Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CAMPATH-1 (CD52) antigen is a 21-28 kDa glycopeptide which is highly expressed on lymphocytes and macrophages and is coupled to the membrane by a glycosylphosphatidylinositol (GPI) anchoring structure. The function of this molecule is unknown. However, it is an extremely good target for complement-mediated attack and antibody-mediated cellular cytotoxicity. The humanized CAMPATH-1H antibody, which is directed against CD52, is very efficient at mediating lymphocyte depletion in vivo, and is currently being used in clinical trials for lymphoid malignancy and rheumatoid arthritis. It is therefore important to examine the functional effects of this antibody on different lymphocyte sub-populations. Because several other GPI-linked molecules expressed on the surface of T lymphocytes are capable of signal transduction resulting in cell proliferation, we have investigated whether the CAMPATH-1 antigen can also mediate these effects. In the presence of phorbol esters and cross-linking anti-Ig antibodies, mAbs specific for CD52 induced proliferation and lymphokine production in highly purified resting CD4+ and CD8+ T lymphocytes. The rat IgG2c YTH 361.10 anti-CD52 antibody, however, was able to activate resting CD4+ and CD8+ T cells directly without cross-linking or phorbol myristate acetate in the absence of Fc-bearing cells. Anti-CD52 antibodies also augmented the anti-CD3 mediated proliferative response of CD4+ and CD8+ T cells when the two antibodies were co-immobilized onto the same surface or cross-linked in solution by the same second antibody. Both CD4+ CD45RA and CD4+ CD45RO T cells were stimulated to proliferate by anti-CD52 antibodies in the presence of appropriate co-stimulatory factors. Anti-CD52 mAbs did not, however, synergize with anti-CD2 or CD28 mAb to induce CD4+ T cell proliferation. The activation of CD4+ T cells by anti-CD52 antibodies was inhibited by cyclosporin A, suggesting a role for the calcineurin-dependent signal transduction pathways. Although CD52 could transduce a signal in T cells, anti-CD52 antibodies did not inhibit antigen-specific or polyclonal T cell responses, suggesting this molecule does not play an essential co-stimulatory role in normal T cell activation.
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PMID:Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lymphocytes. 771 16

Type 1 diabetes mellitus affects about 1 in 300 people in North America and Europe. Epidemiological studies indicate that the incidence and thus prevalence of type 1 diabetes is rising worldwide. Intervention in autoimmune type 1a diabetes could occur at the time of diagnosis or, preferably, prior to clinical presentation during the 'prediabetic' period (e.g. prevention). Prediabetes is best recognised by the detection of islet autoantibodies in the serum. Promising intervention strategies include monoclonal antibody therapies (e.g. anti-CD3, anti-CD25, anti-CD52 or anti-CD20 monoclonal antibodies), immunosuppression (e.g. calcineurin inhibitors, B7 blockade, glucocorticoids, sirolimus (rapamycin), azathioprine or mycophenolate mofetil), immunomodulatory therapies (e.g. plasmapheresis, intravenous immunoglobulin, cytokine administration, adoptive cellular gene therapy) and tolerisation interventions (e.g. autoantigen administration or avoidance, altered peptide ligand or peptide-based therapies). To date, islet and pancreas transplantation have essentially been reserved for patients with long-standing diabetes who have complications and are also in need of a concurrent kidney transplant. None of the therapies attempted to date has produced long-term remissions in new-onset type 1 diabetes patients and no therapies have been shown to prevent the disease. Nevertheless, with advances in our understanding of basic immunology and the cellular and molecular mechanisms of tolerance induction and maintenance, successful intervention therapies will be developed. The balance between safety and efficacy is critical. Higher rates of adverse events might be more tolerable in new-onset type 1 diabetes patients if the therapy is extremely effective at inducing a permanent remission. However, therapies must not harm the beta-cells themselves or any organ system that is a potential target of diabetes complications, such as the nervous system, retina, cardiovascular system or kidney. In the treatment of prediabetes, successful therapies should provide a level of safety similar to that of currently used vaccines and a high level of efficacy.
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PMID:Prevention strategies for type 1 diabetes mellitus: current status and future directions. 1253 19

A decade of spectacular innovation in maintenance immunosuppression drugs has resulted in dramatic reductions in acute rejection and improvement in short and long term outcome after renal transplantation. However the new drugs continue to lack specificity, many require frequent therapeutic drug monitoring and all are associated with acute and chronic toxicities. The new biologic agents, monoclonal antibodies (chimeric, humanized, and fully human) and receptor-fusion proteins, lack immunogenicity, have long half-life and prolonged biologic effects, require intermittent administration and have minimal toxicity. The specificity and selectively of the targets of the new biologic agents render them less toxic than the oral maintenance drugs and thus could possibly replace the maintenance drugs most associated with long-term toxicity such as the corticosteroids and the calcineurin inhibitors. The recently introduced anti-interleukin 2 receptor (IL-2R) monoclonal antibodies (mAbs) are the prototype of future biologic agents; selective, safe, and inducing prolonged biologic effects. The IL-2R mAbs have been used with a variety of maintenance immunosuppression regimens double therapy with cyclosporine and prednisone, triple therapy with cyclosporine, azathioprine and prednisone and with newer regimens such as cyclosporine or tacrolimus, mycophenolate mofetil (MMF) and prednisone, and most recently with sirolimus, MMF and prednisone. The major thrust of the new biologics in clinical development is to block the co-stimulatory pathway. The first attempt at blockade of the CD40-CD154 with anti-CD154 mAbs was disappointing. Anti-CD 154 therapy was associated with thromboembolic events and acute rejection. Attempts at blocking the CD28-B7s (CD80-CD86) pathway are currently underway with the receptor fusion protein, LEA29Y a second generation CTL4Aig, and humanized mAbs to CD 80 and CD86. LFA1, an adhesion molecule that also participates in the co-stimulatory pathway, has also been targeted with a mAb that binds to the CD11a chain of LFA1. Efalizumab, a humanized anti-CD11a mAb, was shown in a phase I trial to be potentially effective in renal transplantation. A humanized anti-CD45 RB mAb is currently in pre-clinical studies and will likely be tested in a phase I trial of renal transplantation within 1 year. While excellent results with anti-CD45 RB mAbs have been published in experimental transplantation, the mechanism of action of anti-CD45 RB mAbs remains to be determined. Several antibodies that are currently approved for non-transplant indications are currently used in single center clinical trials in renal transplantation including Campath 1 H, a humanized anti-CD52 mAb, Rituxamab, an anti-CD20 chimeric mAb, and Infliximab an anti-TNFa chimeric mAb. In addition, several humanized mutagenized anti-CD3 mAbs, huOKT3g1, aglycosyl CD3 and HuM291 have been used in limited trials in renal transplantation but have yet to have a formal clinical development. Humanized mAbs and receptor fusion proteins offer the potential of providing renal transplant recipients with a novel algorithm for immunosuppression that relies on chronic intermittent intravenous administration of safe, non-toxic agents replacing oral drug therapy maintenance.
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PMID:New monoclonal antibodies in renal transplantation. 1277 67

Campath-1H is a humanized, monoclonal antibody directed against CD52 determinants on the surface of human B- and T-cells and monocytes. Reports of Campath-1H use as induction in adult renal transplantation have been encouraging with low rejection rates and minimal adverse events. We report four high risk pediatric kidney transplant patients who received Campath-1H for unique indications with variable results. Children ranged in age from 20 months to 16 years. Immunosuppression regimens varied. Three of four patients experienced acute rejection, two of which were C4d positive. Serial flow cytometry was performed on all four patients. The patient who received only Campath-1H has an absolute lymphocyte count that remains less than 50% of baseline at 12-months post-transplant. In addition, in this patient CD3, CD4, CD8 and CD20 remain less than 50% of baseline. From this initial experience using Campath-1H in pediatric renal transplantation we conclude that; (1) the use of Campath-1H does not prevent recurrence of FSGS, (2) as seen in adults, lack of calcineurin inhibition when using Campath-1H may increase the risk of antibody-mediated rejection and (3) prolonged lymphocyte depletion remains even after a single dose of Campath-1H in children.
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PMID:Campath-1H use in pediatric renal transplantation. 1588 71

Remarkable advances in understanding the mechanisms of immune recognition and allograft rejection have been made in the past few years, leading to the development of innovative immunosuppressive strategies in the field of renal transplantation. Monoclonal antibodies (mAbs) have emerged as a new class of immunosuppressive agents, which appear to be effective (in both the treatment and the prevention of acute rejection) and well-tolerated in renal transplant recipients. The highly specific effects of these drugs make them less toxic than the oral long-term maintenance agents such as corticosteroids and the calcineurin inhibitors. Some of these mAbs have already confirmed their efficacy in preventing acute rejection in clinical phase III studies, and are now part of the well-established immunosuppressive regimens; these are the anti-CD25 mAbs (basiliximab and daclizumab). Other recently developed mAbs, like anti-CD52 (Campath-1H), anti-CD20 (rituximab), anti-LFA-1, anti-ICAM-1 and anti-tumour necrosis factor (TNF)-alpha (infliximab), are currently being tested, and show encouraging immunosuppressive potential. Blocking either the binding of cell-surface molecules or intracellular signal transduction, these mAbs could become an effective method to promote the holy grail of solid-organ transplantation, antigen-specific tolerance.
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PMID:New immunosuppressive therapies in renal transplantation: monoclonal antibodies. 1629 78

Renal transplantation is the best treatment for end-stage renal disease, but requires efficient immunosuppressive therapy. The latter has evolved over recent years with the development of more powerful drugs and of monoclonal antibodies with very specific target. The first monoclonal antibodies, acting against the interleukin 2 receptor, named basiliximab and daclizumab, have showed an excellent tolerance profile and efficacy to reduce acute graft rejection. However, in spite of these properties, the development of delayed graft function or the graft and patient survivals at 1 year were not modified by the use of such specific treatment. One potential advantage could yet be a decreasing need for corticosteroids and sometimes calcineurin inhibitors which could provide some long term benefits for the renal graft, but also the patient. Alemtuzumab, another monoclonal antibody, aimed at the membrane glycoprotein CD52, can also decrease the incidence of acute rejection and the depth of the required immunosuppressive therapy. Other antibodies are still in development with some interesting preliminary results which however demand confirmation in larger studies.
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PMID:[Monoclonal antibodies in renal transplantation]. 1964 61

The introduction of new immunosuppressive agents into clinical transplantation in the 1990s has resulted in excellent short-term graft survival. Nonetheless, extended long-term graft outcomes have not been achieved due in part to the nephrotoxic effects of calcineurin inhibitors (CNIs) and the adverse effects of steroid on cardiovascular disease risk factors. Induction therapy with lymphocyte depleting antibodies has originally been introduced into renal transplantation to provide intense immunosuppression in the early post-transplant period to prevent allograft rejection. Over the past half decade, induction therapy with both non-lymphocyte depleting (basiliximab and daclizumab) and lymphocyte-depleting antibodies (antithymocyte antibodies, OKT3, alemtuzumab) has increasingly been utilized in steroid or CNI sparing protocols in the early postoperative period. Alemtuzumab is a humanized monoclonal antibody targeted against CD52 on the surface of circulatory mononuclear cells. The ability of alemtuzumab (Campath-1H) to provide rapid and profound depletion of lymphocytes from the peripheral blood has sparked interest in the use of this agent as induction therapy in steroid and/or CNI minimization or avoidance protocols. This article provides an overview of the literature on the evolving role of alemtuzumab in renal transplantation.
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PMID:The evolving role of alemtuzumab (Campath-1H) in renal transplantation. 1992 Sep 20

Induction therapy refers to the initiation of intense immunosuppression in the initial days after transplantation when the recipient's immune system contacts donor antigens for the first time. Induction therapy may also be used to permit delayed initiation of calcineurin inhibitors (CNIs) for maintenance immunosuppression among patients with significant renal failure (RF). The rationale of its use is to provide intensive immunosuppression at the time when the alloimmune response is most intense. In general, induction therapy can be divided into 2 categories: depleting antibodies (eg, polyclonal antibodies [horse or rabbit antithymocyte globulin], anti-CD3 antibodies [OKT3], and human monoclonal anti-CD52 [alentuzumab]) and nondepleting antibodies (eg, anti-CD25 antibodies [daclizumab, basiliximab] or fusion proteins with natural binding properties currently being studied, eg, CTLA4-Ig [belatacept]). The advantages and disadvantages of induction therapy are discussed.
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PMID:Controversies about induction therapy. 2183 91