-four consecutive kidney transplant recipients treated with different immunosuppressive drugs, either stable and or with previous acute rejection or acute urologic obstruction, entered this study. Lymphocytotoxic Ab and anti-HLA Ab were evaluated by complement-dependent cytotoxicity and by ELISA. Ab donor-specificity was determined by flow cytometry. Both lymphocytotoxic Ab and anti-HLA Ab were significantly increased in acute rejection whatever the immunosuppressive regimen and almost significantly in urologic obstruction treated with azathioprine (AZA) groups. The presence of antidonor-specific Ab was associated with a significantly higher rate of graft loss. Mycophenolate mofetil (MMF) therapy significantly down-regulated Ab synthesis in all patients groups when compared with AZA. The development of humoral antidonor response post-transplantation is associated with a dismal graft prognosis. This is the first report that acute urologic obstruction may be followed by unspecific lymphocytotoxic and anti-HLA Ab synthesis, surmising that a protracted obstruction may promote renal fibrosis through antibody mediation. The significant down-regulation of the humoral response by MMF when compared with AZA may herald a lower risk to mount a chronic rejection process.

Induction of Tissue Factor Expression on Human Umbilical Vein Endothelial Cells by Cell-Specific HLA Class I Antibody: Preliminary Data

Donor-specific antibodies may play an important role in the development of chronic allograft rejection process. However, the mechanisms leading to intimal vascular proliferation and fibrosis remain poorly understood. The aim of this study was to examine whether donor-specific HLA antibodies induce overexpression of tissue factor (TF) by endothelial cells. HLA typed human umbilical vein endothelial cells (HUVEC) were incubated for 1 to 12 hours with LPS (10 μg/mL), and increasing concentrations (1 to 500 μg/mL) of anti-HLA A1 antibody specific for an antigen expressed by HUVEC and of an anti-HLA A2 antibody for which A2 was not expressed by the HUVEC. Expression of TF mRNA transcripts was quantified using real time Q-RT PCR and TF activity was tested in cell lysates of cultured HUVEC using a chromogenic TF activity assay. HUVEC-specific anti-HLA A1 antibody at low concentrations (10 μg/mL) induced both a significant increase of TF mRNA transcripts after 1 hour of incubation and TF activity after 3 hours incubation compared to incubation with medium alone or with the nonspecific anti-HLA A2 antibody ( n = 4 for all experiments, P < .05). These data show for the first time that specific anti-HLA antibody can induce overexpression of TF on endothelial cells. TF, a transmembrane glycoprotein involved not only in the onset of the coagulation cascade, but also in cell proliferation and anti-apoptotic processes, may play a role in the development of alloantibody-induced chronic rejection.

Role of the ICOS-B7h Costimulatory Pathway in the Pathophysiology of Chronic Allograft Rejection

Inducible costimulator (ICOS) is the third member of the CD28 superfamily and has a unique role in T cell activation and function. Recent studies indicated that the ICOS-B7h pathway plays an important role in alloimmune responses. We further investigated the role of the ICOS pathway in the pathologic process of chronic rejection in vivo. An established major histocompatibility complex class II disparate cardiac transplantation model was used. We treated mice with a blocking anti-B7h monoclonal antibody (mAb) either in the initiation phase (early blockade) or in the progression phase (delayed blockade) of disease. In addition, some mice received mAb in the entire period (whole blockade). At 6 weeks after transplantation, cardiac grafts were evaluated by histopathologic analysis in terms of vasculopathy, fibrosis, and cellular infiltration. The intragraft expressions of cytokines and chemokines were also examined by quantitative real-time polymerase chain reaction analysis. Early blockade of the ICOS-B7h pathway did not show any protective effect on chronic allograft rejection compared with untreated controls. In contrast, delayed blockade significantly inhibited the development of vasculopathy, fibrosis, and cellular infiltration (P=0.043, P=0.004, and P=0.03 vs. untreated control, respectively). Interestingly, whole blockade did not prevent the chronic rejection process. Furthermore, the inhibitory effect of delayed ICOS blockade on chronic rejection was associated with down-regulation of local intragraft expression of several cytokines and chemokines. These data suggest that the ICOS-B7h pathway is critical in the activation of effector/memory T cells that are necessary for the progression of chronic rejection and provide the rationale to develop novel and specific therapies to prevent this process.

Anti-HLA Class I Antibodies Activate Endothelial Cells and Promote Chronic Rejection

Transplant recipients exhibiting a humoral immune response to the allograft demonstrate lower graft survival and increased risk for the development of chronic rejection and transplant arteriosclerosis. Our studies suggest that anti-HLA class I antibodies (Ab) play an important role in controlling endothelial cell (EC) function by binding to class I molecules on the surface of the EC and transducing intracellular signals. Anti-HLA Ab exhibit two primary effector functions: stimulation of cell proliferation and up-regulation of cell survival genes. Importantly, the intracellular events initiated by class I ligation appear to be influenced by the concentration of the Ab. High-titered anti-HLA Ab stimulate cell proliferation whereas low-titered Ab activate the PI3K/Akt pathway and promote expression of cell survival proteins including Bcl-2 and Bcl-xL. Anti-HLA class I Ab may contribute to the process of chronic allograft rejection by promoting EC survival and proliferation.

Transplantation pulmonaire

Almost twenty years after the first successful clinical lung transplantations, the procedure has been recognized as an effective treatment of several forms of end-stage pulmonary disease, in patients filling the selection criteria. According to the indication, three types of procedures may be performed : single, bilateral or heart-lung transplantation, the optimal indication of each procedure being still evolutive. The selection criteria have also evolved but precises guidelines are now available. The one-year survival is according to the centers between 65 and 85 % and the five-year survival is approximately 40-50 %. These results are explained by the numerous complications that may occur postoperatively and by the fact that at least half of the patients will develop early or late in the postoperative course a graft deterioration attributed to a chronic rejection process. The primary goal is now to prevent more effectively these various complications in order to improve the survival results.

Histological and immunological characteristics of, and the effect of immunosuppressive treatment on, xenograft vasculopathy.

Like allografts, vascularized xenografts are susceptible to a process of chronic rejection. We have used the hamster-to-rat aortic transplant model to study characteristics of this phenomenon and to determine whether it could be controlled or prevented by immunosuppressive therapy. Golden Syrian hamster aortas were transplanted into untreated Lewis rats, athymic rats, and Lewis rats receiving cyclosporin (10 mg/kg), leflunomide (5, 10 or 15 mg/kg), or 10 mg/kg of both drugs. Grafts were harvested on days 2, 7, 14, 28 and 56. Grafts and recipient spleens were analysed using computerized morphometry, immunohistochemistry and immunofluorescence. Blood was taken on various days for the measurement of anti-hamster antibodies (flow cytometry) and of the leflunomide metabolite A77 127. In untreated rats, by day 56, transplanted aortas developed a cell-free media with a mature neointimal lesion consisting of actin-positive cells, CD4 T cells, and macrophages. There were large increases in anti-hamster immunoglobulin M (IgM) and IgG, collections of proliferating cell nuclear antigen (PCNA)-positive cells in splenic germinal centres, and IgM, C3 and C5a deposition in aortas. In athymic recipients, the media architecture was preserved, and the changes in the neointima and in anti-hamster IgM and IgG were markedly abrogated, but not prevented. In Lewis rats receiving leflunomide, absence of circulating or deposited IgM did not prevent neointimal formation by day 14. Combination treatment was the most effective at preventing neointimal formation and humoral changes. Leflunomide monotherapy was the least effective. There were no changes in peak concentrations of the main metabolite of leflunomide over 8 weeks. The hamster-to-rat aortic transplant model is suitable for the study of xenograft vasculopathy, the histological and serological changes of which are predominantly T-cell dependent. Combination treatment with 10 mg/kg of cyclosporin and 10 mg/kg of leflunomide was most effective in preventing xenograft vasculopathy.

Chronic rejection: failure of immune regulation.

Current strategies for immunosuppression following organ transplantation focus on the prevention of acute rejection. As new generations of immunosuppressants have been developed, acute rejection rates have diminished markedly. The new challenge, then, is to prevent the devastating complications of chronic rejection, which have remained largely unchanged over the decades. The process of chronic rejection is a complex one, and it is likely that most, if not all, components of the immune system play some role in the long-term, smoldering failure of organs following transplantation. Through a better understanding of their individual contributions as well as interactions, new strategies may be developed to overcome this problem. We present here an overview of the major immune components thought to be involved in chronic rejection.

Development of an antibody specific to major histocompatibility antigens detectable by flow cytometry after lung transplant is associated with bronchiolitis obliterans syndrome.

Chronic allograft rejection manifested as bronchiolitis obliterans syndrome (BOS) is the leading cause of late death after lung transplantation. Although increasing evidence suggests an association between anti-human leukocyte antigens (HLA) antibodies and chronic rejection of kidney or heart allografts, the clinical significance of anti-HLA antibodies in lung recipients is less clear, especially in previously unsensitized recipients. The use of flow cytometry based panel reactive antibody (flow-PRA) provides a highly sensitive means to identify the development of de novo anti-HLA antibodies in lung recipients. Flow-PRA testing was used to analyze the pre- and posttransplant sera in stable BOS free lung recipients who survived at least 6 months. Patients without prior sensitization as defined by a negative pretransplant flow-PRA were analyzed posttransplant for the presence of anti-HLA antibodies by flow-PRA. A proportional hazards model was used to determine the impact of anti-HLA antibody on BOS risk. Sera from 90 recipients at Duke University with negative pretransplant flow-PRA were tested by flow-PRA at various time points after transplant. Sera from 11% (10/90) of recipients were found to contain anti-HLA antibodies detectable by flow-PRA. Nine patients (90%) developed anti-HLA antibodies specific for donor antigens, and one patient developed anti-HLA class II antibodies, not specific to donor antigens. Among the nine patients with donor antigen specific antibodies, flow-PRA specificity analysis demonstrated eight were specific for class II antigens and one for class I antigens. In a multivariate model that controls for other BOS risk factors, a positive posttransplant flow-PRA was significantly associated with BOS grades 1,2, or 3 (hazard ratios [HR] 3.19; 95% confidence interval [CI]: 1.41-7.12, P=0.005) and BOS grade 2 or 3 (HR 4.08; 95% CI: 1.66-10.04, P=0.002). Four patients with de novo anti-HLA antibodies died during follow-up; all four had BOS. Among BOS patients, the presence of anti-HLA antibodies was associated with a significantly worse survival (P =0.05, log-rank test). Although uncommon, previously unsensitized lung transplant recipients can develop anti-HLA antibodies to donor class II antigens. The development of de novo anti-HLA antibodies significantly increases the risk for BOS, independent of other posttransplant events. Furthermore, de novo anti-HLA antibodies identify BOS patients with significantly worse survival. Additional studies are needed to determine if class II-directed anti-HLA antibodies contribute mechanistically to the chronic rejection process in lung recipients.

Recent advances in the immunology of chronic rejection.

Chronic allograft rejection is a slowly progressive, insidious process in which the host immune system continues to mount an immunological attack on a transplanted organ, ultimately resulting in the failure of the graft. To varying degrees, all solid organ grafts are at risk for chronic rejection and undergo a stereotypic process of injury and inflammation, eventually leading to parenchymal fibrosis. The clinical consequences of chronic rejection are particularly apparent in thoracic transplantation, where both patient and graft survival decline steadily over time and the opportunities for re-transplantation or long-term extracorporeal support are limited. A variety of antigen-dependent and antigen-independent factors are known to modulate the propensity for an organ to undergo chronic rejection. Recent clinical and laboratory research has suggested that distinct immunologic mechanisms may underlie the process of chronic rejection. Ultimately, strategies to induce long-term tolerance to alloantigens will be necessary to prevent chronic rejection and to abrogate the deleterious sequelae of chronic immunosuppression.

Recommendations of the National Heart, Lung and Blood Institute Heart and Lung Tolerance Working Group.

Recommendations of the National Heart, Lung and Blood Institute Heart and Lung Tolerance Working Group.

The role of neutrophils in the pathogenesis of obliterative bronchiolitis after lung transplantation.

Obliterative bronchiolitis (OB) represents the most important long-term complication after lung transplantation. Elevated numbers of neutrophils within the airways are a hallmark of OB. It is unclear what causes the recruitment and activation of neutrophils in the airways of patients with OB: the process of chronic rejection itself or infection, which may (especially in latent virus infection) often be overlooked by the currently applied diagnostic procedures. It is well known that besides their physiologic functions in the clearance of invading micro-organisms, activated neutrophils have a remarkable potential to cause damage to lung tissue. This is attributable to their capability to generate reactive oxygen species and to release potentially toxic proteases. It has been shown that the increased numbers of neutrophils in bronchoalveolar lavage fluid of patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation are associated with elevated levels of interleukin-8, the predominant neutrophil chemotactic factor in the lung. As evidence for the impact of neutrophils on the pathogenesis of BOS, there is significant oxidative stress within the airways of patients with BOS. In addition, the milieu within the airways is characterized by an imbalance between neutrophil elastase (NE) and molecules that inhibit NE as a result of an increased burden of NE released by neutrophils. A defective antiprotease shield due to the loss of secretory leukoprotease inhibitor could be demonstrated in BOS. These mechanisms may provide possible targets to develop new therapeutic strategies that either prevent neutrophil sequestration and activation, or inhibit neutrophil products in order to prevent or attenuate airway damage.

Involvement of interleukin-2 and growth factors in chronic kidney allograft rejection in rats

THE MOST IMPORTANT obstacle to organ transplantation today is the ill-defined process of chronic rejection. Chronically rejecting allografts are infiltrated with mononuclear cells, including T lymphocytes. As IL-2- and IL-2R-positive lymphocytes are constantly detected in chronically rejecting kidneys, they may determine the pace of chronic rejection.1 The development of interstitial fibrosis in chronic rejection has been attributed to local TGF-b and PDGF production.2 As it has been well described that cyclosporin A (CyA) induces TGF-b1 in vitro,3 we hypothesized that a suppression of the IL-2 pathway by this drug may be harmful over the long-term. To test this hypothesis, we studied how a continuous inhibition of the IL-2 pathway by either CyA or Tac interfered with the pace of chronic kidney allograft rejection in rats. We put a particular emphasis on their effects upon PDGF and TGF-b.

Role of cytomegalovirus infection in transplant arteriosclerosis and chronic rejection

Chronic rejection is a serious limitation to long-term survival of all solid-organ allografts. The common pathologic feature of chronic rejection seen across all allografts is transplant arteriosclerosis (TA), an obliterative and fibrotic process involving the vasculature and other hollow structures. These changes are most apparent in cardiothoracic organ transplants, in which the majority of grafts are lost as a result of TA affecting the coronary artery disease after heart transplantation, and obliterative bronchiolitis (OB) after lung transplantation. Recently, considerable evidence has emerged supporting an important role for microorganisms in the disease process of vascular injury leading to chronic rejection. This evidence is based on epidemiologic and observational data from transplant recipients, as well as native organs, experimental models, and therapeutic trials. The organisms that have been implicated in the pathophysiology of arteriosclerosis, include Helicobacter pylori , chlamydia, and herpes viruses, most notably, cytomegalovirus (CMV). CMV infection has been reported as a risk factor for TA and OB, and patients who develop CMV disease after heart transplantation have been shown to have a higher incidence of TA and death from TA compared with those who remain free from the disease. Endomyocardial biopsies from patients during CMV viremia show endothelial and vascular smooth muscle cell proliferation, as well as endothelialitis, independent of acute rejection. These changes, which are consistent with vascular injury induced by CMV, have been shown to be markers of subsequent diffuse TA. Rodent models of heterotopic heart transplantation infected with rat CMV develop TA at an accelerated rate, and this process is partially inhibited by early, prophylactic treatment with the antiviral drug, ganciclovir. Similarly, patients treated prophylactically with ganciclovir during the initial 28 days after heart transplantation had a lower incidence of TA compared with placebo. However, this benefit was not seen in seronegative patients receiving hearts from seropositive donors, consistent with the high-risk nature of this group (D+/R−) for developing acute CMV disease. Recent studies have addressed the question of whether improved prophylaxis could be achieved with the addition of CMV hyperimmune globulin (CMVIG) in high-risk patients, including all donor or recipient seropositivity at lung transplantation. Using historical controls, these studies suggest that a combined regimen of ganciclovir plus CMVIG reduces the incidence of acute CMV disease, TA, OB, and death from OB. These observations emphasize the need for future, randomized, controlled trials to confirm a causal role for CMV (and other pathogens) in the disease process of TA and chronic rejection.

Low-potassium dextran preservation solution improves lung function after human lung transplantation

J Thorac Cardiovasc Surg 2001;120:594-6

LONG-TERM RESULTS AFTER CONVERSION FROM CYCLOSPORINE TO TACROLIMUS IN PEDIATRIC LIVER TRANSPLANTATION FOR ACUTE AND CHRONIC REJECTION

Tacrolimus is beneficial in liver transplantation for reversing steroid-resistant acute rejection, and for controlling the process of chronic rejection in allograft recipients receiving Cyclosporine- (CyA) based regimens. Very little is known about the long-term efficacy of tacrolimus in pediatric transplantation after conversion from CyA. Our study examines the long-term outcome after conversion to tacrolimus for acute or chronic rejection in pediatric liver transplant (LTx) recipients. Seventy-three children (age < 18 years) receiving their primary LTx under CyA between August 1989 and April 1996 were converted to tacrolimus for ongoing acute rejection (n=22, group I) or chronic rejection (n=51, group II). Mean age at the time of conversion was 10.2+/-5.5 years with a mean interval from LTx to conversion of 3.5+/-2.9 (range 0.5-10.1 years). There were 33 boys and 40 girls. All patients were followed until June 1999. Mean follow-up was 97.3+/-17.4 months (range 62.4-118.9 months). Overall 5-year actual patient survival was 78.1% and 8-year actuarial survival was 74.6%. Patients converted to tacrolimus therapy to resolve acute rejection (group I) experience significantly better patient and graft survival at 5 and 8 years than those converted to resolve chronic rejection (group II). Eight-year patient survival and graft survival was 95.5 and 90.9% for group I compared to 74.6 and 53.5% for group II, respectively (long rank P=0.035 and 0.01, respectively). Nearly 75% of children were weaned off steroids after conversion. There was a marked improvement in hypertension, gum hyperplasia, hirsutism, and cushingoid appearance. One child in group I (4.5%) and four children in group II (7.8%) developed posttransplant lymphoproliferative disorder after conversion. There was an improvement in growth in children who were less than the age of 12 years at the time of conversion and who were weaned off steroids; more significantly girls responded more favorably than boys. The benefit of transplantation is maintained long-term after conversion to tacrolimus for acute or chronic rejection. The response rate was significantly better in group I as compared with group 11. Marked improvement in growth, hypertension, and reversal of the brutalizing effects of CyA was noted after conversion to tacrolimus. The results suggest that early conversion of pediatric liver transplant patients is warranted for the treatment of acute and chronic rejection, and for improvements in quality of life.