Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immune status of thirteen living and related kidney transplant recipients with stable allografts were examined. The immunological assays consisted of a mixed lymphocyte reaction (MLR), cell-mediated lympholysis (CML) assay, interleukin-2 (IL-2) production in mixed lymphocytes culture (MLC) and IL-2 receptor (IL-2 R) expression on MLC cells. The suppression rates of the monoclonal antibodies (mAbs) against IL-2 R were tested on MLRs. The stimulation indices (SI) of the MLR against both donor and third-party cells increased compared with those of pretransplantation. The MLC responder cells stimulated by donor cells produced detectable amounts of IL-2, these amounts were lower than those by third-party cells. The MLC cells against donor cells expressed IL-2 R alpha and beta chains to the same degree as those against third-party cells. Anti-IL-2 R mAbs equally inhibited the MLRs between recipient and donor or third-party cells. Cytotoxic T lymphocytes (CTL) against donor cells were not generated, even with the addition of recombinant IL-2 in any of recipients except one, while anti-donor CTL had been detected prior to transplantation and the CTL against third-party cells were induced in posttranspalnt CML assays. These results indicate that the clonal anergy phenomenon might mediate the specific CTL unresponsiveness observed in kidney transplant recipients and the anergy phenomenon might serve in the long-term acceptance of allograft.
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PMID:Analysis of the immune status in the recipients with long-term well-functioning kidneys allografts. 1124 75

CIA in the rhesus monkey is an autoimmune-based polyarthritis with inflammation and erosion of synovial joints that shares various features with human rheumatoid arthritis (RA). The close phylogenetic relationship between man and rhesus monkey makes the model very suitable for preclinical safety and efficacy testing of new therapeutics with exclusive reactivity in primates. In this study we have investigated the prophylactic and therapeutic effects of a humanized monoclonal antibody (Daclizumab) against the alpha-chain of the IL-2 receptor (CD25). When Daclizumab treatment was started well after immunization but before the expected onset of CIA a significant reduction of joint-inflammation and joint-erosion was observed. A therapeutic treatment, initiated as soon as the first clinical signs of CIA were observed, proved also effective since joint-degradation was abrogated. The results of this study indicate that Daclizumab has clinical potential for the treatment of RA during periods of active inflammation and suppression of the destruction of the joint tissues.
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PMID:Prophylactic and therapeutic effects of a humanized monoclonal antibody against the IL-2 receptor (DACLIZUMAB) on collagen-induced arthritis (CIA) in rhesus monkeys. 1135 52

Epidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal blistering disease characterized by IgG anti-basement membrane autoantibodies to collagen VII. Since autoantibody formation in EBA patients is thought to be T-cell-dependent, the degree of T cell activation in three patients (all males, ages 33-44 years) was assessed by quantitation of soluble Tac, a fragment of the alpha-subunit of the high-affinity IL-2 receptor (CD25). Soluble Tac levels in all patients were elevated [highest random values, 2430, 920, and 560 IU/ml (normal range, 112-502)]. Based on such findings, these patients were treated with the humanized murine monoclonal anti-Tac antibody daclizumab (1 mg/kg, 6-12 iv treatments at 2- to 4-week intervals). All patients had a significant, rapid, and persistent decrease in lymphocyte CD25 expression. Though a moderate decrease in lymphocyte expression of 7G7, an IL-2 receptor epitope not bound by daclizumab, was noted, stable levels of CD3 cells and in vitro saturation studies indicated that daclizumab effectively bound CD25 and did not promote clearance of such cells from peripheral blood. There were no complications and no patient developed antibodies against daclizumab. While no apparent clinical benefit was seen in two patients with dermolytic disease, one patient with inflammatory EBA had a favorable response. While on daclizumab, this patient stopped prednisone, significantly reduced dapsone, and improved clinically. Furthermore, his disease flared when treatment was stopped, and resumption of daclizumab again effected improvement within 2 weeks. Daclizumab therapy is safe and well tolerated in EBA patients. It may be effective as a corticosteroid sparing agent in patients with inflammatory EBA.
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PMID:Treatment of epidermolysis bullosa acquisita with the humanized anti-Tac mAb daclizumab. 1168 73

This article focuses on the recent dramatic advances in the applications of monoclonal antibody therapy to hematopoietic and neoplastic disease. The increase in the understanding of the role of growth factors and their receptors in the pathogenesis of malignancy and other undesirable hematological events taken in conjunction with the ability to produce humanized chimeric monoclonal antibodies to these targets is providing a new perspective for the treatment of leukemia, lymphoma and breast cancer, autoimmune disease and for prevention of ischemic complications. Dr. Waldmann describes approaches targeting the Her2/neu and the II-2/IL-15 receptor systems. The Her2/neu receptor is overexpressed in select breast, ovarian, gastric and pancreatic neoplasms. The use of trastuzumab (Herceptin) in the treatment of patients with breast cancer whose tumors overexpress this receptor are reviewed. The IL-2 receptor (Tac) is expressed on select malignant cells (adult T cell leukemia, hairy cell leukemia) and activated T cells involved in autoimmune disease and organ rejection. Humanized anti-Tac alone (daclizumab, Zenapax) or armed with toxins or radionuclides have been used successfully in the treatment of leukemia. Dr. Levy updates the experience with rituximab targeting CD20 on B cell lymphomas and reviews the antibodies to CD3, CD22, CD33, CD52, HLA-DR beta chain and HLA-D currently in or proposed for clinical trials, including radiolabelled antibodies. In the last section, Dr. Coller reviews the therapeutic results achieved with abciximab (ReoPro), an antagonist of platelet receptor GPIIbIIIa for the prevention of restenosis in percutaneous coronary interventions and the treatment of unstable angina. The mechanism of action, pharmacology and safety and efficacy of abciximab are reviewed.
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PMID:Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy. 1170 53

Tacrolimus inhibits lymphocyte responses by blocking calcium-dependent signalling pathways important in IL-2 generation. Daclizumab, a humanized monoclonal antibody, binds with high affinity to the Tac subunit of the IL-2 receptor complex. We reasoned therefore that the absence of IL-2R should permit lower doses of tacrolimus and thereby less toxicity. Twenty-eight patients were randomized and followed for 6 months: Group 1, high dose (HD) tacrolimus (trough 12-17 ng/mL; n = 13); Group 2, low dose (LD) tacrolimus (trough 5-10 ng/mL; n = 15). All patients received daclizumab induction (2 mg/kg) on days 0 and 14, mycophenolate mofetil (2 g/d except for one patient who received 1 g) and rapid prednisone taper. Serious infections were minimal in both groups. Hospitalizations, for various reasons, were HD (n = 12) and LD (n = 6). All patients and grafts survived for the 6-month study period. There was one rejection episode in a non-compliant patient at 101 d. LD tacrolimus appears equally effective as HD tacrolimus in preventing rejection episodes and may be associated with fewer adverse events.
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PMID:Daclizumab induction/tacrolimus sparing: a randomized prospective trial in renal transplantation. 1237 41

Daclizumab and basiliximab, the antibodies to the interleukin-2 receptor (anti-IL-2R), decrease the incidence of acute rejection in renal transplantation. However, prolonged blockade of IL-2 receptor (IL-2R:CD25) may hamper apoptosis of reactive T-cell clones and thus may obstruct tolerance induction. We determined the effect of varying doses of anti-IL-2R on the number of CD3+CD25+ cells as an index of CD 25 blockade. The number of CD3+CD25+ cells was determined in four groups of induction therapies: no antibody induction; two doses of 50 or 25 mg daclizumab on day 0 and day 14; and two doses of 20 mg basiliximab at day 0 and day 4 (n=10, 24, 10, and 10, respectively). The number of CD3+CD25+ cells were monitored in whole blood before antibody infusion as well as 24 hours thereafter and weekly after transplantation. With two doses of 50 mg daclizumab, two doses of 25 mg daclizumab, and two doses of 20 mg basiliximab, the expression of CD3+CD25+ cells was completely suppressed for 12, 10, and 12 weeks posttransplantation, respectively. The reappearance of CD3+CD25+ cells above the baseline for each induction regimen was: 17 weeks for two doses of 50 mg daclizumab, 11 weeks for two doses of 25 mg daclizumab, and 13 weeks for two doses of 20 mg basiliximab. Monitoring of CD3+CD25+ cells may be utilized to tailor anti-IL-2R administration at a minimal dosage, yet retaining adequate IL-2R blockade for at least 3 months posttransplantation.
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PMID:Monitoring of T-cell subsets in patients treated with anti-CD 25 antibody. 1504 94

The last two decades have witnessed significant advances in the renal transplantation immunosuppressive protocols. The introduction of mycophenolate mofetil, tacrolimus, sirolimus and polyclonal antibodies has significantly improved graft survival. However, intensification of immunosuppression results in complications such as malignant diseases, opportunistic infections and metabolic disturbances with consequential increase in cardiovascular mortality. Advances in molecular engineering have made possible the development of monoclonal humanized or chimeric antibodies, which will not induce the host immune response with production of neutralizing antibodies or serum sickness. Antibodies directed against the alpha chain of human IL-2 receptor have recently been introduced into immunosuppressive protocols. Daclizumab is a humanized antibody, and basiliximab is a chimeric antibody, engineered by cloning segments of the murine immunoglobulin sequence into the human-immunoglobulin gene. It decreases immunogenicity while maintaining high specificity for IL-2R alpha chain. The efficacy and safety of both preparations have been reported in large randomized studies. Their use in induction resulted in a significant decrease in acute graft rejections after renal transplantation. The possibility of decreasing the dose or complete withdrawal of certain immunosuppressive agents with the use of IL-2R blockers seems promising for further improvement in the longterm graft survival. Longterm follow-up is necessary to determine their role in solid organ transplantation.
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PMID:[Interleukin-2 receptor blockers in renal transplantation]. 1575 6

Daclizumab, a humanized IL-2 receptor antagonist, has been found to be safe and effective in adults with refractory graft-versus-host disease (GVHD); however, data describing its efficacy for refractory GVHD in children are limited. We report a series of 14 children who were treated with daclizumab for severe acute and/or chronic corticosteroid refractory GVHD. Patients were treated with 2 mg/kg weekly for 8 weeks followed by 1 mg/kg weekly for 4 weeks. Nine of 14 patients responded to daclizumab as measured by improvement of GVHD symptoms, and the ability to substantially wean corticosteroid dose. Five of 11 patients with acute GVHD had complete symptom resolution, and 2/11 had a partial response. Two of four patients with chronic GVHD had complete symptom resolution. In these patients, daclizumab was only effective in treating skin GVHD. Seven of the nine patients who had a complete or partial response eventually had recurrence of GVHD; however, the GVHD was less severe and no longer corticosteroid refractory. There was no infusional toxicity, and no infections that could be attributable to the drug. Daclizumab is a relatively safe and effective medication for corticosteroid refractory GVHD in children and larger studies are needed to evaluate its role in treatment.
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PMID:Daclizumab for children with corticosteroid refractory graft-versus-host disease. 1624 17

Twenty-five years ago, we reported the production of the monoclonal antibody, anti-Tac that identifies the IL-2 receptor alpha subunit and blocks the interaction of IL-2 with this growth factor receptor. In 1997, daclizumab (Zenapax), the humanized form of this antibody, was approved by the FDA for use in the prevention of renal allograft rejection. In addition, we demonstrated that daclizumab is of value in the treatment of patients with noninfectious uveitis, multiple sclerosis, and the neurological disease human T-cell lymphotropic virus I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Others demonstrated therapeutic efficacy with daclizumab in patients with pure red cell aplasia, aplastic anemia, and psoriasis. Thus, translation of basic insights concerning the IL-2/IL-2 receptor system obtained using the monoclonal antibody daclizumab provided a useful strategy for the prevention of organ allograft rejection and the treatment of patients with select autoimmune diseases or T-cell leukemia/lymphoma.
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PMID:Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: a 25-year personal odyssey. 1721 65

Daclizumab (Zenapax) identifies the alpha subunit of the interleukin-2 (IL-2) receptor and blocks the interaction of this cytokine with its growth factor receptor. The scientific basis for the choice of the IL-2 receptor alpha subunit as a target for monoclonal antibody-mediated therapy of leukemia/lymphoma is that very few normal cells express IL-2R alpha, whereas the abnormal T cells in patients with an array of lymphoid malignancies express this receptor. In 1997, daclizumab was approved by the FDA for use in the prevention of renal allograft rejection. In addition, anti-Tac provided effective therapy for select patients with T-cell malignancies and an array of inflammatory autoimmune disorders. Finally, therapy with this antibody armed with (90)Y has led to clinical responses in the majority of patients with adult T-cell leukemia. These insights concerning the IL-2/IL-2 receptor system facilitated the development of effective daclizumab antibody therapy for select patients with leukemia/lymphoma.
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PMID:Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma. 1753 23


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