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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 effect of recombinant interleukin-2 (IL-2) on the proliferation of T-cell depleted leukemic blasts was evaluated in 23 patients with acute myelogenous leukemia (AML). For this purpose, the effect of IL-2 on cell growth, [3H]-thymidine incorporation into the blasts and the expression of IL-2 receptors on cell surface using T-cell depleted blasts were studied. The results showed that IL-2 stimulated [3H]-thymidine incorporation significantly in blasts of 8 out of 23 cases of AML. An IL-2 induced increase in cell number was directly demonstrated in seven out of eight IL-2 responsive patients studied. IL-2 stimulated the proliferation of blasts in monocytic lineage (M4 and M5), but not all M4/M5 leukemics responded to rIL-2. Stimulation of the growth of leukemic cells was not correlated with the expression of Tac antigen on the cell surface, but it was significantly correlated with the expression of IL-2 receptor (IL-2R) beta chain on the cell surface. These results indicate that IL-2 is an active growth factor in certain myeloid leukemia cells, especially of monocytic type.
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PMID:Growth of certain myeloid leukemic cells can be stimulated by interleukin-2. 177 32

The in vitro immunosuppressive properties of a novel, marine-derived compound, discodermolide, are reported here. Discodermolide suppressed the proliferative responses of splenocytes in the murine two-way mixed lymphocyte reaction (MLR) and concanavalin A stimulated cultures, with IC50 values of 0.24 microM and 0.19 microM, respectively. There was no evidence of cytotoxicity for murine splenocytes at concentrations of discodermolide as high as 1.26 microM. Similarly, discodermolide suppressed the proliferative responses of human peripheral blood leukocytes (PBL) in the two-way MLR, and Con A and phytohemagglutinin mitogenesis. The IC50 values were 5.65 microM, 28.02 microM, and 30.12 microM for the MLR, Con A, and PHA mitogenic responses, respectively. There was no evidence of cytotoxicity toward human PBL at discodermolide concentrations as high as 80.64 microM. Discodermolide was equally effective, compared with cyclosporine, in suppressing the PMA-ionomycin induced proliferation of purified, murine T cells, with IC50 values of 9.0 nM and 14.0 nM for discodermolide and CsA, respectively. The production of IL-2 by PMA-ionomycin stimulated T cells was not inhibited by discodermolide; however, the percentage of IL-2 receptor-bearing cells as measured by immunofluorescence with 7D4 antibody, specific for the 55-kDa chain (p55) comprising the murine IL-2 receptor, was reduced. The expression of a similar chain comprising the human IL-2 receptor (Tac antigen, p55) by PHA or Con-A-stimulated PBL was similarly suppressed by discodermolide. The precise mechanism of action of discodermolide remains to be elucidated.
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PMID:Discodermolide--a new, marine-derived immunosuppressive compound. I. In vitro studies. 183 64

The interleukin 2 receptor is a multisubunit receptor known to consist of at least two IL-2 binding subunits, alpha and beta. We report here kinetic evidence defining the contribution of an affinity-modulating element(s) intimately involved in modulation of the ligand-binding affinity of the beta chain and alpha/beta complex. The principal effect of this modulating element on the beta chain is to slow the dissociation of IL-2 more than 150-fold and thus raise its low intrinsic IL-2 binding affinity (Kd = 70 nM) as defined in transfected fibroblast cells to the level observed in lymphoid cells (Kd = 1.2 nM). The alpha subunit also increases the ligand-binding affinity of the beta chain, although in this case principally by increasing the association rate constant more than 1200-fold. The additional effect of the affinity-modulating element on the alpha/beta complex is minimal with regards to the equilibrium binding affinity. It does, however, have a detectable 14-fold effect on slowing the IL-2 dissociation rate. The existence of multiple forms of IL-2 receptor complexes with widely varying ligand affinities and dissociation rates illustrates the need for careful evaluation of binding data in studies of receptor subunit composition and reconstitution.
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PMID:Quantitative characterization of the intrinsic ligand-binding affinity of the interleukin 2 receptor beta chain and its modulation by the alpha chain and a second affinity-modulating element. 188 16

Previously, using flow cytometric resonance energy transfer and lateral diffusion measurements, we demonstrated that a 95-kDa protein identified by two monoclonal antibodies (OKT27 and OKT27b) interacts physically with the 55-kDa alpha protein of the high-affinity interleukin 2 (IL-2) receptor. In the present study, this 95-kDa protein (p95) was purified and amino acid sequence data were obtained that showed strong homology to the human intercellular adhesion molecule 1 (ICAM-1). The identity of the p95 protein with ICAM-1 was confirmed by sequential immunoprecipitations using OKT27 and an antibody, WEHI-CAM-1, that is directed toward ICAM-1. We confirmed the physical proximity of p95/ICAM-1 to the IL-2 receptor alpha subunit by demonstrating that radiolabeled IL-2 could be cross-linked to this protein expressed on activated T cells. In functional studies, the antibodies OKT27 and OKT27b inhibited T-cell proliferative responses to OKT3, to soluble antigen, and to heterologous cells (mixed lymphocyte reaction). However, these antibodies did not inhibit IL-2-induced proliferation of an IL-2-dependent T-cell line. Taken together with our previous observations, the present studies suggest that ICAM-1 is in proximity and interacts physically with the high-affinity IL-2 receptor. The association of ICAM-1 with the IL-2 receptor may facilitate the paracrine IL-2-mediated stimulation of T cells expressing IL-2 receptors by augmenting homotypic T-T-cell interaction, by receptor-directed focusing of IL-2 release by helper T cells, and by focusing IL-2 receptors of the physically linked cells to the site of lymphocyte function-associated antigen 1-ICAM-1-IL-2 receptor interaction.
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PMID:Association of intercellular adhesion molecule 1 with the multichain high-affinity interleukin 2 receptor. 197 56

T-lineage cells in human decidua of early pregnancies were tested for surface markers, proliferative response, interleukin-2 (IL-2) production, and natural killer (NK) activity. T-lineage (CD2+) cells that were obtained from decidua by the use of E-rosette formation contained fewer CD3+ mature T cells and CD4+ cells than those from the peripheral blood of the same donors, while no differences were seen in the frequencies of CD8+ cells. P55 molecules of IL-2 receptor (IL-2R/p55, Tac antigen) were hardly detected on fresh decidual T-lineage cells, though approximately 20% were positive for HLA-DR. More than a half of decidual T-lineage cells expressed CD56 molecules on their surface and killed K562 cells, the prototype target of NK cells, while most of them were negative for CD16 and CD57. Upon stimulation with IL-2, decidual T-lineage cells demonstrated dose-dependent proliferative response. In addition, they were induced to produce high amounts of IL-2 by stimulation with mitogens but not with alloantigens. These results suggest that human decidua contains high numbers of CD2+3-CD16 +/- 56+ lymphocytes and that this population responds to IL-2, produces IL-2 and mediates NK activity.
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PMID:Studies on T-lineage cells in human decidua of first trimester pregnancies. 207 84

We have proposed a multichain model for the high-affinity interleukin-2 (IL-2) receptor involving two IL-2-binding peptides, a 70/75 kilodalton (kD) and a 55 kD, reactive with the anti-Tac monoclonal antibody, which are associated in a receptor complex. With the use of coprecipitation analysis, radiolabeled interleukin-2 cross-linking procedures, and flow cytometric resonance energy transfer measurements, a series of additional peptides of molecular weight 22,000, 35,000, 40,000, 75,000 (non-IL-2 binding), 95,000-105,000, and 180,000 has been associated with the two interleukin-2-binding peptides. In contrast to resting T cells, the abnormal T cells of patients with human T-cell lymphotropic virus I-associated adult T-cell leukemia, patients with select autoimmune disorders, and individuals rejecting allografts express the Tac peptide (p55) of the IL-2 receptor. To exploit this difference in Tac antigen expression, we have initiated therapeutic trials using unmodified anti-Tac, conjugates of anti-Tac with truncated Pseudomonas exotoxin PE-40, interleukin-2-truncated toxin fusion proteins, and alpha- and beta-emitting isotopic chelates of anti-Tac. Furthermore, by genetic engineering humanized hyperchimeric anti-Tac molecules have been prepared in which the molecule is entirely human IgG1, except for the small complementarity-determining regions that are retained from the mouse antibody. This "humanized" antibody manifested the ability to perform antibody-dependent cellular cytotoxicity absent in the original mouse monoclonal. The clinical application of anti-interleukin-2 receptor-directed therapy represents a new perspective for the treatment of certain neoplastic diseases and autoimmune disorders and for the prevention of allograft rejection.
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PMID:Lymphokine receptor-directed therapy: a model of immune intervention. 208 86

Recombinant human interleukin-4 (rhIL-4) and transforming growth factor-beta 1 (TGF-beta 1) suppressed the induction of lymphokine-activated killer (LAK) activity induced by recombinant human interleukin-2 (rhIL-2) in peripheral blood lymphocytes. DNA synthesis and the expression of the p55 alpha chain of the IL-2 receptor (Tac antigen) were also inhibited. The inhibitory effect was greatest when these factors were added during the first 48 h of a 4-day culture, with reduced cytolytic activity against both natural killer (NK) resistant and NK-sensitive tumour cell line targets. The suppressive action of both cytokines was accompanied by a reduction in tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) levels in lymphocyte culture supernatants. Recombinant human IFN-gamma (rhIFN-gamma), but not recombinant human TNF-alpha (rhTNF-alpha) was able to overcome the inhibitory effect of recombinant human interleukin-4 (rhIL-4) on LAK induction and DNA synthesis but not Tac antigen expression. However, cytotoxicity induced by rhIFN-gamma alone was also suppressed by rhIL-4 and TGF-beta 1, inferring that rhIFN-gamma-mediated abrogation of rhIL4 suppression was not simply a direct IL-2-independent effect on cytotoxicity. In addition, rhIL-4 did not increase TGF-beta production from rhIL-2-activated peripheral blood mononuclear cells, suggesting that rhIL-4 did not mediate reduction of rhIL-2 responses through the induction of TGF-beta release.
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PMID:Suppression of lymphokine-activated killer (LAK) cell induction mediated by interleukin-4 and transforming growth factor-beta 1: effect of addition of exogenous tumour necrosis factor-alpha and interferon-gamma, and measurement of their endogenous production. 212 61

The high-affinity cell-surface receptor for interleukin-2 (IL-2R) consists of the 75-kilodalton (kd) chain and a 55-kd glycoprotein known as Tac. This report examines the cellular expression of IL-2R and secretion of the soluble form of Tac in immunosuppressed blunt trauma (n = 20, injury severity score -20) and thermally injured (n = 20, Total body surface area greater than 35%) patients. The percentage of IL-2R-expressing peripheral blood mononuclear cells (PBMC) in mitogen-stimulated cultures from patients and age-matched normal donors was determined by direct immunofluorescence with a monoclonal anti-Tac followed by flow cytometry analysis. Levels of soluble Tac in patient sera were measured by a monoclonal antibody-based enzyme-linked immunosorbent assay. Expression of Tac antigen by mitogen-activated PBMC cultures from blunt trauma patients was transiently reduced (by as much as 40%) in 4 of 14 patients examined. Levels of serum Tac were significantly elevated (p less than 0.05) in 15 of 20 blunt trauma patients ranging from 750 to 3000 U/mL compared with 180 to 420 U/mL in control subjects. All burn patients studied 10 to 50 days after the injury demonstrated a significant reduction (by 50% to more than 90%) in the percentage of IL-2 receptor-bearing cells. Similarly serum levels of IL-2R increased significantly (p less than 0.001 to 0.05) in all burn patients studied, reaching concentrations as high as 5500 U/mL. These results suggest that major trauma, whether mechanical or thermal, induces alterations in the T-lymphocyte activation process. However the degree and duration of such changes may vary based on the nature of the injury.
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PMID:Expression and secretion of IL-2 receptor in trauma patients. 214 78

Cell line PER-315 was established from a bone marrow sample of a 5-year-old boy diagnosed with acute lymphoblastic leukemia (ALL) of T cell lineage. PER-315 cells express the surface markers present on immature thymocytes, express cytoplasmic CD3, and their growth is dependent on interleukin-2 (IL-2). Hence, this cell line represents a new type of precursor T-ALL, which is IL-2 dependent. Assessment of the T cell receptor rearrangements confirmed the clonal origin of cell line PER-315, and comparison with the patient's leukemia cells revealed an identical pattern. PER-315 cells show strong cytotoxicity against cell lines K562, Daudi, and Molt-4. They do not express the Tac antigen, but bind IL-2 with a Kd of 650 pM. Since PER-315 cells represent immature thymocytes, this new cell line may provide a model to further investigate the IL-2 receptor structure present at this stage of T cell differentiation.
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PMID:Characterization of an interleukin-2 dependent human leukemic cell line, PER-315, with an immature T cell phenotype which does not express the tac antigen. 216 20

Anti-Tac(Fv)-PE40 is a recombinant single-chain immunotoxin containing the heavy and light variable regions of the anti-Tac monoclonal antibody fused to a mutant form of Pseudomonas exotoxin (PE). Anti-Tac binds to the p55 subunit of the human interleukin 2 (IL-2) receptor, and anti-Tac(Fv)-PE40 kills human or monkey cell lines that contain either the intact IL-2 receptor or its p55 subunit alone. To assess the usefulness of anti-Tac(Fv)-PE40 in treatment of IL-2 receptor-positive leukemia, we tested peripheral blood mononuclear cells from six patients with adult T-cell leukemia. In each of the six patients, anti-Tac(Fv)-PE40 was extremely cytotoxic to the malignant cells. Metabolic activity and sensitivity of the fresh cells improved when a small amount of IL-2 (10 units per ml) was present during incubation. The toxin concentration necessary to inhibit protein synthesis by 50% after 16-hr incubation of cells with immunotoxin varied from 1.6 to 16 ng/ml (2.5-25 x 10(-11) M). In every case, binding was by means of the Tac antigen because anti-Tac(Fv)-PE40 cytotoxicity was prevented by adding excess anti-Tac antibody. Moreover, anti-Tac alone or an inactive mutant of anti-Tac(Fv)-PE40 without ADP-ribosylation activity had very little cytotoxic activity. Peripheral blood mononuclear cells from normal controls, from a patient with Tac-negative leukemia, and from adult T-cell leukemia patients without significant peripheral blood involvement were not sensitive to anti-Tac(Fv)-PE40. These results indicate that anti-Tac(Fv)-PE40 is a potent cytotoxin against adult T-cell leukemia cells in vitro and warrants clinical testing.
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PMID:The recombinant immunotoxin anti-Tac(Fv)-Pseudomonas exotoxin 40 is cytotoxic toward peripheral blood malignant cells from patients with adult T-cell leukemia. 223 41


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