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)

Recent reports suggest that recombinant interleukin-2 may be effective in the treatment of cancer patients with low tumor burden. Considering the poor long-term survival, 11 ovarian cancer patients with minimal residual disease at second-look have so far been selected for rIL-2 intravenous continuous infusion therapy: two induction courses (3 x 10(6) U/m2/day: 120 h + 108 h) followed by three maintenance courses (3 x 10(6) U/m2/day: 120 h) and third-look laparotomy. At present, three patients are still on treatment, three have completed it, and five have discontinued treatment. Sixty-seven per cent of the planned dose was administered in 49 cycles of which 42 (86%) required dose modifications due to hypotension (greater than or equal to grade III) and nephrotoxicity (greater than grade I). CNS and GI toxicity, allergies and fever, even though requiring dose modifications in a few cases, significantly affected patient compliance. The rebound lymphocytosis was clearly dose-related and a significant percentage increase after rIL-2 was detected only for IL-2 receptor positive cells. To date, four patients are evaluable for response after a median follow-up of 7 months, two progressed during the maintenance period, while one CR and one progression were detected in the two patients so far submitted to third-look laparotomy.
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PMID:Recombinant interleukin-2 continuous infusion in ovarian cancer patients with minimal residual disease at second-look. 278 2

Activated killer cells, unrestricted by major histocompatibility (MHC) antigens circulate in the peripheral blood of patients who have undergone autologous and allogeneic bone marrow transplant (BMT) and may contribute to the reduced risk of leukemic relapse observed after these procedures. Interleukin-2 (IL-2) in vitro augments this cytotoxicity and used therapeutically might thereby promote the eradication of minimal residual disease. In order to assess whether these effects on cytotoxicity can be reproduced in vivo, we studied changes in number, phenotype, and MHC unrestricted cytotoxicity of peripheral blood mononuclear cells obtained from patients with hematologic malignancy receiving IL-2 infusions. Patients with acute myeloid leukemia and multiple myeloma were treated after cytotoxic chemotherapy or autologous BMT. IL-2 infusions produced an initial lymphopenia, followed by a progressive recovery in mononuclear cell numbers and a rebound lymphocytosis after the termination of treatment. This affected all lymphocyte subsets; in particular CD25 (IL-2 receptor) positive cell numbers rose sevenfold. Cells with the ability to kill a natural killer (NK)-resistant, lymphokine activated killer cell (LAK)-sensitive target appeared in the circulation during 16 of 19 infusions and mean LAK activity rose from 5.9% to 15.5% during infusion (E:T ratio, 50:1; P less than .001). During IL-2 infusion, cells present in the peripheral blood inhibited the growth of myeloid leukemia blasts in agar after overnight co-culture. Depletion experiments showed that LAK activity was mediated by cells of both CD3- CD16+ (NK derived) and CD3+ CD16- (T derived) subsets. LAK precursor activity in peripheral blood also significantly increased during IL-2 infusion. Increases in major histocompatibility complex (MHC) unrestricted cytotoxicity can be produced by IL-2 infusions in vivo and may result in improved relapse-free survival following chemotherapy or BMT.
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PMID:Effects of recombinant interleukin-2 administration on cytotoxic function following high-dose chemo-radiotherapy for hematological malignancy. 280 69

The purpose of this study was to investigate the effect of dose and duration of infusion of recombinant interleukin-2 (IL-2) on toxicity and immunomodulation. In a phase I/II study, IL-2 was administered intravenously (IV) daily for five consecutive days every other week for 4 weeks of treatment to 23 patients with progressive melanoma, renal, colon, or ovarian cancer by one of four regimens: groups I and II received 3 X 10(5) U/m2/d by two-hour or 24-hour infusion, respectively; groups III and IV received 3 X 10(6) U/m2/d by two-hour or 24-hour infusion, respectively. In a subsequent study, six patients (group V) received a single priming cycle of daily IL-2 for five days at 3 X 10(6) U/m2/d in divided 15-minute infusions every eight hours, before undergoing leukapheresis for lymphokine-activated killer (LAK) cell generation. Toxicity was mild with 3 X 10(5) U/m2/d, but severe chills and fever, moderate hypotension (not requiring IV pressors), and weight gain were observed with 3 X 10(6) U/m2/d. Toxicity was also related to the duration of infusion. In group IV (continuous infusion), fluid retention, weight gain, and azotemia were more frequent and severe than in groups III or V, in which the same total dose was administered by two-hour infusion or in three divided 15-minute infusions. IL-2 induced rebound lymphocytosis, which was directly dose-related and significantly higher in group IV (continuous infusion) than in groups III or V. Dramatic increases in the percentage and absolute number of cells expressing the IL-2 receptor were also most pronounced in group IV. With the higher dose of IL-2, LAK cells appeared in the circulation, and natural killer (NK) cytotoxicity was augmented. The results showed that the toxicity and immunomodulation by IL-2 are dose-dependent and are maximal by continuous infusion compared with two-hour or divided every eight hours infusions.
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PMID:Influence of dose and duration of infusion of interleukin-2 on toxicity and immunomodulation. 325 31

In this study we identify and characterize a subset of human peripheral blood T cells, present in all individuals, that has features previously described for T cells either separately or in special circumstances. These cells are found in purified suspensions of resting peripheral blood lymphocytes within the CD8+ T lymphocytes, express alpha beta T cell receptor (TCR), and can be identified and isolated because of high-density expression of surface CD11b (TCR alpha beta +/CD3+/CD8+/CD11b+ cells). They coexpress constitutively the IL-2 receptor beta chain, Fc gamma RIIIA, and CD56. Although they do not mediate spontaneous cytotoxicity, CD3+/CD8+/CD11b+ cells have cytotoxic potential, demonstrated in redirected cytotoxicity assays with P815 target cells in the presence of anti-Fc gamma RIII (CD16) or anti-CD3 monoclonal antibodies. Stimulation of CD3+/CD8+/CD11b+ cells with rIL-2 induces proliferation, cytotoxicity against NK-sensitive and NK-resistant target cells, and expression of surface activation antigens, including IL-2 receptor alpha chain (CD25). CD3+/CD8+/CD16+/CD56+ cell clones with cytotoxic functions including those mediated by engagement of surface CD16 were obtained by limiting-dilution cloning of purified CD3+/CD8+/CD11b+ cells in the presence of rIL-2 and autologous feeder cells. Our data support the hypothesis that the CD3+/CD8+/CD11b+/CD16+ cells represent a discrete peripheral blood lymphocyte subset that could be the physiological counterpart of that expanded in several pathological conditions and in large granular lymphocyte lymphocytosis.
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PMID:Coexpression of Fc gamma receptor IIIA and interleukin-2 receptor beta chain by a subset of human CD3+/CD8+/CD11b+ lymphocytes. 768 65

Accumulating evidence has suggested the involvement of HTLV-1 in the inflammatory lesions of various organs, including the lung. However, the causal relationship between HTLV-1 and inflammatory responses in the organs remains to be elucidated. In order to evaluate the expression of HTLV-1 and its effects in the lung, we examined the expression of mRNA for the HTLV-1 tax/rex gene in fresh bronchoalveolar lavage cells (BALC) and peripheral blood mononuclear cells (PBMC) of 23 seropositive individuals, including six patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), by use of an improved method of reverse transcription-polymerase chain reaction (RT-PCR). The tax/rex mRNA was more frequently detected in BALC than in PBMC. All the HAM/TSP patients and eight of 17 carriers without neurological symptoms showed the expression of tax/rex mRNA in the BALC. IgM class antibodies to HTLV-1 were preferentially detected in sera of the tax/rex mRNA-positive individuals. The detection of tax/rex mRNA correlated closely with the presence of lymphocytosis accompanied by an elevated proportion of IL-2 receptor-bearing T cells in the BALC. Our findings indicate the crucial role of viral expression in the inflammatory response in the lung in HTLV-1-infected individuals.
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PMID:Expression of human T lymphotropic virus type 1 (HTLV-1) tax/rex gene in fresh bronchoalveolar lavage cells of HTLV-1-infected individuals. 791 May 32

Interleukin-2 (IL-2) was administered locally by constant intra-arterial infusion in four escalating doses from 3 x 10(4)-3 x 10(7) IU/day to 12 patients with squamous cell carcinoma of the head and neck (SCCHN) in a phase I trial. Lymphocyte phenotypic markers and serum cytokine concentrations were measured over the course of treatment. Serum IL-1-alpha, -beta and IL-6 were not induced at any dose level. Tumour necrosis factor (TNF)-alpha was induced in the 2 patients who showed a clinical response (at the lowest dose) as well as in 4/10 of the non-responders. In addition TNF-beta was induced in 3/10 and IFN-gamma in 5/10 non-responders. Soluble IL-2 receptor concentrations were increased at the two higher doses. The highest dose of IL-2 produced a lymphocytosis after day 5 until the end of administration reflected by a general rise in lymphocyte phenotypic markers. CD25, CD3/HLA-DR and CD56 showed an additional upregulation not accounted for by the lymphocytosis with a suggestion of a bell-shaped dose-response curve for CD25 and CD3/HLA-DR. Administration of IL-2 in this manner has been shown to be well tolerated and has some anti-tumour activity at low doses, with little toxicity.
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PMID:Immune changes in peripheral blood resulting from locally directed interleukin-2 therapy in squamous cell carcinoma of the head and neck. 818 May 73

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

Infection with bovine leukemia virus (BLV) leads to a persistent lymphocytosis (PL) characterized by a marked increase in circulating B lymphocytes that express the orthologue of CD5. To gain insight into the factors accounting for lymphocytosis, experiments were conducted to determine the functional activation status of lymphocytes from BLV seronegative and BLV infected aleukemic cows with PL. Stimulation with the B lymphocyte mitogen Staphylococcus aureus Cowan strain I (SAC), recombinant human interleukin-2 (rIL-2), or pokeweed mitogen (PWM), a T lymphocyte-dependent B lymphocyte mitogen, revealed differences in the pattern of expression of IL-2 receptor alpha (IL-2R alpha) and major histocompatibility (MHC) class II molecules on B and T lymphocytes from uninfected and BLV infected PL cows. rIL-2 induced expression of IL-R alpha on B lymphocytes from PL cows but not B lymphocytes from BLV seronegative cows. SAC alone, or in combination with rIL-2, had no effect on B lymphocytes from BLV seronegative cows. However, rIL-2 alone or in combination with SAC induced expression of IL-2R alpha on B lymphocytes from PL cows. PWM stimulated expression of IL-2R alpha on bovine B lymphocytes regardless of BLV status, and induced a significantly higher level of expression on B lymphocytes from PL cows. Mitogens and rIL-2 had a similar stimulatory effect on induction of IL-2R alpha expression on CD4 T lymphocytes regardless of BLV status. Only PWM induced expression of IL-2R alpha on bovine CD8 T lymphocytes and induced a significantly higher level of expression on this T lymphocyte subset from PL cows. Examination of freshly isolated B lymphocytes from PL cows revealed increased spontaneous expression of the MHC class II molecule compared to B lymphocytes from control cows. None of the culture conditions examined induced MHC-II expression on CD4 and CD8 T lymphocytes from BLV seronegative cows. In contrast, SAC+IL-2 and PWM induced MHC-II expression on CD4 and CD8 T lymphocytes from BLV infected PL cows, resulting in a significantly greater proportions of these lymphocyte subsets expressing this molecule compared to CD4 and CD8 T lymphocytes from control cows. The data indicate that infection with BLV affects the response of B and T lymphocytes to signals of activation, up-regulating the expression of surface molecules involved in both direct contact and cytokine-mediated T lymphocyte-dependent B lymphocyte activation.
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PMID:Up-regulation of IL-2 receptor alpha and MHC class II expression on lymphocyte subpopulations from bovine leukemia virus infected lymphocytotic cows. 853 17

Chronic beryllium disease (CBD) provides a model for study of the Ag-stimulated, cell-mediated immune response that, over time, progresses to granulomatous lung disease. Using cells obtained with bronchoalveolar lavage from patients with CBD and normal individuals, we evaluated beryllium salt-stimulated T lymphocyte proliferation and production of proinflammatory cytokines. Our findings demonstrate that beryllium sulfate stimulates production of both IL-2 and IFN-gamma, not IL-4 and IL-7. We observed a brief time course for IL-2 protein (6-48 h after BeSO4 stimulation) and mRNA production (3-6 h) and a protracted time course for IFN-gamma protein (24-168 h) and mRNA (0.25-168 h). Beryllium-stimulated T lymphocyte proliferation and IFN-gamma release were only partially inhibited by neutralization of IL-2. On the basis of these findings, we hypothesized that IFN-gamma and the IL-2/IFN-gamma-inducible alpha subunit of the soluble IL-2 receptor were elevated in serum and bronchoalveolar lavage fluid of individuals with disease and were molecular markers of granulomatous disease. The data demonstrate that levels of the alpha subunit of the soluble IL-2 receptor, but not IFN-gamma, are elevated in the serum (median = 1428 U/ml; interquartile range = 823-2137 U/ml) and bronchoalveolar lavage fluid (median = 1.56 U/ml, interquartile range = 1.04-4.22 U/ml) of patients with CBD and correlate with the degree of pulmonary lymphocytosis and clinical measures of disease severity. We conclude that IL-2 and IFN-gamma are produced in the beryllium-stimulated, cell-mediated immune response with different time courses and that the alpha subunit of the soluble IL-2 receptor may serve as a biomarker of disease progression.
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PMID:Beryllium induces IL-2 and IFN-gamma in berylliosis. 897 30

Bovine leukemia virus (BLV)-induced persistent lymphocytosis is characterized by a polyclonal expansion of CD5+ B lymphocytes. To examine the role of the cytokine microenvironment in this virus-induced B-lymphocyte expansion, the expression of interleukin-2 (IL-2), IL-4, IL-10, and gamma interferon (IFN-gamma) mRNA, was measured in stimulated peripheral blood mononuclear cells from persistently lymphocytotic BLV-infected cows, nonlymphocytotic BLV-infected cows, and uninfected cows. IL-2 and IL-10 mRNA expression and IL-2 functional activity were significantly increased when peripheral blood mononuclear cells from persistently lymphocytotic cows were stimulated with concanavalin A (ConA). Additionally, during persistent lymphocytosis, peak IL-2 and IL-10 mRNA expression was delayed, and elevated expression was prolonged. To determine the potential biologic importance of increased IL-2 and IL-10 expression, the response of isolated B lymphocytes from persistently lymphocytotic cows to human recombinant cytokines and to cytokine-containing supernatants from isolated T lymphocytes was examined. While recombinant human IL-10 (rhIL-10) did not consistently induce detectable changes, rhIL-2 increased viral protein (p24) and IL-2 receptor expression in isolated B lymphocytes from persistently lymphocytotic cows. Additionally, rhIL-2 and supernatant from ConA-stimulated T lymphocytes enhanced B-lymphocyte proliferation. The stimulatory activity of the T-lymphocyte supernatant could be completely inhibited with a polyclonal anti-rhIL-2 antibody. Finally, polyclonal anti-rhIL-2 antibody, as well as anti-BLV antibody, inhibited spontaneous proliferation of peripheral blood mononuclear cells from persistently lymphocytotic cows, demonstrating that the spontaneous lymphoproliferation characteristic of BLV-induced persistent lymphocytosis is IL-2 dependent and antigen dependent. Collectively, these findings strongly suggest that increased T-lymphocyte expression of IL-2 in BLV-infected cows contributes to development and/or maintenance of persistent B lymphocytosis.
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PMID:B-lymphocyte proliferation during bovine leukemia virus-induced persistent lymphocytosis is enhanced by T-lymphocyte-derived interleukin-2. 952 43


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