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)

Even though blood transfusion-associated immunomodulatory effects have been reported, the basic immune mechanism is still not understood. Data from studies on the clinical effects of allogeneic blood-induced immunosuppression are contradictory. However, there are indications that autologous blood transfusion is not immunologically neutral but has intrinsic immunomodulatory potential. Therefore we investigated in vivo different immunological mediators in 56 randomized patients of a study comparing autologous and allogeneic blood transfusion in colorectal cancer surgery. Soluble IL-2 receptor, which is an indicator of general immune activation and the following immunologic refractory phase, indicated immunosuppression was more elevated at the seventh postoperative day in patients with allogeneic transfusions (p = .013) and autologous transfusions (p = .0003). The immunologic determination of TNF-alpha showed a significant postoperative increase in patients with autologous transfusions only (p = .0031). However, postoperative increase of soluble TNF-receptors p55 and p75 was also significant in patients transfused with allogenic blood (p = .022; p = .0014). The response to tetanus toxoid vaccination, an indicator of humoral immunity, was higher in patients transfused with allogeneic rather than autologous blood (p = .082), whereas responses of patients with autologous transfusions were even lower than in nontransfused patients. The reciprocal was already found for cell-mediated immunity determined by epicutaneously tested delayed-type hypersensitivity-reactions. IL-10 levels, an indicator of cellular immunosuppression, were determined in 27 additional patients before operation, immediately postoperative, and at the seventh postoperative day. IL-10 was found elevated immediately postoperative in allogeneic (p = .011) and nontransfused patients only (p = .042). The data from this study substantiate recent findings of a different immunomodulatory potential of allogeneic and autologous blood transfusion. They furthermore support the hypothesis that autologous blood transfusion does not contain immunologically neutral effects of allogeneic blood, but itself exerts an immunomodulatory effect.
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PMID:Modulation of immune response by blood transfusion: evidence for a differential effect of allogeneic and autologous blood in colorectal cancer surgery. 942 52

The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and possible antitumor activity of a ligand fusion-protein, DAB389IL-2, in a phase I trial. This was a multicenter, open-label, dose-escalation trial. Patients with preserved organ function and histologically confirmed relapsed cutaneous T-cell lymphoma (CTCL), other non-Hodgkin's lymphomas (NHL), or Hodgkin's disease (HD) were eligible if their cancer was shown to express the interleukin (IL)-2 receptor by an immunohistochemical assay for the p55 or the p75 subunit. Patients received up to eight courses of DAB389IL-2 given as a short intravenous infusion daily for 5 days with subsequent courses every 21 days. The maximum tolerated dose (MTD) and tumor response was determined according to standard criteria. Seventy-three patients (44 men/29 women), aged 16 to 81 years (mean, 50.7) with CTCL (n = 35), NHL (n = 17), and HD (n = 21) were enrolled. The patients were extensively treated, failing 0 to 15 previous therapies (median, 4). Patients received one to six courses (mean, 3.3) of DAB389IL-2 over a range of 3 to 31 micrograms/kg/day. The dose-limiting toxicity was asthenia, establishing the maximum tolerated dose of 27 micrograms/kg/day. Approximately half of all patients had significant titers of antibody to diphtheria toxin or to DAB389IL-2 at the time of enrollment compared with 92% with titers at the end of treatment. The presence of antibody did not preclude clinical response. There were five complete (CR) and eight partial (PR) remissions in patients with CTCL with one CR and two PR occurring in NHL. The median time to response was 2 months and the duration of response was 2 to 39+ months. No responses were documented in patients with HD. DAB389IL-2 is well tolerated with an MTD of 27 micrograms/kg/day. This ligand fusion-protein showed antitumor effects in patients with IL-2 receptor expressing CTCL and NHL. Additional trials in these diseases are warranted.
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PMID:Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. 942 92

It has been hypothesized that the immune system plays a pathogenetic role in psychiatric disorders, in particular in major depression and schizophrenia. This hypothesis is supported by a number of reports on altered circulating levels and in vitro production of cytokines in these disorders. However, the respective evidence is not consistent. This may be in part due to an incomplete control for numerous confounding influences in earlier studies. We investigated the plasma levels of cytokines and soluble cytokine receptors in psychiatric patients (N = 361) upon hospital admission and compared the results to those obtained in healthy controls (N = 64). By multiple regression analysis we found that circulating levels of interleukin-1 receptor antagonist (IL-1Ra), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R p55, sTNF-R p75) and IL-6 were significantly affected by age, the body mass index (BMI), gender, smoking habits, ongoing or recent infectious diseases, or prior medication. Cytokine or cytokine receptor levels were significantly increased in patients treated with clozapine (sIL-2R, sTNF-R p75), lithium (TNF-alpha, sTNF-R p75, IL-6) or benzodiazepines (TNF-alpha, sTNF-R p75). Taking all these confounding factors into account, we found no evidence for disease-related alterations in the levels of IL-1Ra, sIL-2R, sTNF-R p75 and IL-6, whereas levels of TNF-alpha and sTNF-R p55 in major depression and sTNF-R p55 in schizophrenia were slightly decreased compared to healthy controls. We conclude that, if confounding factors are carefully taken into account, plasma levels of the above mentioned cytokines and cytokine receptors yield little, if any, evidence for immunopathology in schizophrenia or major depression.
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PMID:Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. 1050 9

Previously the authors showed that interleukin-4 (IL-4), used in combination with IL-2, increases the reduced proliferation rate of T cells of glioblastoma-bearing patients after in vitro autologous immunization. In this report, they sought to determine whether this effect is caused by a direct mitogenic effect of IL-4, or rather by an indirect effect through an increased expression of the IL-2 receptor subunits or an enhanced recruitment of responsive cells. Flow cytometric analysis confirmed that the IL-2 receptor subunits are less expressed on circulating T cells from patients with glioblastoma than on those from healthy donors. Because no significant modification of the expression of the p55 and p75 subunits of the IL-2 receptor is observed in cultures treated with both IL-2 and IL-4, the reported enhanced proliferation rate cannot be attributed to an increased level of IL-2 receptor expression. Limiting dilution assays, using autologous target cell immunization, show that treatment with both cytokines (IL-2 plus IL-4) significantly increases the number of recruitable precursor cells without affecting their proliferation rate. These results indicate that IL-4 facilitates an immune response against the autologous tumor cells in glioblastoma-bearing patients by increasing the recruitable precursor T-cell frequency.
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PMID:Interleukin-4 enhances the in vitro precursor cell recruitment for tumor-specific T lymphocytes in patients with glioblastoma. 1068 33

A 46-year-old woman with a previous diagnosis of sarcoidosis presented with morphologically typical large granular lymphocyte (LGL) leukemia/lymphoma with an aggressive clinical course. Epstein-Barr virus DNA was detected in peripheral blood mononuclear cells by PCR. The phenotype was typical of the T cell lineage (CD2+ CD3+ CD5+ CD7+ CD8+ TCRalphabeta+) but with the absence of the CD16, CD56, CD57 NK cell markers. In addition, the LGLs expressed CD122 (p75) in the absence of CD25 which is characteristic of LGLs. These leukemic LGLs did not exhibit NK activity. The clonal nature of this proliferation was demonstrated by the rearrangement of the TCRgamma gene. This phenotypically unusual but morphologically typical LGL leukemia/lymphoma may represent the clonal expansion of a minor normal subset of T-LGLs which do not express any NK cell markers, probably corresponding to in vivo activated T cells.
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PMID:Aggressive variant of morphologically typical T large granular lymphocyte leukemia/lymphoma lacking NK cell markers. 1115 85

Genetic engineering has led to the development of fusion protein toxins, which are targeted effector molecules that combine a targeting ligand such as a growth factor with a cytocidal moiety such as a plant or bacterial toxin. The first genetically constructed family of fusion proteins used diphtheria toxin as the toxophore for receptor-binding domain substitution. Diphtheria toxin consists of three domains: an enzymatically active adenosine diphosphate (ADP) ribosyltransferase domain, a hydrophobic transmembrane domain, and a C-terminal receptor-binding domain. Introduction of the enzymatically active domain into the cytosol via receptor-mediated endocytosis results in inhibition of protein synthesis by ADP ribosylation of elongation-factor 2. DAB(486)IL-2, in which the native receptor-binding domain of diphtheria toxin was replaced with the full-length interleukin-2 (IL-2) gene, was capable of intoxicating high-affinity IL-2 receptor-bearing cells in vitro with an IC(50) of 10(-10) M; whereas, cells lacking the full component of the high-affinity IL-2 receptor (p55, p75, p64) were relatively resistant (IC(50) of 10(-8) M). Because of a short in vivo half-life of DAB(486)IL-2, efforts to reengineer the molecule were undertaken, leading to the DAB(389)IL-2 construct, which had a twofold to threefold higher Kd than DAB(486)IL-2 and a longer half-life, resulting in a tenfold increase in potency. Thus far, the clinical activity of both IL-2 chimeric fusion toxins has been similar, with the DAB(389)IL-2 molecule displaying more favorable pharmacokinetics.
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PMID:DAB(389)IL-2 (denileukin diftitox, ONTAK): a new fusion protein technology. 1170 60

IL-16 is a multi-functional cytokine that uses CD4 as a receptor to signal diverse biological activities by target cells including T-lymphocytes, monocytes and eosinophils. IL-16 has been shown to repress HIV-1 infection in lymphocytes and monocytic cells and it is active against both laboratory and naturally acquired virus isolates. In lymphocytes, the repressive effect of IL-16 occurs at the level of virus transcription, while it appears to inhibit viral entry in monocytic cells. Clinical studies comparing serum IL-16 levels with the state of HIV-1 disease suggest that this cytokine is a functionally significant endogenous antiviral factor. The antiviral activity of IL-16 may be of therapeutic benefit in HIV/AIDS but its greatest potential is for immune reconstitution. Stimulation of CD4+ T-cells with IL-16 primes cells to respond to IL-2, by upregulating the expression of IL-2 receptor p75 (CD25). Co-treatment of peripheral blood mononuclear cells (PBMC) with IL-16 plus IL-2 (or IL-15) in vitro selectively expands the population of CD4+ T-cells. Clinical trials of recombinant IL-2 have already shown promise in HIV/AIDS. In combination with IL-16, the beneficial effects of IL-2 may be augmented and specifically targeted to CD4+ T-cells. Thus, IL-16 shows considerable promise as an agent for the biological therapy of HIV/AIDS.
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PMID:Prospects for IL-16 in the treatment of AIDS. 1172 16

DAB(389)IL-2 (ONTAK) is a fusion protein consisting of the ADP-ribosyltransferase and membrane translocating domains of native diphtheria toxin and the full-length sequence for interleukin-2 (IL-2) gene. In vitro data demonstrates that DAB(389)IL-2 is cytotoxic to cells expressing the high affinity IL-2 receptor (IL-2R). In Phases I and II clinical trials of patients whose tumor cells express a component of the IL-2R, the response rates were 18% for B-cell non-Hodgkin lymphoma (NHL) and 30% for cutaneous T-cell lymphoma (CTCL). In this study, we examined the effects of arginine butyrate on IL-2R expression and susceptibility of leukemia cells to intoxication by DAB(389)IL-2. We demonstrate that the p75 subunit of the IL-2R (IL-2Rbeta) is upregulated in the presence of low concentrations of arginine butyrate (0.06mM) which had no direct growth inhibitory effect on the cells. To explore mechanisms of this upregulation, we examined the effect of 0.06mM arginine butyrate on relevant transcriptional elements and on histone deacetylase and found activation of cAMP response element (CRE) but not NFAT or NFKB, as well as inhibition of histone deacetylase (HDAC). Our results suggest that the effects of physiologically achievable concentrations of butyrate on IL-2R expression could be exploited to enhance the susceptibility of intermediate and low-affinity IL-2R expressing leukemia cells to DAB(389)IL-2.
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PMID:Arginine butyrate increases the cytotoxicity of DAB(389)IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rbeta gene. 1244 77

The goal of this study was to determine the relationship among lipid concentrations, cytokine concentrations, and clinical outcomes of burn patients. Twenty-eight patients admitted within 24 hours of burn injury, segregated based on burn size, had blood samples drawn 24 and 48 hours after burn injury and then weekly for 3 weeks. Measurements included total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, interleukin (IL)-6, soluble IL-2 receptor, and soluble necrosis factor p55 and p75 receptors. Infection, length of stay (LOS), and survival were monitored. Cholesterol and lipoprotein concentrations decreased by at least 40% in patients with burns >20% total body surface area and inversely correlated with IL-6. Lower cholesterol and higher IL-6 values correlated with higher infection rates and longer LOS. IL-6 was the strongest predictor for LOS. In conclusion, outcomes after burn injury are related to low cholesterol and elevated IL-6 levels.
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PMID:Cholesterol and interleukin-6 concentrations relate to outcomes in burn-injured patients. 1279 32

Denileukin diftitox, a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin-2 (IL-2), efficiently targets lymphoma cells expressing the high-affinity IL-2 receptor (IL-2R) consisting of the alpha/p55/CD25, beta/p75/CD122, and gamma/p64/CD132 chains. In vitro studies demonstrated that the retinoid X receptor (RXR) retinoid, bexarotene, at biologically relevant concentrations of 10(-6) M to 10(-8) M, upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox. To determine whether this biomodulatory effect could be recapitulated in vivo, we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene (75 mg/day-300 mg/day) and denileukin diftitox (18 mcg/kg per day x 3 days every 21 days) in a phase 1 trial. Overall response was 67% (4 complete responses, 4 partial responses). Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day. Four patients experienced grade 2 or 3 leukopenia, and 2 had grade 4 lymphopenia. Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses (150 mg/day) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells.
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PMID:A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. 1581 59


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