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)

Varying the concentration of anti-CD3 immobilized on Sepharose beads allowed us to study both the inhibitory and the stimulatory effects of IL-4 on purified T cells and contrast IL-4 versus IL-2-driven T-cell proliferative responses. In the presence of low density immobilized anti-CD3, IL-4 was unable to stimulate purified T cells and was inhibitory to IL-2-driven T-cell responses. The inhibitory effects of IL-4 were enhanced by preincubation of T cells with IL-4 prior to stimulation. In contrast, the inhibitory effects of IL-4 could be avoided by delaying the addition of IL-4 until Days 3-5 of culture or they could be reversed by the addition of IL-1. In the presence of high-density anti-CD3, IL-4 elicited an IL-2-independent proliferative response by purified T cells or sorted CD8+ cells. Comparison of IL-4-driven versus IL-2-driven T-cell responses demonstrated that IL-2 was able to upregulate mRNA for IL-4 receptors and interferon-gamma, while IL-4 had minimal effects on upregulating mRNA for either the p55 or the p75 IL-2 receptor subunits or interferon-gamma. The timing of the presence of IL-4, the state of T-cell activation, and the nature and strength of the stimulatory signal influenced the regulatory effect of IL-4 on the immune response.
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PMID:Low versus high density of immobilized anti-CD3 influences IL-4 regulation of T-cell immune responses. 845 80

Mutation of Asp20 in human interleukin-2 (IL-2) to Lys is known to result in an IL-2 molecule with unchanged binding to the p55 subunit of the IL-2 receptor, but with greatly decreased affinity for the p75 subunit (Collins, L., Tsien, W.-H., Seals, C. et al. Proc. Natl. Acad. Sci USA 1988. 85: 7709). Here we demonstrate that Lys20 IL-2 competed with a reduced (10-fold) affinity for high-affinity IL-2 receptors on two murine cell lines HT2 and CTLL. In parallel with this difference in receptor interaction, Lys20 IL-2 stimulated half-maximal HT2 cell proliferation at a 10-fold higher concentration than wild-type IL-2. However, half-maximal stimulation of CTLL cells required a 100-fold higher concentration of Lys20 IL-2. A similar 100-fold reduction in bioactivity of Lys20 IL-2 was observed for primary, activated, human or murine lymphocytes. Anti-p55 antibodies increased the concentration of Lys20 IL-2 required to stimulate HT2 cells to that required for CTLL cells. These data suggest that CTLL cells, while able to bind Lys20 IL-2 with high affinity, are lacking a p55-dependent function necessary for optimal stimulation. Therefore, p55 has a dual role, being important both for high-affinity IL-2 binding and for optimal cell triggering.
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PMID:Mutation of Asp20 of human interleukin-2 reveals a dual role of the p55 alpha chain of the interleukin-2 receptor. 845 77

The effect of dose and schedule of continuous i.v. rIL-2 infusions on leucocyte subset counts, activation status of CD56+CD3- natural killer (NK) and CD3+ T lymphocytes, and cytolytic activities of peripheral blood mononuclear cells (PBMC) was studied. A single 4-day course of rIL-2 in escalating doses (0.9-11.5 x 10(6) U/m2 per day) was given to 18 patients with various types of metastatic cancer. The serum IL-2 concentration during rIL-2 therapy ranged between 23 and 64 U/ml and was proportional to the administered rIL-2 dose, as was the rebound lymphocytosis following therapy. Before therapy, the CD56+CD3- NK cells expressed low levels of the p75 chain of the IL-2 receptor (IL-2R) and virtually no IL-2R(p55). Most CD3+ T cells were IL-2R(p55-,p75-). Between 2 and 4 days following therapy, i.e. at the time of lymphocytosis, the percentage of CD56+,CD3- NK cells among the lymphocytes had increased proportional to the administered rIL-2 dose. The levels of IL-2R(p75) expression by the CD56+,CD3- NK cells had increased. The percentages of CD3+ T cells expressing IL-2R(p55), HLA-DR and CD45RO had increased proportional to the administered rIL-2 dose. The level of lymphokine- activated killer (LAK) activity against Daudi cells was also positively correlated with rIL-2 dose. Subsequently, seven patients received 4-weekly cycles of rIL-2 (2.9-4.4 x 10(6) U/m2 per day) during 4 consecutive weeks. This schedule led to marked increments in lymphocyte and eosinophil counts, and to increased cytolytic activities compared with pretreatment. We conclude that CD56+,CD3- NK and CD3+ T cells are activated differentially by continuous i.v. rIL-2 proportional to dose and duration of treatment.
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PMID:Activation of the immune system of cancer patients by continuous i.v. recombinant IL-2 (rIL-2) therapy is dependent on dose and schedule of rIL-2. 848 6

In this study we have investigated, at the population and the clonal levels, the immunophenotypes and the non-specific cytotoxic functions of peripheral blood lymphocytes from three stage IV neuroblastoma patients receiving treatment with recombinant interleukin-2 (IL-2) and interferon alpha (IFN alpha). Both IL-2 alone and the combination of IL-2 and IFN alpha caused an in vivo expansion of CD56+, CD3- NK cells most of which expressed the p75 molecule, i.e. the beta chain of the IL-2 receptor. Peripheral blood mononuclear cells (PBMC), drawn after treatment, displayed an increased NK activity, but no lymphokine-activated killer (LAK) activity. However, the subsequent in vitro culture of PBMC with high-dose IL-2 induced the generation of a potent LAK activity, which was mediated by an expanded population of CD3+, CD8+ T cells. Finally lymphocytes that had been isolated after cytokine therapy were cloned, in the presence of low-dose phytohemagglutin, immediately or following culture with IL-2. Clones derived from LAK cells expanded in vitro had predominantly a CD3+, CD8+ immunophenotype, whereas those raised from freshly separated lymphocytes were either CD3+, CD4+ or CD3+, CD8+ in equal proportions. Most of the above clones were poorly or not at all cytolytic against NK-sensitive or NK-resistant targets. In contrast, the few NK clones obtained (CD3-, CD56+) lysed all targets with high efficiency.
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PMID:Clonal analysis of peripheral blood lymphocytes from three patients with advanced neuroblastoma receiving recombinant interleukin-2 and interferon alpha. 851 51

We investigated the effects of Il-12 on functional properties of CD3+ CD8+ granular lymphocytes (GL) of of patients with lymphoproliferative disease of granular lymphocytes (LDGL). To this aim, in 10 cases with clonal CD3+ GL proliferation (nine cases with an associated TCR alpha/beta receptor and one case with a TCR gamma/delta receptor) we studied the proliferative and cytotoxic activities of resting and alpha CD3 monoclonal antibody (mAb) activated cells in the presence of rIL-12 and anti-IL-12 blocking antibodies. Specific mRNA for IL-12 p40 subunit was also investigated. Our results showed that rIL-12 increased the proliferation of alpha CD3 pre-stimulated GL (2 to 6 times). Further, anti-IL-12 antibodies partially inhibited alpha CD3-induced cell growth, suggesting a role for this cytokine in the alpha CD3-mediated GL activation. The addition of antibodies blocking the p55 and p75 chains of IL-2 receptor (IL-2R) did not inhibit the rIL-12-mediated cell proliferation, indicating that the activity of rIL-12 is dependent of IL-2 in the in vivo expanded GL of patients under study. Concerning the cytotoxic activity, rIL-12 increased the alpha CD3-mediated NK activity against K-562 target cells and alpha CD3 redirected cytotoxicity against P815 target cells. Molecular analysis pointed out that, following alpha CD3 stimulation, patients' GL increased the expression of specific mRNA for the p40 subunit of IL-12 as compared to baseline conditions. Our data indicate that IL-12 is involved in the mechanisms of activation of clonal CD3+ GL in patients with LDGL; these features are consistent with the possibility that this discrete subset of GL might represent in vivo primed cytotoxic T lymphocytes.
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PMID:IL-12 is involved in the activation of CD3+ granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. 860 90

NK cells can exert potent anti-leukemia activity after either autologous or allogeneic BMT. However, in autologous blood or marrow transplant patients, NK cell number and/or function could be reduced, and also may vary according to the sampling site. In order to evaluate the hypothesis that blood or marrow grafts from autologous transplant patients exhibit impaired NK cell activity that could contribute to disease recurrence, we evaluated the immunologic characteristics of NK cells in the bone marrow (BM) and peripheral blood (PB) from 27 patients undergoing autologous BMT, and also from 20 normal donors. We measured baseline and interleukin-2 (IL-2)-activated NK cell cytotoxicity, as well as expression of IL-2 receptors (IL-2R) (alpha-chain (p55) and beta-chain (p75)), and adhesion molecules. The cytotoxic activity of PB NK cells was significantly lower in autologous transplant patients than in normal donors (P < 0.0005) and this difference was not mitigated following IL-2 activation. In contrast, BM from autologous patients showed normal NK cell cytotoxicity, but contained higher numbers of NK cells (P < 0.025), with more intense CD56 expression (P < 0.05). Expression of p75 was lower on BM than on PB NK cells in both patients and normal donors. In addition, induction of p55 by IL-2 was abrogated in autologous PB NK cells. Therefore, depending on the site of harvest and the nature of donor cells (pre-BMT vs normal), our results show significant differences in NK cell number, function, and IL-2 receptor expression. This may affect relapse rates following autologous transplants performed with either PB or BM grafts.
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PMID:Phenotypic and functional characterization of peripheral blood and bone marrow natural killer cells prior to autologous transplantation. 870 80

The recently cloned cytokine interleukin-15 (IL-15) shares several functional activities with IL-2 in different cell systems. Although IL-15 does not show sequence homology with IL-2, it uses components of the IL-2 receptor (IL-2R) for binding and signal transduction, namely, p75 (beta) and the p64 (gamma) chains of IL-2R. To evaluate whether IL-15 is involved in the activation of granular lymphocytes (GL) in patients with lymphoproliferative disease of granular lymphocytes (LDGL), we evaluated the ability of IL-15 to stimulate GL proliferation, cytotoxic function, and the role of IL-2R beta and gamma molecules on relevant cells. Our results show that IL-15 stimulates cell proliferation and cytotoxic activity of GL in LDGL patients. Reverse-transcriptase polymerase chain reaction (RT-PCR) and phenotypic analyses using the anti-IL-2R gamma-chain-specific TUGh4 monoclonal antibody (MoAb) indicate that both CD3+ and CD3- GL express the p64 IL-2R, a result previously unknown. IL-15 activity was inhibited by antibodies against p75 and p64 IL-2R chains, while no inhibitory effects are detectable with anti-p55 IL-2R antibody. The association of anti-p75 and anti-p64 IL-2R MoAbs resulted in a nearly complete (95%) inhibition of IL-15-induced GL proliferation. Using RT-PCR analysis, we demonstrated that highly purified CD3+ and CD3- GL did not express mRNA for IL-15 or IL-2. By contrast, a clear-cut IL-15 mRNA signal was detected by RT-PCR in patients' peripheral blood mononuclear cells, with monocytes likely accounting for the source of IL-15 in LDGL patients. However, even in concentrated supernatants from enriched monocyte populations, we could not demonstrate the presence of IL-15 protein. Using anti-IL-15 specific MoAbs, a membrane-bound form of this cytokine was demonstrated both on CD3+ and CD3- LDGL cells. By RT-PCR analysis, purified GL from these patients were found to express the message for IL-15 receptor alpha chain. Taken together, these results indicate that both CD3+ and CD3- GL are stimulated by IL-15 and that this cytokine mediates its activity through the beta and gamma chains of the IL-2R, providing further suggestions for the interpretation of the mechanisms that lead to cell expansion in patients with LDGL.
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PMID:Interleukin-15 triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. 897 93

The occurrence of brain tumors is associated with broad suppression of the immune system function; however, the mechanisms involved in this impairment are not fully characterized. In this study, we have examined mechanisms involved in diminished T lymphocyte reactivity in patients with glioblastomas as compared to patients with other types of brain tumors. We found that the proliferative response of T lymphocytes stimulated with phytohemagglutinin or anti-CD3 was significantly reduced in these patients as compared to patients with meningiomas, oligodendrogliomas and healthy individuals. Stimulated T cells appear to express lower levels of the alpha-subunit (p55) of the IL-2 receptor (IL-2R), and increased levels of soluble IL-2R in cell supernatants, whereas no significant differences were observed in the level of the beta (p75)- or gamma-subunits. In addition, we found that competent T cells of glioblastoma patients exhibit lower levels of tyrosine phosphorylation in response to IL-2 as compared with cells of healthy donors. The decrease in the levels of IL-2 and its receptor was selective since no significant changes were observed in the secretion of other Th1- and Th2-derived cytokines (IFN-gamma and IL-4) and the expression of their respective receptors. These results indicate that the diminished response of T cells obtained from patients with glioblastomas may be due to a selective defect in the production of IL-2 and in the expression of functional IL-2R due to a decreased expression of the membranal IL-2R alpha and to lower levels of tyrosine phosphorylation in response to IL-2.
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PMID:A selective impairment of the IL-2 system in lymphocytes of patients with glioblastomas: increased level of soluble IL-2R and reduced protein tyrosine phosphorylation. 932 45

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


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