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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was undertaken to investigate the pathways involved in the interleukin 2 (IL-2)-driven growth of tumour-infiltrating lymphocytes (TILs). For this purpose, TIL lines and freshly isolated TILs obtained from 16 patients with solid cancer (three melanoma, seven primary colorectal carcinoma, four hepatic metastases from colorectal cancer and two lung cancer) were evaluated for (a) expression of IL-2 receptor (IL-2R) both at the RNA level and on the cell surface by flow cytometric analysis and (b) their proliferative activity in response to IL-2 and the role of IL-2R subunits in the IL-2-driven TIL growth. Northern blot analysis showed that TILs express a strong message for both the p55 and the p75 IL-2R. Accordingly, flow cytometric analysis demonstrated that TILs bear both IL-2R chains. TILs cultured in vitro in the presence of rIL-2 were able to proliferate in response to different concentrations of this cytokine. Monoclonal antibodies (MAbs) specifically recognising the p55 and p75 IL-2R chains (anti-Tac and TU27 respectively) exhibited a marked inhibitory effect on IL-2-driven growth when added individually or in appropriate combinations. Our results demonstrated that TILs are equipped with a fully functional IL-2 receptor system, thus suggesting the involvement of this structure in the activation and expansion of TILs following immunotherapy with IL-2.
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PMID:Functional role of IL-2 receptors on tumour-infiltrating lymphocytes. 819 69

The immune system of patients with head and neck cancer is frequently depressed. Serum inhibitory factors and immune cell dysfunction are known contributors to this depression, but their relative roles are unclear. We have examined these factors to determine whether a common pathway is involved. Is the defect an unresponding "switched-off cell" or is it a remedial defect responsive to the removal of serum inhibitory factors and/or to lymphokine restoration? Immune tests were performed in 66 patients with high-stage head and neck cancer. Serum inhibitory factors were measured by incubation of heat-inactivated serum (10%) with phytohemagglutinin (PHA)-stimulated lymphocytes or natural killer (NK) cells using the K562 assay. Lymphokine-activated killer (LAK) cell cytotoxicity was measured (in the presence/absence of serum) using chromium 51-labeled Raji tumor cells cultured 5 days with interleukin-2 (IL-2) (100 or 1,000 U/mL) and/or interferon-alpha (INF-alpha) (100 U/mL). IL-2 receptors, CD25 or p55 (low affinity) and p75 (high affinity), were measured by flow cytometry through fluorescence-activated cell sorter analysis. Serum inhibitory factors were detected in more than 50% of the patients. Head and neck cancer sera significantly inhibiting the normal lymphocyte response to PHA (11 of 22 patients), as well as significantly inhibiting the NK response of normal lymphocytes and the functional expression of the IL-2 receptor. LAK cell function at low-dose IL-2 was depressed in 45% of the patients (9 of 20) and was restored by increased IL-2 (1,000 U/mL) or a combination of IL-2 and INF-alpha. Twenty-five percent of the patients were unresponsive to maximum lymphokine stimulation. Half of the patients had depressed expression of the low-affinity IL-2 receptor (CD25). The cause of immune depression in patients with head and neck cancer is multifactorial and is related to serum inhibitory factors, as well as to inherent cellular defects. Based on these data, we would suggest a therapeutic approach in selected patients that includes the removal of serum inhibitory factors by plasmapheresis and restoration of cellular defects by combined IL-2 with or without INF-alpha.
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PMID:Contribution of serum inhibitory factors and immune cellular defects to the depressed cell-mediated immunity in patients with head and neck cancer. 821 99

T cell responsiveness to in vitro stimulation is severely diminished in the aged. Recent studies would suggest that this may be due, at least in part, to a reduction in interleukin 2 (IL-2) secretion and high-affinity IL-2 receptor (HA-IL-2R) expression. In this report we confirm and extend these studies to show that the fall in IL-2 production is not due to reduced numbers of IL-2 mRNA producing T cells but rather to a decline in the relative amount of IL-2 mRNA expressed per cell. Although we found an age-related reduction in the number of high-affinity binding sites on phytohaemagglutinin-activated T cell blasts by ligand-binding studies, we did not observe alterations in the number of cells that expressed both chains of the HA-IL-2R by two-colour immunofluorescence using monoclonal antibodies specific for p55 (alpha) chain and p75 (beta) chain. However, we did observe a substantial diminution in the number of activated T cells expressing p55 alone in the aged. Given that IL-2 upregulates p55 expression and is involved in the formation of HA-IL-2R, our results suggest that defective IL-2 expression is the primary lesion in age-related T cell senescence.
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PMID:Age-related changes in the expression of IL-2 and high-affinity IL-2 binding sites. 821 75

IL-2 is a cytokine that plays a central role in immune response. It stimulates cellular as well as humoral reactivity. The effect of IL-2 depends on the interaction with its receptor. Recent reports have documented that high affinity interleukin-2 receptors consist of two distinct IL-2 binding proteins, one being alpha chain (p55) and the other being IL-2 beta chain (p75). Expression of the alpha chain or the beta chain alone allows for low affinity or intermediate affinity IL-2 binding, respectively. Alpha receptor is present on activated cells, beta chain is present on resting cells. Decreased production of IL-2 and decreased expression of IL-2 receptor (IL-2R) after stimulation was found in primary and secondary immune deficiencies. Leukemic cells in adult T cell leukemia and hairy cell leukemia express markedly large numbers of IL-2 receptors. Since IL-2 receptors are present on malignant cells but not on normal resting cells, clinical trials have been initiated in which patients with adult T cell leukemia are treated with monoclonal antibody that binds to IL-2 receptor.
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PMID:[Interleukin 2 (IL-2) and its receptor (IL-2R) in healthy individuals and with various disease states]. 830 76

Melanoma cells can secrete several cytokines and express various cell surface molecules, such as the intercellular adhesion molecule ICAM-1, class II histocompatibility antigens, and the CALLA antigen, typically found in cells of the immune system. We have investigated the possible expression of interleukin-2 (IL-2) receptors in melanoma using monoclonal antibodies specific for the p55/alpha chain (TAC antigen) and the p75/beta subunit. Flow cytometric analysis of cultured melanoma cells showed the presence of low levels of the TAC antigen and of the beta chain on the surface of several cell lines. Similar results were obtained in vivo by immunohistochemistry on cryosections prepared from cutaneous and ocular melanoma explants. Positive staining was observed for the alpha chain of the IL-2 receptor in a high percentage of tumour cells. The beta chain could also be detected, although in a limited number of specimens. Analysis of RNA from melanoma cell lines by Northern blot showed the presence of typical 4 Kb transcripts for the p75 subunit, while low-abundance message for the p55 chain could be detected using combined reverse transcription/polymerase chain reaction analysis. Together, these results suggest that melanoma cells may express high affinity receptors for IL-2.
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PMID:Expression of IL-2 receptors in human melanoma cells. 831 84

This report addresses the role of individual IL-2 binding proteins of the IL-2 receptor in the stimulation of cell proliferation by IL-2. Murine IL-3-dependent cell lines were established which expressed the human p75 IL-2-binding protein, in the absence or presence of the human p55 IL-2-binding protein. Whereas p75 expression was sufficient to confer response to an intermediate (half-maximal stimulation at 100 pM) concentration of IL-2, additional expression of p55 increased the sensitivity of the cells to half-maximal stimulation at 10 pM IL-2. A mutant IL-2 molecule, Lys-20 IL-2 which is known to be defective of p75 interaction, was unable to stimulate cells expressing only p75: p55 co-expression could restore its activity. Under conditions of low p75 expression, Lys-20 IL-2 could act as an antagonist of wild-type IL-2 action. These data support a role for p55 in the enhancement of responsiveness to IL-2.
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PMID:The role of IL-2 interaction with p75 and p55 receptor molecules in the stimulation of cell proliferation. 831 57

Hairy cell leukemia (HCL) is a B-cell chronic lymphoproliferative disorder in which the pathologic cells show a strong expression of CD25 (interleukin-2 [IL-2] receptor alpha chain or p55). "Variant" cases of HCL, characterized by hyperleukocytosis, neoplastic elements with a prominent nucleolus and a higher nucleo/cytoplasmic ratio, and an easily obtained bone marrow aspirate, lack surface CD25 determinants. Limited information is available on the expression of the IL-2 receptor beta chain (p75) on normal and neoplastic B cells. In this study, we have assessed by immunofluorescence and mRNA analysis the presence of the IL-2 receptor alpha and beta chains on 12 cases of classic HCL, as well as on 3 variant cases. The results obtained show that, while the alpha chain of the IL-2 receptor is present only on classic HCL, the IL-2 receptor beta chain (p75) is expressed on both the classic and variant form. Unlike hairy cells, only 8 of the 15 B-cell chronic lymphocytic leukemia cases tested showed a weak expression of the p75 antigen on a small proportion of cells. Purified B lymphocytes from normal healthy controls, as well as Epstein-Barr virus-transformed lymphoblastoid cell lines, showed a weak staining for the p75 determinant, while being CD25-. The results of this study suggest that the expression of the alpha and beta chains of the IL-2 receptor appears to be upregulated or downregulated during the process of B-cell-lineage activation and differentiation.
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PMID:Phenotypic analysis of hairy cell leukemia: "variant" cases express the interleukin-2 receptor beta chain, but not the alpha chain (CD25). 832 8

DAB486IL-2, a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with interleukin-2 (IL-2), has displayed significant activity in patients with chemotherapy refractory hematological cancers. To further investigate the safety and antitumor effect of this agent, we conducted a single arm, dose escalation study of a 90-min infusion of DAB486IL-2 daily for 5 days. Patients with cancers of a histology previously reported to express the p55 component of the IL-2 receptor and who could not receive potentially more effective therapy were eligible for enrollment. Fifteen men and 8 women with a median age of 49 years were given a total of 51 courses of DAB486IL-2. The maximum tolerated dose was 0.3 mg/kg/day defined by renal insufficiency associated with hemolysis and thrombocytopenia. The clearance of DAB486IL-2 from serum fit a one-compartment model with a half-life of 11.5 +/- 4.3 (SD) min at the 0.2-mg/kg dose. Two patients sustained a partial response and 4 patients had tumor reduction not qualifying for an objective response. No tumors that were negative for expression of the p55 subunit of the receptor responded to DAB486IL-2 treatment. Reduction in size occurred in 2 tumors in which p55 expression was unknown and 4 patients with tumors that were known to be p55 positive. Dosing determined by specific activity rather than mass also appeared to be an important determinant of response. This study suggests that the presence of p55 expression on tumor cells is necessary, but alone may not be sufficient to achieve a tumor response. The correlation of additional variables such as specific activity of DAB486IL-2 and tumor expression of the p75 subunit of the IL-2 receptor and receptor function will also require further study.
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PMID:Phase I trial of a 90-minute infusion of the fusion toxin DAB486IL-2 in hematological cancers. 835 20

Cell line PER-423 was derived from the cells of a patient with an immature acute T-lymphoblastic leukaemia and the growth of this human cell line is strictly dependent on interleukin-2 (IL-2). PER-423 cells express the p75 (beta) subunit of the IL-2 receptor (IL-2R beta), while the p55 chain (IL-2R alpha) is not detectable by immunofluorescence. The analysis of the IL-2R revealed that it is of intermediate affinity and the median effective IL-2 concentration for PER-423 cells (EC50 value) was determined to be 1.44 +/- 0.29 nM. Chemical crosslinking studies showed that the receptor consists of one polypeptide of approximately 95 kDa as well as a doublet of 70 kDa and 60 kDa and does not include the IL-2R alpha-chain. The steady-state mRNA level for the p75 subunit was similar to that present in a cell line expressing an IL-2R alpha+ beta+, while only traces for the alpha-chain were detectable. PER-423 cells can be induced to express the alpha-chain of the IL-2R on the cell surface, concomitant with a much reduced EC50 level. Since cell line PER-423 is functionally dependent on IL-2, it provides an ideal model for IL-2 signal transduction studies and for investigations focusing on the requirements for ligand binding vs activation.
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PMID:Functional interleukin-2 receptor on a Tac negative human leukaemia T-cell line. 842 80

Numerous studies have demonstrated that the generation of alloreactive effector cells depends on cytokines. Conversely, there is evidence that cytokine metabolism is altered at the clonal level in tolerant chimaeras. This has led to preclinical and clinical studies using antibodies that antagonize interleukin-2 (IL-2), with the hope of achieving immunosuppression and inducing tolerance. Monoclonal antibodies against the alpha-chain (p55) of the human IL-2 receptor are being applied to prevent transplant rejection and graft-versus-host disease in several clinical trials. The antibodies that have been applied clinically so far antagonize the binding of IL-2 to the IL-2 receptor alpha-chain which is part of the high affinity IL-2 receptor, but they do not deplete the receptor-bearing cells. Our study investigates the immunosuppressive effect of monoclonal antibodies against the alpha-chain (p55) and beta-chain (p75). In mixed lymphocyte cultures the p55 antibody causes a reduction in T-cell proliferation to about 50%. The generation of cytotoxic T cells is reduced more effectively (up to 80%). By additional blocking of the IL-2 receptor beta-chain we achieved an additional but still incomplete immunosuppressive effect. Moreover we show that IL-2 receptor-blocked alloreactive T cells escape suppression by using IL-4 as an alternative stimulating signal. To prevent T lymphocytes benefiting from this alternative and thwarting the immunosuppressive effect, cytotoxic IL-2 receptor antibodies that deplete the high affinity receptor-bearing cells are needed.
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PMID:Interleukin-4 bypass of the immunosuppressive effect mediated by interleukin-2 receptor antibodies. 843 32


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