sirolimus and Lymphoproliferative-Disorders

Autoimmune Lymphoproliferative Syndrome (ALPS) is an autoimmune disease that has been reported in over 2200 patients. It is a rare, genetic disease where pathogenic variants occur in the extrinsic pathway of apoptosis. Various mutations in different genes, such as FAS, FASL, and CASP10, can result in ALPS. Most commonly, pathogenic variants occur in the FAS receptor. This malfunctioning pathway allows for the abnormal accumulation of lymphocytes, namely CD3 + TCRαβ+CD4 - CD8- (double negative (DN) T) cells, which are a hallmark of the disease. This disease usually presents in childhood with lymphadenopathy and splenomegaly as a result of lymphoproliferation. Over time, these patients may develop cytopenias or lymphomas because of irregularities in the immune system. Current treatments include glucocorticoids, mycophenolate mofetil, sirolimus, immunoglobulin G, and rituximab. These medications serve to manage the symptoms and there are no standardized recommendations for the management of ALPS. The only curative therapy is a bone marrow transplant, but this is rarely done because of the complications. This review serves to broaden the understanding of ALPS by discussing the mechanism of immune dysregulation, how the symptoms manifest, and the mechanisms of treatment. Additionally, we discuss the epidemiology, comorbidities, and medications relating to ALPS patients across the United States using data from Cosmos.

Topics: Autoimmune Diseases; Autoimmune Lymphoproliferative Syndrome; fas Receptor; Humans; Lymphoproliferative Disorders; Mutation; Sirolimus; Splenomegaly

Topics: Allografts; Class I Phosphatidylinositol 3-Kinases; Class Ia Phosphatidylinositol 3-Kinase; Enzyme Inhibitors; Humans; Immunologic Deficiency Syndromes; Lymphoproliferative Disorders; Mutation; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Respiratory Tract Infections; Sirolimus; Stem Cell Transplantation

The mammalian target of the rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly being used in pediatric kidney transplantation in different combinations and doses. Several studies have shown beneficial effects of using mTOR inhibitors in children after pediatric renal transplantation. A switch to a low-dose calcineurin inhibitor (CNI) and mTOR inhibitor has been proven to stabilize the glomerular filtration rate. Additionally, de novo studies using a low-dose CNI and an mTOR inhibitor have shown good graft survival and a low number of rejections. Side effects of mTOR inhibitors, such as hyperlipidemia, wound healing problems, and proteinuria, mainly occur if high doses are given and if treatment is not combined with a CNI. Lower doses of mTOR inhibitors do not result in growth impairment or reduced testosterone levels. Treatment with mTOR inhibitors is also associated with a lower number of viral infections, especially cytomegalovirus. Due to their antiproliferative effect, mTOR inhibitors could theoretically reduce the risk of post-transplant lymphoproliferative disease. mTOR inhibitors, especially in combination with low-dose CNIs, can safely be used in children after kidney transplantation as de novo therapy or for conversion from CNI- and mycophenolate mofetil-based regimens.

Topics: Animals; Calcineurin Inhibitors; Child; Cytomegalovirus Infections; Drug Approval; Everolimus; Gonadal Steroid Hormones; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Sirolimus; TOR Serine-Threonine Kinases; Wound Healing

Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage.. 1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased).. We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion.. Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI).  Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity.. We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73).Th. There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.

Topics: Abatacept; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Prednisone; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

Controlled trials of mTOR inhibitors in children following solid organ transplantation are scarce, although evidence from prospective single-arm studies is growing. Everolimus with reduced CNI therapy has been shown to be efficacious and safe in de novo pediatric kidney transplant patients in prospective trials. Prospective and retrospective data in children converted from CNI therapy to mTOR inhibition following kidney, liver, or heart transplantation suggest preservation of immunosuppressive efficacy. Good renal function has been maintained when mTOR inhibitors are used de novo in children following kidney transplantation or after conversion to mTOR inhibition with CNI minimization. mTOR inhibition with reduced CNI exposure is associated with a low risk for developing infection in children. Growth and development do not appear to be impaired during low-dose mTOR inhibition, but more studies are required. No firm conclusions can be drawn as to whether mTOR inhibitors should be discontinued in children requiring surgical intervention or whether mTOR inhibition delays progression of hepatic fibrosis after pediatric liver transplantation. In conclusion, current evidence suggests that use of mTOR inhibitors in children undergoing solid organ transplantation is efficacious and safe, but a number of issues remain unresolved and further studies are required.

Topics: Calcineurin Inhibitors; Child; Everolimus; Fibrosis; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver; Liver Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Risk; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Wound Healing

Epstein-Barr virus (EBV)-associated postallogeneic stem cell transplantation (SCT) lymphoproliferative disorder (PTLD) is often life threatening. The risk of EBV reactivation is highest in older patients, T cell-depleted SCT (in vivo or vitro), and in unrelated or mismatched SCT. Cumulative numbers of patients with EBV reactivation and PTLD are rising as more patients at high risk for EBV reactivation and PTLD are receiving allo-SCT. Novel but easily applicable strategies are needed to prevent EBV reactivation and PTLD to serve the needs of the increasingly enlarging population of high-risk SCT recipients across the globe.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; DNA, Viral; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppression Therapy; Lymphoproliferative Disorders; Risk; Rituximab; Sirolimus; Stem Cell Transplantation; T-Lymphocytes, Cytotoxic; Transplantation, Homologous; Viral Load; Virus Activation

SRL, an mTOR inhibitor that inhibits cell cycle progression, represents an important alternative to CNIs, which are still the cornerstones of pediatric solid organ tx. Because there are still limited data on SRL use among pediatric solid organ recipients, further studies are needed to verify the efficacy and safety of SRL. It has unique pharmacokinetic characteristics concerning dosing intervals and reduction of the dose in combination with other immunosuppressants. SRL also has antineoplastic, antiviral, and antiatherogenic advantages over other immunosuppressive agents. The adverse effects of SRL including thrombocytopenia, hyperlipidemia, proteinuria, impaired wound healing, mouth ulcers, edema, male hypogonadism, TMA, and interstitial pneumonitis must be considered carefully in pediatric population. This article reviews the most recent data on SRL application in the field of pediatric renal tx.

Topics: Child; Drug Therapy, Combination; Female; Graft Rejection; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Pediatrics; Pneumonia; Proteinuria; Sirolimus; Thrombocytopenia; Time Factors; TOR Serine-Threonine Kinases; Wound Healing

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell growth, protein synthesis, and cell-cycle progression through interactions with a number of signalling pathways, including PI3K/AKT, ras, TCL1, and BCR/ABL. Many haematological malignancies have aberrant activation of the mTOR and related signalling pathways. Accordingly, mTOR inhibitors, a class of signal transduction inhibitors that were originally developed as immunosuppressive agents, are being investigated in preclinical models and clinical trials for a number of haematological malignancies. Sirolimus and second-generation mTOR inhibitors, such as temsirolimus and everolimus, are safe and relatively well-tolerated, making them potentially attractive as single agents or in combination with conventional cytotoxics and other targeted therapies. Promising early clinical data suggests activity of mTOR inhibitors in a number of haematological diseases, including acute lymphoblastic leukaemia, chronic myeloid leukaemia, mantle cell lymphoma, anaplastic large cell lymphoma, and lymphoproliferative disorders. This review describes the rationale for using mTOR inhibitors in a variety of haematological diseases with a focus on their use in leukaemia.

Topics: Antineoplastic Agents; Autoimmune Diseases; Hematologic Neoplasms; Humans; Leukemia; Lymphoproliferative Disorders; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

To summarize recent advances that contribute to our understanding of the pathobiology of Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD), the host immune response to virally infected B cells, and the molecular basis for the effects of mammalian target of rapamycin inhibitors on EBV+ B-cell lymphomas.. Cytogenetic and genomic analyses support the concept that the underlying biology of EBV-associated PTLD is complex. Transplant recipients can generate and maintain significant populations of EBV-specific CD8+ memory T cells but the function of these cells may be impaired. EBV invokes multiple strategies to subvert and evade the host immune response. The phosphoinositide-3 kinase/Akt/mammalian target of rapamycin signal transduction pathway is a nexus for growth and survival signals in PTLD-associated EBV+ B-cell lymphomas.. Multiple factors influence the development of EBV-associated PTLD including the host immune response to EBV, virally induced effects on the infected cell and the host immune system, and the type and intensity of immunosuppression.

Topics: Animals; CD8-Positive T-Lymphocytes; Epstein-Barr Virus Infections; Graft Survival; Herpesvirus 4, Human; Humans; Immunologic Memory; Immunosuppressive Agents; Lymphoma, B-Cell; Lymphoproliferative Disorders; Organ Transplantation; Protein Kinases; Signal Transduction; Sirolimus; T-Lymphocytes, Regulatory; TOR Serine-Threonine Kinases

The proliferation signal inhibitors [PSIs; mammalian target of rapamycin (mTOR) inhibitors] are widely used for immunosuppression in transplant recipients. Alongside their immunosuppressive properties, PSIs also have substantial anti-neoplastic activity, as a result of their inhibition of cellular signalling pathways involved in critical functions such as cell division, T-cell activation, invasion and growth factor production. In vitro and in vivo studies have shown that PSIs can prevent the growth of experimentally transformed cells and tumour-derived cell lines, and can also increase the sensitivity of cells to apoptosis-inducing agents. The mechanisms of anti-tumour activities of PSIs identified in pre-clinical studies include up-regulation of adhesion molecules with reversion to less invasive phenotypes, and inhibition of angiogenesis resulting from both decreased vascular endothelial growth factor production and decreased endothelial sensitivity to such growth factors. In clinical trials of PSIs in transplant recipients, results show that the incidence of malignancies is substantially lower in patients receiving PSIs than in those receiving calcineurin inhibitor (CNI)-based immunosuppression, with significantly longer times to the development of malignancy. This protective effect of the PSIs is also present in patients receiving combination therapy with a CNI and a PSI. There is also evidence to suggest a role for PSIs in the management of post-transplantation malignancy, with reports of complete resolution of primary and metastatic tumours after conversion from a CNI to a PSI. These beneficial effects have led to the investigation of everolimus and an analogue of sirolimus as a treatment for patients with advanced solid tumours.

Topics: Animals; Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Neoplasms; Protein Kinases; PTEN Phosphohydrolase; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases characterized by abnormal lymphoid proliferation following transplantation. These lymphomas, in particular, have been shown to have a higher incidence in renal transplant recipients compared with the general age-matched population. The effect of different immunosuppressive regimens on the incidence of PTLD has been assessed in a number of studies. Although there are conflicting data on the role of calcineurin inhibitors (CNIs) in promoting the development of PTLD, an increase in risk is described in most studies and is usually related to the aggressiveness of immunosuppression. The proliferation signal inhibitors (PSIs), everolimus and sirolimus, have both immunosuppressive and antiproliferative actions and pre-clinical data suggest that everolimus has an inhibitory effect on the growth of PTLD-derived cell lines. There is currently limited clinical data on the use of PSIs in the management of PTLD, therefore, clinical experience from nine European Transplant centres has been pooled and analysed to assess their potential. Conversion to PSIs and subsequent minimization or withdrawal of CNIs was analysed in 19 renal transplant recipients with PTLD and remission was observed in 15 patients. These data suggest that PSIs may assist with the management of PTLD following renal transplantation.

Topics: Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Adult; Aged; Angiogenesis Inhibitors; Donor Selection; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Lymphoproliferative Disorders; Male; Middle Aged; Neoplasms; Organ Transplantation; Randomized Controlled Trials as Topic; Reoperation; Risk Factors; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Tissue Donors; TOR Serine-Threonine Kinases; Tumor Escape

As newer immunosuppressive regimens have steadily reduced the incidence of acute rejection and have extended the life expectancy of allograft recipients, posttransplant malignancy has become an important cause of mortality. In fact, it is expected that cancer will surpass cardiovascular complications as the leading cause of death in transplant patients within the next 2 decades. An understanding of the underlying pathobiology and how to minimize cancer risks in transplant recipients are essential. The etiology of posttransplant malignancy is believed to be multifactorial and likely involves impaired immunosurveillance of neoplastic cells as well as depressed antiviral immune activity with a number of common posttransplant malignancies being viral-related. Although calcineurin inhibitors and azathioprine have been linked with posttransplant malignancies, newer agents such as mycophenolate mofetil and sirolimus have not and indeed may have antitumor properties. Long-term data are needed to determine if the use of these agents will ultimately lower the mortality due to malignancy for transplant recipients.

Topics: Azathioprine; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Cyclosporine; Hepatitis, Viral, Human; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Neoplasms; Sirolimus; Skin Neoplasms; Tacrolimus; Transplantation Immunology; Transplantation, Homologous

This review covers the new immunosuppressive drugs that have appeared in the past 5 years. It begins with the newest formulation (Neoral, Sandoz Pharmaceuticals, East Hanover, NJ, USA) of the clinically "mature" drug cyclosporin A and then reviews the literature on tacrolimus, sirolimus, and mycophenolate mofetil. In each case, the emphasis is on the evolution of experience with the drug and on the questions that the drug poses for pediatricians considering the risk-benefit ratio of the drug in children.

Topics: Child; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Sirolimus; Tacrolimus

Pediatric renal transplant recipients were enrolled in a multicenter, randomized, double-blind trial of steroid withdrawal. Subjects received basiliximab, calcineurin inhibitor, sirolimus and steroids. Of 274 subjects enrolled, 19 (6.9%) subjects developed posttransplant lymphoproliferative disorder (PTLD). The relative hazard (RH) for PTLD was 5.3-fold higher in children aged < or =5 versus those >12 years (p = 0.0017). EBV seronegative subjects had a 4.7-fold higher RH compared to EBV positive subjects (p = 0.02). Among EBV donor+/recipient- (D+/R-) subjects, the RH increased by 6.1-fold (p = 0.0001). In a multivariate model, risk factors included recipient age < or =5 years (RH 3.2, 95% CI: 1.1-9.6, p = 0.034) and EBV D+/R- status (RH 7.7, 95% CI: 1.6-35.9, p = 0.010). Of 19 patients with PTLD, 17 are alive with functioning grafts and 2 lost their grafts, 1 of whom subsequently died of recurrent PTLD. This 'robust' immunosuppression protocol was associated with low rejection rates but an unacceptably high incidence of PTLD. The combination of basiliximab, calcineurin inhibitor, sirolimus and steroids resulted in over-immunosuppression in a high-risk pediatric population and we do not recommend its use. Future studies must include routine viral monitoring to permit early identification of viral activity and a protocol driven reduction of immunosuppression aimed at avoiding complications.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Child; Child, Preschool; Cyclosporine; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Lymphoproliferative Disorders; Male; Multivariate Analysis; Postoperative Complications; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

Sirolimus is a promising immune suppressive agent, with the potential to reduce calcineurin inhibitor associated nephrotoxicity, halt progression of chronic rejection and prevent tumor proliferation. The aim of this study was to review the experience using sirolimus in pediatric liver transplant recipients at a single center. Database and medical charts of all pediatric liver transplant recipients receiving sirolimus at the Hospital for Sick Children in Toronto were reviewed. Eight patients received sirolimus between October, 2000 and September, 2002. Indications for using sirolimus were post-transplant lymphoproliferative disease (PTLD) (n = 6) and hepatoblastoma (n = 2). Two patients with PTLD concurrently had renal impairment and chronic rejection. Sirolimus dosages ranged between 1.5 and 5 mg once daily. Median duration of follow-up was 17 months. Persistently elevated liver transaminase levels in the two children with chronic rejection decreased during sirolimus therapy. Recurrence of PTLD occurred in one patient. Two patients were diagnosed with acute cellular rejection after transition to maintenance sirolimus monotherapy. Resolution of adverse effects including mouth sores (n = 3), leg swelling (n = 2) and hyperlipidemia (n = 3) occurred either spontaneously or with dose reduction. Sirolimus was discontinued in four patients because of persisting bone marrow suppression, interstitial pneumonitis, life-threatening sepsis and refractory diarrhea. Children with PTLD or hepatoblastoma may benefit from immune suppression with sirolimus after liver transplantation. Further multi-center, prospective, randomized controlled trials will be instrumental to further the knowledge of long-term efficacy, safety and tolerability of sirolimus for selected children following liver transplantation.

Topics: Adolescent; Antibiotics, Antineoplastic; Child; Child, Preschool; Graft Rejection; Hepatoblastoma; Humans; Immunosuppressive Agents; Infant; Liver Neoplasms; Liver Transplantation; Lymphoproliferative Disorders; Sirolimus

Belatacept is employed alongside calcineurin inhibitor (CNI) therapy to prevent graft rejection in kidney transplant patients who are Epstein-Barr virus (EBV) seropositive. Preliminary data suggested that rates of post-transplant lymphoproliferative disorder (PTLD) were higher in individuals treated with belatacept compared to CNI therapy alone.. The records of 354 adults who underwent kidney only transplantation from January 2015 through September 2021 at one medical center were evaluated. Patients underwent treatment with either low-doses of mycophenolate, tacrolimus and sirolimus (B. Non-belatacept (MMF, tacrolimus and sirolimus) and belatacept-based (MMF, tacrolimus and belatacept) regimens do not appear to pose any increased risk of early onset PTLD. Both cohorts benefited from low rates of rejection, malignancy, mortality and graft failure. Recipients will continue to be monitored as PTLD can manifest as a long-term complication.

Topics: Abatacept; Adult; Calcineurin Inhibitors; Epstein-Barr Virus Infections; Graft Rejection; Graft Survival; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Neoplasms; Sirolimus; Tacrolimus

Topics: Apoptosis; Autoimmune Diseases; Autoimmune Lymphoproliferative Syndrome; Child; fas Receptor; Humans; Lymphoproliferative Disorders; Sirolimus

Post-transplant lymphoproliferative disorder is a life-threatening complication of immunosuppression following transplantation mediated by failure of T cells to control Epstein-Barr virus (EBV)-infected and transformed B cells. Typically, a modification or reduction of immunosuppression is recommended, but insufficiently defined thus far. In order to help delineate this, we characterized EBV-antigen-specific T cells and lymphoblastoid cell lines from healthy donors and in patients with a kidney transplant in the absence or presence of the standard immunosuppressants tacrolimus, cyclosporin A, prednisolone, rapamycin, and mycophenolic acid. Phenotypes of lymphoblastoid cell-lines and T cells, T cell-receptor-repertoire diversity, and T-cell reactivity upon co-culture with autologous lymphoblastoid cell lines were analyzed. Rapamycin and mycophenolic acid inhibited lymphoblastoid cell-line proliferation. T cells treated with prednisolone and rapamycin showed nearly normal cytokine production. Proliferation and the viability of T cells were decreased by mycophenolic acid, while tacrolimus and cyclosporin A were strong suppressors of T-cell function including their killing activity. Overall, our study provides a basis for the clinical decision for the modification and reduction of immunosuppression and adds information to the complex balance of maintaining anti-viral immunity while preventing acute rejection. Thus, an immunosuppressive regime based on mTOR inhibition and reduced or withdrawn calcineurin inhibitors could be a promising strategy for patients with increased risk of or manifested EBV-associated post-transplant lymphoproliferative disorder.

Topics: Calcineurin; Cyclosporine; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lymphoproliferative Disorders; MTOR Inhibitors; Mycophenolic Acid; Prednisolone; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic clonal plasma cell or lymphoplasmacytic proliferative disorder. Recently, some case reports have described the association of pure red cell aplasia (PRCA) with MGUS, even with a relatively low monoclonal immunoglobulin burden. T large granular lymphocyte leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by clonal expansion of T large granular lymphocytes, which is rare in China. There are some reports about T-LGL leukemia in patients with B-cell lymphoma; however, it is very rare that T-LGLL coexists with MGUS and clonal B-cell lymphoproliferative disorders (CB-LPD).. A 77-year-old man was hospitalized because of anemia. He was diagnosed with MGUS, CB-LPD, and PRCA. During the development of the disease, a group of abnormal T lymphocytes was detected by flow cytometry of peripheral blood.. Combining clinical manifestations with the result of T cell receptor gene rearrangement and immunophenotype, it was consistent with the diagnosis of T large granular lymphocyte leukemia.. The patient was treat with bortezomib and dexamethasone regimen, Rituximab and sirolimus.. The patient was transfusion independent after therapies.. We report a patient with 4 concomitant hematological disorders: T-LGLL, MGUS, CB-LPD, and PRCA, aiming to represent the clinical and flow cytometry characteristics of these concomitant diseases, analyze the mechanism between diseases, and provide a clinical reference.

Topics: Aged; Anemia; Antineoplastic Agents; Bendamustine Hydrochloride; Bortezomib; Dexamethasone; Humans; Leukemia, Large Granular Lymphocytic; Lymphoproliferative Disorders; Male; Monoclonal Gammopathy of Undetermined Significance; Red-Cell Aplasia, Pure; Rituximab; Sirolimus

CNI-free immunosuppression with conversion to mTORi-based immunosuppression has been demonstrated to reduce CNI-toxicity and to exhibit anti-proliferative properties. However, the experience of CNI-free immunosuppression in paediatric heart transplantation is limited.. A retrospective analysis was conducted of 129 paediatric heart transplants performed between 1997 and 2015. Fifteen patients with clinically indicated conversion from CNI-based to CNI-free immunosuppression were identified. Survival data, rejection episodes, renal function, post-transplantation lymphoproliferative disorder and CAV, including examination with OCT were analysed.. Immunosuppression conversion was successful in all patients. Fourteen of 15 patients (93%) are currently living with good graft function. Median post-transplant survival was 15 years (range, 5-23 years), and median follow-up since conversion was 6 years (range, 1-11 years). Mild (grade 1R) ACR was present in three patients after discontinuation of CNIs. The recovery of renal function with a significant increase in eGFR was observed at 1 and 3 years after conversion. No patient had angiographic signs of macroscopic CAV according to the current ISHLT classification; however, OCT showed the signs of angiographically silent CAV in all patients. CAV did not progress in any patient, implying CAV was stabilised by mTORi-based CNI-free immunosuppression.. CNI-free immunosuppression based on mTORis is a safe and appropriate strategy for maintenance therapy in selected paediatric patients, significantly improves renal function and stabilises CAV. OCT revealed early development of angiographically silent CAV.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Everolimus; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Retrospective Studies; Sirolimus; Tomography, Optical Coherence; Young Adult

Topics: Allografts; Animals; B-Lymphocytes; Epstein-Barr Virus Infections; Female; Graft Rejection; Graft Survival; Heart Transplantation; Heterocyclic Compounds, 3-Ring; Humans; Inhibitory Concentration 50; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Organ Transplantation; Phosphoinositide-3 Kinase Inhibitors; Postoperative Complications; Proto-Oncogene Proteins c-akt; Purines; Quinazolinones; Sirolimus; TOR Serine-Threonine Kinases

Success after solid organ transplantation is dependent on the proper balance of immunosuppression to prevent rejection of the allograft while limiting the risk of developing infections and malignancy. We present a 9-year-old girl, remote from transplant, who presented with airway plaque after a change in immunosuppression to include the mTOR inhibitor sirolimus. Differential diagnosis included direct medication side effect, infection, and neoplasia.

Topics: Child; Epstein-Barr Virus Infections; Female; Graft Rejection; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Lymphoproliferative Disorders; Postoperative Complications; Sirolimus

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte apoptosis. Children present with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias. Recent advances show efficacy of treatment with immunosuppressive drugs. Sirolimus, an mammalian target of rapamycin inhibitor, improves autoimmune cytopenias and lymphoproliferation, with a safe profile. We present 2 patients, a 5-year-old girl and 15-year-old boy, diagnosed with ALPS with initial partial response to steroid treatment. Autoimmune cytopenias and lymphoproliferation then became refractory to treatment, with recurrence of symptoms. In both cases, treatment with sirolimus was started, with a rapid response, complete remission of cytopenias, and resolution of lymphoproliferation, with no significant adverse effects.. sirolimus is an effective and safe drug for controlling children with cytopenias and lymphoproliferation linked to ALPS.

Topics: Adolescent; Autoimmune Lymphoproliferative Syndrome; Child, Preschool; Female; Humans; Lymphoproliferative Disorders; Male; Pancytopenia; Sirolimus; Treatment Outcome

Topics: Anemia, Hemolytic, Autoimmune; Disease Management; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Middle Aged; Salvage Therapy; Sirolimus; Tacrolimus; Transplantation, Homologous; Waldenstrom Macroglobulinemia

Posttransplant lymphoproliferative disease (PTLD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. We describe here the case of a boy with history of induction failure of a T-cell acute lymphoblastic leukemia, who presented a life-threatening situation of nonengraftment and rituximab-refractory PTLD after the first hematopoietic stem cell transplantation. We decided to use an unusual strategy of combining a nonmyeloablative conditioning (fludarabine and cyclophosphamide) with a calcineurin inhibitor-free GvHD prophylaxis (sirolimus and mycophenolate mofetil). This strategy had permitted the control of an Epstein-Barr virus PLTD in umbilical cord blood transplantation without further reactivation.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Calcineurin; Child; Combined Modality Therapy; Drug Resistance, Neoplasm; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Rituximab; Sirolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Posttransplant lymphoproliferative disorder (PTLD) continues to be a devastating and potentially life-threatening complication in organ transplant recipients. PTLD is associated with EBV infection and can result in malignant B cell lymphomas. Here we demonstrate that the PI3K/Akt/mTOR pathway is highly activated in EBV+ B cell lymphoma lines derived from patients with PTLD. Treatment with the mTORC1 inhibitor Rapamycin (RAPA) partially inhibited the proliferation of EBV+ B cell lines. Resistance to RAPA treatment correlated with high levels of Akt phosphorylation. An mTORC1/2 inhibitor and a PI3K/mTOR dual inhibitor suppressed Akt phosphorylation and showed a greater anti-proliferative effect on EBV+ B lymphoma lines compared to RAPA. EBV+ B cell lymphoma lines expressed high levels of PI3Kδ. We demonstrate that PI3Kδ is responsible for Akt activation in EBV+ B cell lymphomas, and that selective inhibition of PI3Kδ by either siRNA, or a small molecule inhibitor, augmented the anti-proliferative effect of RAPA on EBV+ B cell lymphomas. These results suggest that PI3Kδ is a novel, potential therapeutic target for the treatment of EBV-associated PTLD and that combined blockade of PI3Kδ and mTOR provides increased efficacy in inhibiting proliferation of EBV+ B cell lymphomas.

Topics: Blotting, Western; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Imidazoles; Lymphoma, B-Cell; Lymphoproliferative Disorders; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes; Organ Transplantation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Postoperative Complications; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinolines; Sirolimus; TOR Serine-Threonine Kinases

Few studies examined the clinicopathologic features of PTLD arising in pediatric SBT patients. Particularly, the association between ATG and PTLD in this population has not been described. Retrospective review of 81 pediatric patient charts with SBT--isolated or in combination with other organs--showed a PTLD incidence of 11%, occurring more frequently in females (median age of four yr) and with clinically advanced disease. Monomorphic PTLD was the most common histological subtype. There was a significant difference in the use of ATG between patients who developed PTLD and those who did not (p < 0.01); a similar difference was seen with the use of sirolimus (p < 0.001). These results suggested a link between the combination of ATG and sirolimus and development of more clinically and histologically advanced PTLD; however, the risk of ATG by itself was not clear. EBV viral loads were higher in patients with PTLD, and median time between detection of EBV to PTLD diagnosis was three months. However, viral loads at the time of PTLD diagnosis were most often lower than at EBV detection, thereby raising questions on the correlation between decreasing viral genomes and risk of PTLD.

Topics: Adolescent; Antilymphocyte Serum; Child; Child, Preschool; Female; Gene Rearrangement; Genome, Viral; Humans; Immunosuppressive Agents; In Situ Hybridization; Infant; Intestinal Diseases; Intestine, Small; Lymphoma; Lymphoproliferative Disorders; Male; Postoperative Complications; Retrospective Studies; Risk; Sirolimus; VDJ Recombinases; Viral Load; Young Adult

Sirolimus, a potent inhibitor of B- and T-cell activation. is a commonly used immunosuppressant after renal transplantation. Withdrawal of sirolimus from the immunosuppression regimen may reduce B-cell surveillance. We present a case of rapidly progressive central nervous system (CNS) polymorphic Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder following the withdrawal of sirolimus.

Topics: Adult; Biopsy; Disease Progression; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Sirolimus; Tomography, X-Ray Computed

  Development of KS in pediatric liver transplant recipients is a rare entity and has dismal prognosis. Latent HHV-8 infection, immunosuppression, and genetic predisposition are possible etiological factors. Decreasing the dose or cessation of immunosuppressive drugs, switching to sirolimus with antiproliferative and antitumor properties, and different chemotherapeutic regimens are the current therapeutic strategies. We herein report a pediatric liver transplant recipient who developed generalized KS at post-transplant fifth month. The disease had an aggressive course despite the highly toxic chemotherapy. On the other hand, a prompt and durable response was provided by paclitaxel with tolerable side effects. The patient is now free of disease for at least 24 months and healthy with good graft function under sirolimus therapy as maintenance immunosuppression. Instead of highly toxic chemotherapy, paclitaxel can be used as therapeutic option in cases with generalized disease and in those who are unresponsive to conventional chemotherapy. However, new studies are needed to assess the efficacy of the paclitaxel therapy in KS in the liver transplant recipients.

Topics: Antineoplastic Agents; Female; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Lymphoproliferative Disorders; Paclitaxel; Prognosis; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

Malignancies and opportunistic infections are frequently observed after solid-organ transplantation. Their occurrence strongly affects recipient survival. We report the case of a 29-year-old Tunisian kidney-recipient who was diagnosed simultaneously with post-transplant lymphoproliferative disease (PTLD) and visceral leishmaniasis (VL). Withdrawal of immunosuppressive therapy together with antiparasitic treatment using liposomal amphotericin B, and anti-CD20 antibodies medication resulted in cure of leishmaniasis and remission from PTLD. This case is of clinical interest because of the uncommon association of VL with PTLD after solid organ transplantation. It is also original by the favourable outcome of VL and PTLD, both known as life-threatening diseases. Also, it illustrates the predisposing role of immunosuppressive therapy in occurrence of opportunistic infections and malignancies after solid organ transplantation.

Topics: Adult; Amphotericin B; Antibodies, Monoclonal, Murine-Derived; Antiprotozoal Agents; Antiviral Agents; Epstein-Barr Virus Infections; Ganciclovir; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Leishmaniasis, Visceral; Lymphoproliferative Disorders; Male; Meglumine; Meglumine Antimoniate; Opportunistic Infections; Organometallic Compounds; Postoperative Complications; Remission Induction; Rituximab; Sirolimus

We previously reported that posttransplant lymphoproliferative disorders (PTLD) occurred more frequently in non-African American (AF) kidney transplant recipients. An in-depth analysis of racial differences in the development of PTLD has not been reported.. We assessed Medicare claims for PTLD in a retrospective cohort of 53,719 patients who underwent transplantation from January 2000 to September 2006 and followed up through December 2007.. There were 719 (1.3%) patients with claims for PTLD. Non-AF recipient race (including all races analyzed separately, adjusted hazard ratio [AHR] 1.38, 95% confidence interval [CI] 1.13-1.68), recipient Epstein-Barr virus (EBV) immunoglobulin G (IgG) seronegative status (AHR 1.88, 95% CI 1.53-2.34), and de novo sirolimus (AHR 1.22, 95% CI 1.03-1.45) were associated with an increased risk of PTLD. Furthermore, de novo sirolimus showed a significant interaction with EBV IgG; among EBV IgG-negative recipients, sirolimus use was significant (P = 0.003), but among EBV IgG-positive recipients, it was not significant (P = 0.18). EBV IgG-seronegative status was significant in all races except for AFs, and racial differences were a significant effect modifier for EBV IgG status and risk of PTLD. Mortality subsequent to PTLD did not differ by race. CONCLUSIONS.: AF kidney transplant recipients were at lower risk for PTLD, irrespective of the recipient EBV IgG serostatus. On the contrary, recipient EBV IgG-seronegative status was associated with a higher risk of PTLD in the non-AF population. De novo sirolimus therapy was associated with increased risk of PTLD in EBV IgG-negative recipients, regardless of race.

Topics: Adult; Aged; Black People; Female; Herpesvirus 4, Human; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Medicare; Middle Aged; Multivariate Analysis; Retrospective Studies; Sirolimus; United States; White People

A 53-year-old Caucasian male suffering from idiopathic dilated cardiomyopathy underwent cardiac transplantation. Fifty-seven days following transplant, he developed posttransplant lymphoproliferative disorder (PTLD), which was Epstein-Barr virus positive. The initial episode of PTLD was treated with a dose reduction in cyclosporine (CsA) and a 4-week course of rituximab. Subsequent biopsies showed resolution of PTLD. One year posttreatment, his evaluation revealed severe cardiac allograft vasculopathy (CAV). The patient was switched to sirolimus-based immunosuppression regimen with gradual up-titration of sirolimus in combination with complete withdrawal of previously administered Calcineurin-based immunosuppression approach. The switchover was carried out over a 6-week period. In the following 3 years, there was CAV regression as well as PTLD remission, without any significant episode of rejection. Despite frequent relapses with this form of PTLD, the patient remains in remission, 8 years posttransplantation. In summary, sirolimus has been demonstrated to attenuate the progression of CAV, and this case report illustrates that regression of CAV is possible. In addition to preventing rejection, mammalian target of rapamycin inhibitors directly suppress signaling pathways leading to PTLD and may be effective monotherapy for preventing rejection and suppressing PTLD.

Topics: Antibodies, Monoclonal, Murine-Derived; Calcineurin Inhibitors; Cyclosporine; Heart Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Middle Aged; Rituximab; Sirolimus

Lymphangiomatosis is a rare proliferative disorder of the lymphatic system. The etiology is unknown, rendering it difficult to manage. This case report of lymphangiomatosis with features of Gorham's disease reveals the progressive and unexpected nature of the condition. It highlights the need for further research into the pathophysiology and management of lymphangiomatosis as current treatment options are limited.

Topics: Antibiotics, Antineoplastic; Child, Preschool; Diagnosis, Differential; Disease Progression; Female; Humans; Lymphatic Vessels; Lymphoproliferative Disorders; Osteolysis, Essential; Sirolimus; Watchful Waiting

PTLD is a very severe, life threatening complication after organ transplantation. A 17 years old female patient with kidney transplanted (KTx) 7th months ago on immunosuppression therapy: Tacrolimus (TAC), Cell Cept (MMF), Encorton (Enc) was described. She was admitted to the hospital due to: fever, abdominal pain, diarrhea and enlarged cervical and inguinal lymph nodes on palpation. Histopathological diagnosis revealed monomorphic PTLD; diffuse large B cell lymphoma, immunoblastic. Treatment of PTLD was started immediatly after the final diagnosis. MMF was stopped, dose of TAC was reduced (blood level 3-4 ng/ ml), Enc were continued. Anti-CD20 antibodies (Rituximab) were administered. After 7 days of treatment the patient developed signs of diffuse peritonitis. In the course of surgery, perforation in six sites of the small intestine and sigmoid colon were discovered. The Hartman's surgery was performed (sigmoidectomy) with formation of temporary sigmoideostomy. Resected parts of intestine and sigmoid colon were infiltrated by immnunoblasts and revealed diffuse necrosis - the same process was seen in lymph nodes. After the wounds healed, Rituksymab was continued (8 doses) and chemotherapy was started - CHOP - 6 cycles every month. Eight months after surgery, full remission was obtained, TAC was change to rapamycine (RAP) and closure of sigmoideostomy was performed. At present, almost 10 years after first symptoms of PTLD, the patient remains in full remission of the disease.

Topics: Adolescent; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Remission Induction; Rituximab; Sigmoidoscopy; Sirolimus; Tacrolimus

Autoimmune cytopaenia is a rare, but severe complication after solid organ transplantation. We retrospectively analysed 57 paediatric intestinal transplants performed in 49 patients between 1999 and 2009. Autoimmune cytopaenia was observed in six patients; it appeared after an average of 10 months post-transplant. Warm autoimmune haemolytic anaemia was developed in three patients, cold autoimmune haemolytic anaemia in one and two presented a mixed type. Incidence and causes for haematological cytopaenia such as the following were investigated: immunosuppression, major blood mismatch, viral infection, malignancy, passenger lymphocyte syndrome and lymphoproliferative disorders. Initial treatment included high-dose steroids, intravenous immunoglobulin, plasmapheresis and maintenance of body temperature above 37°C in those with cold autoantibodies. Inclusion of the spleen in multivisceral transplants seems to be an important risk factor. All patients, except one, relapsed after classic therapy, requiring additional treatments. Sirolimus conversion was performed in four patients. One died after infection. The immunosuppressive therapies associated with other concomitant factors, such as viral infections, lymphoproliferative disorders, graft-versus-host disease, passenger lymphocyte syndrome and the inclusion of the spleen as part of multivisceral graft seem to play an important part in the development of autoimmune processes after intestinal transplantation. Therapy is not well established, especially in those resistant to first-line treatment.

Topics: Alemtuzumab; Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Child; Female; Graft Rejection; Humans; Immunosuppression Therapy; Intestines; Lymphoproliferative Disorders; Male; Retrospective Studies; Sirolimus; Spleen; Transplantation, Homologous; Virus Diseases

Liver transplantation (OLT) in children has seen significant improvements in recent years. Long-term immunosuppressive strategies have focused on avoiding the risks of long-term immunosuppression, particularly nephrotoxicity, de novo malignancy and late infections. Since its introduction in renal transplantation in 1999, sirolimus (SRL) has been used by an increasing number of liver transplant centers. The aim of this study was to review the experience using SRL in pediatric liver transplant recipients at a single center.. Between 1989 and 2006, 318 children underwent OLT including 13 who were converted to SRL therapy because of tacrolimus-related side effects. The indications were posttransplant lymphoproliferative disease (PTLD; n = 11), nephrotoxicity (n = 1), and de novo autoimmune hepatitis (n = 1). One patient with PTLD previously concurrently displayed chronic rejection. SRL dosages ranged between 0.4 and 5 mg/d. The median duration of follow-up was 18 months.. PTLD recurred in 1 patient. There were no episodes of acute rejection. One child developed hyperlipidemia that resolved with diet and medication.. Conversion from tacrolimus to SRL in selected pediatric liver transplant recipients is safe. Children with PTLD may benefit from immunosuppression with SRL after liver transplantation.

Topics: Adolescent; Cadaver; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Lymphoproliferative Disorders; Male; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Tissue Donors

Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of the immune system caused by inadequate induction of apoptosis via the Fas pathway, mainly characterized by generalized lymphadenopathy, splenomegaly, and autoimmune cytopenias, as well as increased risk of lymphoma. Although the clinical course of ALPS is highly variable, without treatment long-term prognosis is unsatisfactory for most patients. ALPS has been treated with most of the existing immunosuppressive agents, with variable success. We hereby present a case of a child with ALPS whose greatly enlarged lymph nodes rapidly regressed upon initiation of rapamycin, a novel potential therapeutic agent in the treatment of ALPS.

Topics: Autoimmune Diseases; Female; Humans; Immunosuppressive Agents; Infant; Lymph Nodes; Lymphatic Diseases; Lymphoproliferative Disorders; Remission Induction; Sirolimus

Post transplant lymphoproliferative disorder (PTLD) is the commonest form of post transplant malignancy in children. The incidence in renal transplant recipients varies between 2%-4%. They are characterized by uncontrolled B lymphocyte proliferation, in most cases driven by Epstein Barr virus (EBV). They are more common in younger children, EBV seronegative patients and those who receive aggressive immunosuppression. PTLD commonly presents in an unspecific form and it requires high suspicion rate for its diagnosis, especially in children with risk factors. We report a twelve year-old girl who developed fever, sore throat and lymph node enlargement, six months after receiving a renal allograft. Laboratory assessment and imaging studies were compatible with PTLD, which was confirmed by biopsy. Treatment was reduction of immunosuppression and surveillance. The patient had a favorable evolution.

Topics: Child; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Sirolimus

Composite tissue allotransplantation may have different immunosuppressive requirements and manifest different complications compared with solid organ transplantation. We developed a non-human primate facial composite tissue allotransplantation model to investigate strategies to achieve prolonged graft survival and immunologic responses unique to these allografts.. Composite facial subunits consisting of skin, muscle, and bone were heterotopically transplanted to mixed lymphocyte reaction-mismatched Cynomolgus macaques. Tacrolimus monotherapy was administered via continuous intravenous infusion for 28 days then tapered to daily intramuscular doses.. Five of the six animals treated with tacrolimus monotherapy demonstrated rejection-free graft survival up to 177 days (mean, 113 days). All animals with prolonged graft survival developed posttransplant lymphoproliferative disorders (PTLD). Three animals converted to rapamycin after 28 days of rejection of their allografts, but did not develop PTLD. Genotypic analysis of PTLD tumors demonstrated donor origin in three of the five analyzed by short-tandem repeats. Sustained alloantibodies were detected in rejecting grafts and absent in nonrejecting grafts.. Tacrolimus monotherapy provided prolonged rejection-free survival of composite facial allografts in a non-human primate model but was associated with the development of a high frequency of donor-derived PTLD tumors. The transplantation of a large volume of vascularized bone marrow in composite tissue allografts may be a risk factor for PTLD development.

Topics: Animals; Bone Marrow Transplantation; Disease Models, Animal; Facial Transplantation; Graft Rejection; Graft Survival; Immunosuppressive Agents; Infusions, Intravenous; Isoantibodies; Lymphocyte Culture Test, Mixed; Lymphoproliferative Disorders; Macaca fascicularis; Magnetic Resonance Imaging; Male; Risk Factors; Sirolimus; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Aged; Disease Progression; Drug Therapy, Combination; Female; Herpesvirus 4, Human; Humans; Immunoglobulins, Intravenous; Lymphoproliferative Disorders; Male; Methylprednisolone; Middle Aged; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Failure; Viremia

Posttransplant lymphoproliferative disorder (PTLD) remains one of the most important complications of intensive immunosuppressive therapy. A 65-year-old Caucasian woman received a primary en bloc kidney transplant from a deceased 2-year-old donor. After antithymocyte globulin induction she was treated with a maintenance regimen including cyclosporine and mycophenylate mofetil (MMF). She had a history of recurrent dermatomyositis, suggesting a flawed immune system. After a benign course for 9 months and after an increase in MMF from 2 to 3 g daily, she presented with pneumonia owing to Candida albicans, which was responsive to antibiotics, as was the PTLD. Persistent fever led to a diagnosis of PTLD. The immunosuppressive regimen was converted to sirolimus (SRL) and rituximab, with over 90% necrosis of the neoplasm at 1 month. However, owing to concern at exploration, the allografts were extirpated. This case documented the benefit of the rituximab-SRL combination to treat PTLD while maintaining dermatomyositis in remission.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Appendectomy; Child, Preschool; Dermatomyositis; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Lymphoproliferative Disorders; Ovariectomy; Postoperative Complications; Rituximab; Sirolimus

Post-transplant lymphoproliferative disease (PTLD) can occur in different sites, such as lymph nodes, allograft, and central nervous system. We report a 6-year-old girl with end-stage renal disease secondary to hypoplastic-dysplastic kidneys, who received a kidney transplant. Thirty months post transplant, she developed PTLD in the tongue, an area of muscular tissue only. At that time her peripheral blood Epstein-Barr viral (EBV) load was only 40 copies/10(5) lymphocytes, though the tumor was EB early RNA (EBER) positive. Immunosuppression was reduced with initial improvement in her symptoms. One month later, she returned with abdominal complaints and a contained cecal abscess. The excised cecal tissue revealed CD20 and EBER-positive lymphoid cells. At the same time, her peripheral blood EBV copy number rose to 400 copies/10(5) lymphocytes. She was successfully treated for the progressive PTLD by complete cessation of immunosuppression and a modified reduced-dose chemotherapy protocol plus rituximab. Partial immunosuppression was eventually re-introduced with sirolimus and prednisone. She remains in remission 60 months post transplant, and 30 months post PTLD, with serum creatinine value maintained at 1.3 mg/dL. Unusual localization of PTLD to areas in non-lymphoid tissue without regional lymphoid involvement may result in misleading low peripheral blood EBV viral loads.

Topics: Abscess; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cecum; Child; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Prednisone; Rituximab; Sirolimus; Tongue Neoplasms; Viral Load

Topics: Adult; Epstein-Barr Virus Infections; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell; Lymphoproliferative Disorders; Male; Middle Aged; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

We examined activation of the mTOR signaling pathway in situ in the primary, normal reactive and patient-derived post-transplant lymphoproliferative disorder (PTLD) tissue samples. We accomplished this analysis by immunohistochemistry on formalin-fixed, paraffin-embedded specimens using a set of highly specific antibodies that permitted us to determine phosphorylation status of the key serines in the mTOR target proteins. Our results demonstrate that the mTOR signaling pathway is activated in reactive tissue in a highly distinct fashion with positive, typically enlarged cells being present primarily in the germinal center and, to a lesser degree, in interfollicular areas with mantle zone being conspicuously negative. We could demonstrate mTOR activation in the lesional cells in the entire spectrum of PTLD subtypes, regardless of their Epstein-Barr virus genome expression status. These data demonstrate the ubiquitous activation of the mTOR signaling pathway in PTLD and indicate that mTOR inhibitors may be effective in treatment and, notably, prevention of PTLDs given their immunosuppressive properties. Furthermore, our results define potential biomarkers of the therapeutic response. Because the constitutive mTOR activation has also been identified in cells isolated from other hematologic malignancies, the ability to examine the in vivo mTOR signaling may have implications reaching beyond the PTLD field.

Topics: Adaptor Proteins, Signal Transducing; Cell Cycle Proteins; Cell Line, Tumor; Eukaryotic Initiation Factor-4G; Humans; Immunohistochemistry; Lymphoproliferative Disorders; Organ Transplantation; Phosphoproteins; Protein Kinases; Ribosomal Protein S6; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Previous studies have demonstrated that the NZM2410/NZW 'z' allele of Sle1 on telomeric murine chromosome 1 led to lymphoproliferative autoimmunity, when acting in concert with the FAS(lpr) defect on the C57BL/6 background. The present report shows that the Sle1b sub-locus, harboring the NZM2410/NZW 'z' allele of SLAM, in epistasis with FAS(lpr), may be sufficient to induce lymphoproliferative autoimmunity. Disease in this simplified genetic model is accompanied by significant activation of the AKT signaling axis in both B- and T cells, as evidenced by increased phosphorylation of AKT, mTOR, 4EBP-1 and p70S6K, resulting from increased PI3K and reduced PTEN activity. In addition, blocking this axis using RAD001, an mTOR inhibitor, ameliorated lymphoproliferation and modulated serum IgG anti-nuclear auto-antibodies. Finally, mTOR inhibition also dampened signaling via parallel axes, including the MAPK and NFkB pathways. Hence, hypersignaling via the PI3K/AKT/mTOR axis appears to be an important mechanism underlying autoimmune lymphoproliferative disease, presenting itself as a potential target for therapeutic intervention.

Topics: Animals; Apoptosis; Autoantibodies; Autoimmune Diseases; Epistasis, Genetic; Everolimus; Extracellular Signal-Regulated MAP Kinases; fas Receptor; Female; Immunosuppressive Agents; Lymphocytes; Lymphoproliferative Disorders; Male; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Multigene Family; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Spleen; Survival Analysis

We report on a patient with relapsed chronic lymphocytic leukemia (CLL) treated with the novel mTOR inhibitor RAD001 within a phase II clinical trial. Although the patient initially responded to therapy, RAD001 was discontinued after 32 weeks due to progression and fludarabine-based chemotherapy was started. The patient subsequently developed a rapidly fatal Epstein-Barr-virus-associated lymphoproliferative disorder, clonally unrelated to the CLL. The clinical course suggests caution when using newer immunosuppressive drugs for treatment of CLL, especially in the context of additional purine analog therapy.

Topics: Aged; Epstein-Barr Virus Infections; Everolimus; Fatal Outcome; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoproliferative Disorders; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Vidarabine

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Middle Aged; Neoplasms; Postoperative Complications; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Transplantation, Homologous

Posttransplant lymphoproliferative disorder is a rare and often difficult diagnosis in patients with only cutaneous symptoms. A stepwise approach to diagnosis and classification can lead to successful treatment. We report a case of an EBV-associated posttransplant lymphoproliferative disorder (PTLD) occurring on the face with a primary cutaneous presentation. The appropriate diagnosis was made only after multiple biopsies and special stains. There was near complete resolution with decreased levels of iatrogenic immunosuppression. The diagnosis of Posttransplant lymphoproliferative disorder can be difficult to establish. A proper workup will aid in making an accelerated diagnosis and choosing appropriate treatment options.

Topics: Dose-Response Relationship, Drug; Epstein-Barr Virus Infections; Face; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Prednisone; Pulmonary Fibrosis; Sirolimus; Skin Diseases

Posttransplantation lymphoproliferative disorder (PTLD) is one of the most serious complications of solid-organ transplantation. It potentially is treatable in most cases, but current methods involve withdrawal or reduction of immunosuppression and the consequent risk for graft rejection. Sirolimus was shown in vivo and in vitro to limit proliferation of a number of malignant cell lines, including those of PTLD-derived cells. We present a case of disseminated PTLD in a patient with a renal transplant that resolved completely with conversion of immunosuppression to sirolimus. Graft function was maintained and improved with treatment. This offers a novel means of treating these patients and minimizing transplant loss.

Topics: Adult; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Remission Induction; Sirolimus

This study examined the effects of anti-thymocyte globulin (ATG) and daclizumab immunosuppressive induction therapy on the frequency and severity of acute cellular rejection in lung transplantation patients.. A retrospective analysis was conducted of 335 lung transplantation patients from a single center in the period 1992 to 2003. Patients completed standard ATG (Merieux, 2.5 mg/kg/day, or ATGAM, 12.5 mg/kg/day, for 3 consecutive days) (n = 151) or daclizumab (5 fortnightly treatments at a dose of 1 mg/kg) (n = 151) induction therapy. End points included acute cellular rejection requiring treatment (> or = A2), and moderate/severe acute cellular rejection (A3/A4).. The percentage of patients free of rejection requiring treatment (< A2) was 32% at 3 months and 26% at 2 years after transplantation in the ATG group and 9% and 0%, respectively, in the daclizumab group (p < 0.0001). Compared with the ATG group, a significantly higher proportion of patients in the daclizumab group experienced 3 or more episodes of acute cellular rejection > or = A2 during the first 3 months (p < 0.0001) and the entire 2-year follow-up (p < 0.0001). The daclizumab group also experienced more moderate/severe acute cellular rejection episodes compared with the ATG group during the first 3 months (p = 0.005). Cox regression analysis demonstrated ATG induction therapy was independently associated with a significantly longer duration of freedom from acute cellular rejection requiring treatment (> or = A2) (p < 0.001).. After lung transplantation, ATG induction appears to be superior to daclizumab induction in the reduction in the incidence and severity of acute cellular rejection.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Area Under Curve; Cytomegalovirus Infections; Daclizumab; Graft Rejection; Heart-Lung Transplantation; Humans; Immunoglobulin G; Immunosuppressive Agents; Incidence; Lung Transplantation; Lymphoproliferative Disorders; Reoperation; Retrospective Studies; Sirolimus; Survival Analysis

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.

Topics: Animals; Antibodies, Antinuclear; Autoimmune Diseases; Immunosuppressive Agents; Lymphoid Tissue; Lymphoproliferative Disorders; Mice; Mice, Inbred CBA; Mice, Mutant Strains; Mycophenolic Acid; Protein Kinases; Signal Transduction; Sirolimus; T-Lymphocyte Subsets; TOR Serine-Threonine Kinases

A 12-yr-old girl with end-stage renal disease secondary to primary hyperoxaluria type I received a living related (left lateral segment) liver transplant from her brother as the first step of a staged liver and kidney transplant. Renal transplantation was planned for a later date from the same donor. Nine weeks after transplantation she developed polymorphic PTLD of the tonsils and adenoids. Initial treatment with surgical resection and withdrawal of immunosuppression was insufficient as she developed recurrence of the PTLD lesion 1 wk after surgical resection and reduction of immunsuppression. Treatment with the chimeric monoclonal anti CD20 antibody, rituximab (Mabthera, Hoffman-La Roche AG, Grenzach-Whylen, Germany), resulted in quick response and complete recovery from PTLD within 2 wk, with no recurrence up to 8 months after treatment. Rejection prophylaxis was successfully achieved with Sirolimus (Rapamune, Wyeth Pharmaceuticals Inc., Philadelphia, PA, USA) monotherapy, with no episodes of acute rejection.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Child; Female; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Transplantation; Lymphoproliferative Disorders; Recurrence; Rituximab; Sirolimus

Topics: Adult; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Sirolimus; Transplantation, Homologous

Post-transplant lymphoproliferative disease (PTLD) is an uncommon but life-threatening complication of solid-organ and blood stem-cell transplants. It responds poorly to therapy, including reduction of immunosuppression, interferon, antivirals or chemotherapy. Small series of PTLD successfully treated with rituximab have been reported, and experimental studies suggest that rapamycin inhibits growth of human Epstein-Barr virus-transformed B lymphocytes. We report two cases of PTLD after renal transplantation that were successfully treated with rituximab in association with rapamycin. This report suggests that rituximab associated with rapamycin could be an effective and safe treatment for PTLD.

Topics: Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Rituximab; Sirolimus; Time Factors; Treatment Outcome

Posttransplant lymphoproliferative disorders (PTLDs) represent a life-threatening complication of standard immunosuppressive therapy. The impact of novel, rapamycin-related immunosuppressive drugs on the pathogenesis of PTLDs remains undefined.. We tested the effect of everolimus (RAD, Novartis Pharma AG, Basel, Switzerland) on human PTLD-derived cells using in vitro assays and an in vivo severe combined immunodeficiency disease mouse xenotransplant model.. Everolimus profoundly inhibited the proliferation, cell-cycle progression, and survival of the PTLD-1 cell line established from a pulmonary PTLD. Equally profound inhibition of PTLD-1 growth was achieved in vivo at well-tolerated everolimus doses of 0.5 to 5 mg/kg per day. Five mg/kg per day of everolimus, given once per day, inhibited PTLD-1 tumor volume gain by more than 10-fold in treated mice compared with untreated mice. Because the subsequent pharmacokinetic analysis indicated rapid everolimus absorption, distribution, and clearance in mice (with a half-life of 3 to 6 hr and maximum drug blood concentration reached after 0.5 to 1 hr), treatment was changed to a twice-daily regimen. Everolimus given twice daily at 0.5 mg/kg per dose inhibited tumor-volume gain by more than 60-fold and at 0.25 mg/kg per dose by more than 10-fold. Similar everolimus doses were required to prevent graft rejection in a mouse heart allotransplantation model; the highest dose tested (1.5 mg/kg twice daily) resulted in long-term graft survival in all mice that underwent transplantation.. Everolimus displays a potent inhibitory effect on PTLD-derived cells in vitro and in vivo in a dose range leading to prevention of allograft rejection and may prove effective in both the prevention and treatment of PTLDs in transplant patients.

Topics: Animals; Cell Cycle; Cell Division; Cell Survival; Cell Transplantation; Dose-Response Relationship, Drug; Everolimus; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Mice; Mice, Inbred Strains; Mice, SCID; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Rituximab; Sirolimus

The inhibitors of cyclin-dependent kinase (CDK) 4 (INK4) bind CDK4/6 to prevent their association with D-cyclins and G(1) cell cycle initiation and progression. We report here that among the seven CDK inhibitors, p18(INK4c) played an important role in modulating TCR-mediated T cell proliferation. Loss of p18(INK4c) in T cells led to hyperproliferation in response to CD3 stimulation. p18(INK4c)-null mice developed lymphoproliferative disorder and T cell lymphomas. Expression of IL-2, IL-2R-alpha, and the major G(1) cell cycle regulatory proteins was not altered in p18-null T cells. Both FK506 and rapamycin efficiently inhibited proliferation of p18-null T cells. In activated T cells, p18(INK4c) remained constant, and preferentially associated with and inhibited CDK6 but not CDK4. We propose that p18(INK4c) sets an inhibitory threshold in T cells and one function of CD28 costimulation is to counteract the p18(INK4c) inhibitory activity on CDK6-cyclin D complexes. The p18(INK4c) protein may provide a novel target to modulate T cell immunity.

Topics: Animals; CD28 Antigens; CD3 Complex; CDC2-CDC28 Kinases; Cell Cycle; Cell Cycle Proteins; Cell Division; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p18; Cyclin-Dependent Kinases; Cytokines; Enzyme Inhibitors; G1 Phase; Immunosuppressive Agents; Lymphocyte Activation; Lymphoma, T-Cell; Lymphoproliferative Disorders; Mice; Mice, Knockout; Mice, SCID; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Receptors, Antigen, T-Cell; Sirolimus; T-Lymphocyte Subsets; Tacrolimus; Tumor Suppressor Proteins

The role of sirolimus (SRL) as a rescue agent (n=42) and as a component of primary immunosuppression (n=8) was evaluated in a mixed population of 50 transplanted children receiving tacrolimus (liver: 26, heart: 5, intestinal: 5, liver-intestine: 9, lung: 1, bone marrow: 1, liver-kidney: 1, multivisceral: 1). Rescue indications for tacrolimus (TAC) failure were recurrent acute rejection and acute rejection complicating withdrawal of immunosuppression in posttransplant lymphoproliferative disorder (PTLD). Rescue indications for TAC toxicity were nephrotoxicity, pancreatitis, seizures, hypertrophic cardiomyopathy, and graft-versus-host disease.. Mean age at rescue was 11.5 years and mean follow-up was 204 (range 18-800) days. As primary immunosuppression, SRL+TAC prevented early acute rejection in 7/8 children. The indication for rescue resolved in 33/42 children. In children with TAC toxicity, this was associated with decrease in TAC doses by 50%, significant improvements in renal function, and continuing decline in Epstein-Barr virus (EBV) viral load in PTLD patients. Serious adverse events led to discontinuation of SRL in 9/42 rescue patients, 3 of them also experienced acute rejection. Three additional children also experienced acute rejection on SRL therapy (overall incidence 6/50, 12%). Pharmacokinetic analysis in the first week of SRL administration suggested a short half-life (11.8+/-5.5 hr, n=21).. SRL and reduced-dose TAC may achieve adequate immunosuppression without compromising renal function or enhancing EBV viremia significantly.

Topics: Acute Disease; Adolescent; Adult; Child; Child, Preschool; Epstein-Barr Virus Infections; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Kidney; Lymphoproliferative Disorders; Recurrence; Sirolimus; Tacrolimus; Transplantation Immunology

Whereas the standard immunosuppressive agents foster development of posttransplant lymphoproliferative disorders (PTLDs), the impact of RAD, a macrolide with potent immunosuppressive properties, and other immunosuppressive macrolides on these disorders remains undetermined. We found that RAD had a profound inhibitory effect on in vitro growth of six different PTLD-like Epstein-Barr virus+ lymphoblastoid B cell lines. Similar to normal T cells, RAD blocked cell-cycle progression in PTLD-like B cells in the early (G(0)/G(1)) phase. Furthermore, RAD increased the apoptotic rate in such cells. The drug also had a profound inhibitory effect on the growth of PTLD-like Epstein-Barr virus+ B cells xenotransplanted s.c. into SCID mice. The degree of the RAD effect varied among the three B cell lines tested and was proportional to its effects on the cell lines in vitro. In this in vivo xenotransplant model, RAD markedly delayed growth or induced regression of the established tumors. In one line, it was able to eradicate the tumor in four of eight mice. When RAD treatment was initiated before tumor cell injection, a marked inhibition of tumor growth was seen in all three lines. In two of them, the drug prevented tumor establishment in approximately 50% of mice (5/11 and 5/8). In summary, RAD is a potent inhibitor of PTLD-like cells in vitro and in vivo. These findings indicate that, in contrast to the standard immunosuppressive agents, macrolides such as RAD may be effective in prevention and treatment of PTLDs.

Topics: Animals; Apoptosis; Cell Cycle; Cell Division; Cell Line, Transformed; Everolimus; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; In Vitro Techniques; Lymphoproliferative Disorders; Mice; Mice, Inbred ICR; Mice, SCID; Neoplasm Transplantation; Sirolimus; Transplantation

The aim of this study is to evaluate the effects of RAPA conversion in patients undergoing cyclosporine (CsA) or tacrolimus (Tac) toxicity.. Twenty renal transplant recipients were switched to fixed dose rapamycin (RAPA) (5 mg/day) 0 to 204 months posttransplant. Drug monitoring was not initially used to adjust doses. The indications for switch were chronic CsA or Tac nephrotoxicity (12), acute CsA or Tac toxicity (3), severe facial dysmorphism (2), posttransplant lymphoproliferative disorder (PTLD) in remission (2), and hepatotoxicity in 1. Follow-up is 7 to 24 months.. In the 12 patients switched because of chronic nephrotoxicity there was a significant decrease in serum creatinine [233+/-34 to 210+/-56 micromol/liter (P<0.05) at 6 months]. Facial dysmorphism improved in two patients. No relapse of PTLD was observed. Five patients developed pneumonia (two Pneumocystis carinii pneumonia, one infectious mononucleosis with polyclonal PTLD lung infiltrate) and two had bronchiolitis obliterans. There were no deaths. RAPA was discontinued in four patients, because of pneumonia in two, PTLD in one, and oral aphtous ulcers in one. RAPA levels were high (>15 ng/ml) in 7 of 13 (54%) patients.. RAPA conversion provides adequate immunosuppression to enable CsA withdrawal. However, when converting patients to RAPA drug levels should be monitored to avoid over-immunosuppression and adequate antiviral and Pneumocystis carinii pneumonia prophylaxis should be given.

Topics: Adult; Blood Pressure; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Pneumonia; Sirolimus; Tacrolimus