Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The compound 12-O-tetradecanoylphorbol-13-acetate (TPA) is extremely toxic to the P13 subclone of the Jurkat human T-cell leukemia line. By selecting for growth in the presence of TPA, we have isolated two TPA-resistant variants of these cells, P13-50 and P13-5/A8. Studies of protein kinase C (PKC) enzyme activity, immunoblot analyses, and assays for PKC mRNAs indicate that both of these variants express lower levels of PKC than do the parental P13 cells. We suggest that this protects them from the toxic effects of TPA. The P13-5/A8 cells are of particular interest because not only are they resistant to TPA toxicity but they actually require TPA for optimal growth. These cells have a more profound decrease in PKC expression that do P13-50 cells. In addition, P13-5/A8 cells display very little, if any, surface expression of CD45, a receptor-linked tyrosine protein phosphatase, and lck, a lymphocyte-specific tyrosine kinase. On the other hand, they express a very high level of interleukin-2 receptor. A model is proposed that suggests that these cells are dependent on TPA because they have defects in both the PKC and tyrosine kinase signal transduction pathways, and that TPA compensates for these defects by providing a strong stimulus to the residual level of PKC. This variant may be useful for studying the interactions between tyrosine kinase and PKC pathways in controlling the various functions of T lymphocytes.
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PMID:Altered expression of protein kinase C, lck, and CD45 in a 12-O-tetradecanoylphorbol-13-acetate-dependent leukemic T-cell variant that expresses a high level of interleukin-2 receptor. 153 Aug 79

Many new agents are in or near clinical trials in organ transplantation. The small molecule antibioticlike drugs are inhibitors of key enzymes in T-cell signal transduction (calcineurin target of rapamycin [TOR], and inosine monophosphate dehydrogenase). Calcineurin inhibitors include cyclosporine microemulsion formulation generic cyclosporine preparations, and tacrolimus. Rapamycin (also known as sirolimus) acts on target of rapamycin to abrogate signals necessary for clonal expansion and is now in phase III. Recent trials of mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, have shown that it reduces acute renal graft rejection when used with steroids and cyclosporine. New protein reagents in trials include polyclonal antilymphocyte antibodies, mouse monoclonal antibodies, "humanized" mouse monoclonals, and engineered proteins based on naturally occurring signalling molecules. Humanized antibodies against the interleukin-2 receptor are promising because humanized antibodies should combine low toxicity with the potential for long-term use. Engineered human proteins designed to block costimulatory molecules on antigen-presenting cells could have similar potential for low toxicity and extended use. These agents are designed to reduce acute rejection and the toxicity of the existing drugs and eventually improve long-term patient and graft survival. Organ transplant practice will probably change considerably as these agents become available.
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PMID:Immunosuppressive agents in clinical trials in transplantation. 914 38

From the early 1960s, the mainstay of immunosuppression for kidney transplantation has been corticosteroids. Since then, many new drugs have been developed to maintain the renal allograft. Current maintenance immunosuppression commonly consists of corticosteroids, antiproliferative agents and calcineurin inhibitors (e.g. cyclosporin). More recently, antihuman antibodies, either monoclonal or polyclonal, have been developed to use for induction at the time of transplantation or to treat rejection. With the advances in molecular technology, a new class of antihuman antibodies [the anti-interleukin-2 receptor (IL-2R) antibodies] has emerged that incorporate a murine antigen-binding site on to a human immunoglobulin backbone. Such methodology creates antihuman antibodies with high affinity for the epitope and with prolonged serum antibody half-lives. Interleukin-2 and its receptor are central to lymphocyte activation and are the main targets of calcineurin inhibitors. In addition, the anti-IL-2R antibodies inhibit a key target in immune activation. Daclizumab and basiliximab have been shown to significantly reduce the incidence of acute rejection in kidney transplantation. Since these anti-IL-2R antibodies are well tolerated and since calcineurin inhibitors are intrinsically nephrotoxic, anti-IL-2R antibodies have been used in an attempt to avoid cyclosporin after transplantation. Data from clinical trials seem to indicate that the addition of an anti-IL-2R antibody is not sufficient to warrant complete withdrawal of calcineurin inhibitors for more than a very short period after transplantation. A more promising role for anti-IL-2R antibodies may be in renal transplant recipients with delayed graft function (DGF). Recent data on the use of either low-dose calcineurin inhibitors or sirolimus (rapamycin) in conjunction with the anti-IL-2R antibodies for patients with DGF showed no increased risk of acute rejection. Long-term graft survival with use of these low-dose calcineurin inhibitor protocols has yet to be established.
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PMID:Role of anti-interleukin-2 receptor antibodies in kidney transplantation. 1160 47

The pathogenesis of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is poorly understood, but the cellular immune response is likely to have a major role. Daclizumab, an interleukin-2 receptor (IL-2R) antibody that blunts T-cell activation, leading to a decreased risk for cellular rejection, is used frequently in transplant recipients. The aim of this study is to evaluate the effect of daclizumab therapy on the incidence and severity of recurrent HCV. Forty-one liver transplant recipients (21 patients, HCV positive; 20 patients, HCV negative) at high risk for neurological or renal complications of calcineurin inhibitors were administered daclizumab, mycophenolate mofetil (MMF), and steroids in the early post-LT period, followed by tacrolimus and a steroid taper. All patients were followed up prospectively for graft function and disease recurrence with protocol liver biopsies day 7, month 4, and yearly. Compared with patients without HCV, patients with HCV administered daclizumab had greater 4-month serum alkaline phosphatase, total bilirubin, and alanine aminotransferase (ALT) levels. These biochemical differences resolved by 12 months, except for persistent elevation of ALT levels. Compared with a well-matched HCV control population, patients with HCV administered daclizumab were more likely to have an earlier onset of hepatitis, jaundice, and greater histological activity. Recurrent hepatitis progressed more rapidly in the daclizumab group; 45% developed advanced disease within 1 year. HCV viral load in the daclizumab group was significantly greater at both 4 months and 1 year. Results of this study suggest that the use of adjuvant IL-2R antibodies in combination with MMF in the early peritransplantation period may be associated with early recurrence of hepatitis C and more rapid histological progression of disease.
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PMID:Anti-interleukin-2 receptor therapy in combination with mycophenolate mofetil is associated with more severe hepatitis C recurrence after liver transplantation. 1175 8

Ongoing improvements in immunosuppression and posttransplantation care have dramatically improved patient and graft outcomes after transplantation. The frequency of graft loss due to acute rejection has declined considerably as a result of the availability of a variety of more potent immunosuppressive agents and probably also because of refined clinical care and follow-up. Complications of long-term administration of corticosteroids (steroids) and calcineurin inhibitors, however, have become increasingly apparent as patients live longer with their transplant, and attention is shifting to long-term issues. Use of both steroids and calcineurin inhibitors is associated with metabolic toxicities such as hypertension, hyperlipidemia, diabetes, bone loss, and cataracts. These contribute to posttransplantation morbidity and may negatively affect patient and allograft survival. A variety of troublesome cosmetic side effects, such as hirsutism, gingival hyperplasia, alopecia, obesity, and cushingoid appearance, also are associated with these drugs. These effects can detract from patient self-esteem and compliance with the immunosuppressive regimen. In the past 2 decades, the introduction of second-generation immunosuppressive drugs, such as tacrolimus, mycophenolate mofetil, sirolimus, and anti-interleukin-2 receptor monoclonal antibodies, has provided some alternatives to classic immunosuppressant choices. Patients experiencing undesirable adverse events now can be converted to another immunosuppressive regimen that ultimately will improve graft and patient survival rates and improve quality of life after transplantation.
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PMID:Strategies to reduce toxicities and improve outcomes in renal transplant recipients. 1189 90

NEW KNOWLEDGE: Over the last few years, improved knowledge of the immunological mechanisms underlying transplant rejection have resulted in the development of new immunosuppressive agents capable of selectively blocking various steps of the immune response. NEW MOLECULES: The review focuses on new immunosuppressive drugs that have been developed for clinical use in renal transplantation and mechanism of action, advantages and side effects will be discussed for each of them. Neoral is a cyclosporin microemulsion, characterized by more consistent absorption. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin but presents some differences. Mycophenolate mofetyl selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in large clinical trials. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, their use in transplant therapy remains to be determined. Anti-interleukin-2 receptor antibodies are also reviewed; they are easy to use and have been found effective. NEW STRATEGIES: These new immunosuppressive drugs provide new approaches in transplant therapy to improve their efficacy and safety.
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PMID:[The benefits of new immunosuppressive treatments in adult kidney transplantation]. 1193 40

The risk of acute rejection is at its highest early post-transplant. The use of various antibodies early after transplant achieves potent immunosuppression to prevent acute rejection, allowing the clinician the opportunity to optimise baseline immunosuppressive management and to delay the use of nephrotoxic agents (calcineurin inhibitors), while the graft reaches a baseline function. Basiliximab (Simulect trade mark, Novartis) is a monoclonal antibody that binds specifically to the alpha-subunit of the human high-affinity interleukin-2 receptor (IL-2r) complex, consequently inhibiting interleukin-2 (IL-2) binding. IL-2 receptors are selectively expressed on the surface of the activated lymphocytes. Administration of basiliximab inhibits IL-2 mediated activation of lymphocytes, a critical pathway involved in allograft rejection. Several clinical studies have shown that basiliximab administration as an induction agent significantly reduces the incidence of acute rejection, even in high risk patients. In addition, basiliximab is well-tolerated with minimal side effects.
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PMID:The use of basiliximab in solid organ transplantation. 1243 98

The anti-interleukin-2 receptor (anti-IL-2R) antibody therapy is an exciting approach to the prevention of acute rejection after renal allograft transplantation whereby immunosuppression is exerted by a selective and competitive inhibition of IL-2-induced T cell proliferation, a critical pathway of allorecognition. The anti-IL-2R antibodies specifically block the alpha-subunit of the IL-2R on activated T cells, and prevent T cell proliferation and activation of the effector arms of the immune system. The anti-IL-2R antibodies are used as induction therapy, immediately after renal transplantation, for prevention of acute cellular rejection in children and adults. During acute rejection, the IL-2Ralpha chain is no longer expressed on T cells; thus, the antibodies cannot be used to treat an existing acute rejection. Two anti-IL-2R monoclonal antibodies are currently in clinical use: daclizumab and basiliximab. In placebo-controlled phase III clinical trials in adults, daclizumab and basiliximab in combination with calcineurin inhibitor-based immunosuppression, significantly reduced the incidence of acute rejection and corticosteroid-resistant acute rejection without increasing the risk of infectious or malignant complications, and neither antibody was associated with the cytokine-release syndrome. Children who receive calcineurin inhibitors and corticosteroids for maintenance immunosuppression, as well as children who receive augmented immunosuppression to treat acute rejection, are at increased risk of growth impairment, hypertension, hyperlipidemia, lymphoproliferative disorders, diabetes mellitus, and cosmetic changes. In older children, the cosmetic adverse effects frequently reduce compliance with the treatment, and subsequently increase the risk of allograft loss. Being effective and well tolerated in children, the anti-IL-2R antibodies reduce the need for calcineurin inhibitors while maintaining the overall efficacy of the regimen; thus, the anti-IL-2R antibodies increase the safety margin (less toxicity, fewer adverse effects) of the baseline immunosuppression. Secondly, the anti-IL-2R antibodies decrease the need for corticosteroids and muromonab CD3 (OKT3) in children as a result of decreased incidence of acute rejection. The recommended pediatric dose of daclizumab is 1 mg/kg intravenously every 14 days for five doses, with the first dose administered within 24 hours pre-transplantation. This administration regimen maintains daclizumab levels necessary to completely saturate the IL-2Ralpha (5-10 microg/mL) in children for at least 12 weeks.The recommended pediatric dose of basiliximab for recipients <35 kg is 10 mg, and 20 mg for recipients > or =35 kg, intravenously on days 0 and 4 post-transplantation. This administration regimen maintains basiliximab levels necessary to completely saturate the IL-2Ralpha (>0.2 microg/mL) in children for at least 3 weeks.
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PMID:Anti-interleukin-2 receptor antibodies for the prevention of rejection in pediatric renal transplant patients: current status. 1451 Jun 27

Daclizumab (DZB), an interleukin-2 receptor blocker, has been shown to reduce the rate of acute rejection, while non-heart-beating kidney recipients have high rates of delayed graft function that may be prolonged by high levels of calcineurin inhibitors. This study assessed whether DZB could safely replace calcineurin inhibitors in the immediate postoperative period and promote recovery from ischemic acute tubular necrosis. Patients were randomized into one of two groups: DZB induction and daily mycophenolate mofetil (MMF; 2 g) with steroids (20 mg prednisone) or standard triple therapy with tacrolimus, MMF, and prednisone. Patients in the DZB arm were converted to the control arm when either the serum creatinine dropped to <350 micromol/L or there was biopsy evidence of acute rejection. Over 2 years, Leicester and Newcastle non-heart-beating donor (NHBD) centers recruited 51 patients. There was one patient death in the DZB arm, during the study period, after a nonfunctioning graft was removed. A total of two (8%) grafts in the DZB arm and three (11.5%) grafts in the control arm failed to function. The overall rate of immediate function improved from around 5% (pre-2001) to 28%. There were no significant differences in the incidence of acute rejection or graft function (GFR) at 3 months. Machine-perfused kidneys in DZB-treated recipients had the highest rates of immediate function (53%, P = .015). We found that a calcineurin-sparing regime is safe and may be beneficial for recipients of machine-perfused grafts damaged by warm ischemia.
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PMID:Evaluation of daclizumab to reduce delayed graft function in non-heart-beating renal transplantation: a prospective, randomized trial. 1591 62

Delayed graft function (DGF) occurs in approximately 30% of renal transplant patients, and significantly increases risk of long-term graft loss. This article reviews the potential for use of interleukin-2 receptor (IL-2R) antagonists to reduce the burden of DGF. IL-2R antagonists decrease incidence of acute rejection without increasing risk of cytomegalovirus infection or malignancy, and show equivalent efficacy to lymphocyte-depleting antibody agents in standard risk patients with immediate graft function. The nephrotoxicity associated with calcineurin inhibitors (CNIs) has led to use of delayed or low-dose CNI regimens with induction therapy in patients with DGF. In this setting, use of an IL-2R antagonist with mycophenolate mofetil and steroids with delayed cyclosporine appears to be associated with a low incidence of biopsy-proven rejection and comparable renal function to patients with immediate function. Additionally, there is intriguing evidence to suggests that IL-2R antagonists may reduce risk of DGF occurring. A number of large-scale and smaller studies have reported a trend to reduced incidence of DGF or improved early renal function using IL-2R antagonists compared with placebo, although data are not entirely consistent. In conclusion, the ability of IL-2R antagonists to reduce acute rejection with no additional safety concerns makes them an attractive option for patients with DGF.
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PMID:Use of IL-2 receptor antagonists to reduce delayed graft function following renal transplantation: a review. 1631 13


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