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)

Cellular immunity was investigated in 43 patients with multiple myeloma (MM) by assessing 3HTdR uptake induced by monocyte-dependent [CD3 monoclonal antibodies (MoAbs), phytohemagglutinin (PHA)] and monocyte-independent (CD2 MoAbs, ionomycin + phorbolester) stimulations. The former were evaluated in peripheral blood mononuclear cells (PBMNC) and purified T cells; the latter were evaluated in purified T-cell preparations only. MM showed significantly lower PBMNC responses to PHA (P less than .001), soluble OKT3 (CD3) (P = .01), and immobilized OKT3 MoAbs (P = .01). On purification of T cells, MM responses were still defective to soluble T11(2) + T11(3) (CD2) MoAbs (P = .004), phorbol myristate acetate (PMA) plus ionomycin (P less than .001), but significantly higher to plastic-immobilized OKT3 (P = .004). In some MM, 3HTdR uptake, interleukin-2 (IL-2) receptor (CD25) expression, and IL-2 production were as high on stimulation with plastic-immobilized OKT3 as that observed in normal subjects under optimal conditions (ie, plastic-immobilized OKT3 plus accessory signals). CD3 hyperreactivity correlated with the number of CD8+ HLA-DR+ cells in MM T-cell preparations. MM patients with more than 10% CD8+ HLA-DR+ cells had significantly higher responses to immobilized OKT3 (P less than .001), but lower responses to T11(2) plus T11(3) (P = .01), and PMA plus ionomycin (P = .03) than patients with less than 10% CD8+ HLA-DR+ cells. Phenotyping of CD45RA (naive) and CD45R0 (memory) expressions in resting MM T cells showed a lower ratio of CD45RA to CD45R0 in both CD4 (P less than .05) and CD8 (P less than .001) subpopulations. These data indicate that (a) some MM T cells require significantly fewer accessory signals (if any) to express the IL-2 receptor fully, secrete IL-2, and proliferate on multivalent cross-linking of the CD3/TCR complex; and (b) this peculiar state of activation is associated with high HLA-DR expression in CD8+ lymphocytes.
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PMID:Detection of hyperreactive T cells in multiple myeloma by multivalent cross-linking of the CD3/TCR complex. 156 45

Lymphocyte clones were isolated from CD4+ peripheral-blood lymphocytes (PBL) of melanoma (Me) patient 9923 (HLA-DR7, DQw2, w6), co-cultured for 30 days with autologous accessory cells, allogeneic Me (Me 1811) (HLA-DR7, DQw1, w2), IL-1 beta (2 U/ml) and IL-2 (15 IU/ml). The 55 clones tested displayed a CD3+, CD4+, CD8-, T-cell receptor (TCR) alpha/beta+, gamma/delta- phenotype. Twenty clones were assayed for proliferation in the presence of Me 1811 and B-lymphoblastoid cell line (LCL) 1811, both expressing HLA-class-I and -II (DR7 and DQw2 shared with patient 9923), intercellular adhesion molecule-1 (ICAM-1) and lymphocyte-function-associated antigen-3 (LFA-3) molecules. Eight clones were found to be reactive to Me 1811 but not to LCL 1811. Specificity analysis of these 8 clones revealed that each of them proliferated only to Me 1811, not to other 14 Me and 12 different LCL, suggesting recognition of melanoma-associated antigen (MAA) expressed on the stimulating Me. One clone (103) was analyzed in more detail. A wider specificity analysis showed that it reacted to Me 1811 but not to 10 other Me expressing or not HLA-DR7, 5 normal melanocyte cultures (2 of them typing HLA-DR7-positive when exposed to interferon-gamma--IFN-gamma), 4 tumors other than Me and 20 different LCL. Clones did not show proliferation in the presence of autologous Me cells. Clone proliferation in response to Me 1811 was significantly inhibited by monoclonal antibodies (MAbs) directed to CD3, TCR alpha/beta, TCR beta chain V12, CD4 and HLA-DR. Moreover, following stimulation with Me 1811, clone 103 showed increased surface expression of CD25 (IL-2 receptor) and CD71 (transferrin receptor) and produced significant amounts of IL-2 and IFN-gamma. The supernatant taken from co-culture of clone 103 with Me 1811 augmented the cytotoxicity of PBL 9923 and other allogeneic PBL against K562 and Me 1811. Thus, the lymphocyte clone 103 is a CD4+ Th clone which uses its CD3/TCR alpha/beta complex to recognize an MAA in conjunction with HLA-DR7. Availability of this type of reagent may prove useful to identify and characterize MAA recognized by T lymphocytes.
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PMID:Human allogeneic melanoma-reactive T-helper lymphocyte clones: functional analysis of lymphocyte-melanoma interactions. 183 14

Mitoxantrone (DHAD), an anthracenedione with antineoplastic properties similar to doxorubicin, was tested for therapeutic efficacy and for immunomodulating action on lymphocyte subsets in 16 metastatic breast cancer patients, 12 of whom had been previously treated with chemotherapy. DHAD was given intravenously at a dose of 14 mg/m2 every 21 days. To evaluate total T lymphocytes (CD3), T helper (CD4), and T suppressor/cytotoxic cells (CD8) and the CD4/CD8 ratio, venous blood samples were drawn before and after the first DHAD cycle. Moreover, in 8/16 patients, B lymphocytes (CD20), T suppressor cells (CD8+/CD57+), T cytotoxic cells (CD8+/CD57-), NK (CD16) and IL-2 receptor-expressing cells (CD25) were also measured at the same time. An objective tumor response was achieved in 5/16 (31%) patients and the response rate was significantly higher in patients pretreated with hormone therapy alone than in those pretreated with chemotherapy. No relation was found between clinical response and changes in the CD4/CD8 ratio. Neither the mean number nor the percentage of CD3, CDA and CD8 cells observed after DHAD were significantly different with respect to those seen before. In contrast, the mean number of T suppressor cells, B lymphocytes and CD25-positive cells was significantly lower after than before DHAD administration, whereas no difference was seen in NK cells. These results confirm in humans the immunomodulating properties of DHAD previously described in experimental conditions. However, the DHAD-induced changes in lymphocyte subsets do not seem to be related to the clinical response in breast cancer.
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PMID:Mitoxantrone as a single agent in pretreated metastatic breast cancer: effects on T lymphocyte subsets and their relation to clinical response. 186 50

After a 5-day period of continuous intravenous infusion of recombinant interleukin 2 (rIL-2) in seven patients with malignant melanoma or gastric or pancreatic cancer, different lymphocyte subsets were separated from patients' blood and tested ex vivo for cytotoxic activity against various tumour cell lines. Lytic activity was mediated by CD3+CD56+, CD3-CD56+, CD3-CD2+ and CD8+CD56+ lymphocytes. No cytotoxic activity could be observed within the CD3+CD56-, CD3+CD2+ or CD4+ T cell subsets. To characterize CD56+ cytotoxic cells further, the expression of other antigens on this population was analysed before and after IL-2 therapy. CD3, CD4, CD16 and CD57 antigens were weakly expressed, and the IL-2 receptor (CD25) was not detectable on these cells either before and after treatment with IL-2. In contrast, increased expression of CD2. CD8 and HLA-DR antigens occurred following therapy. The divergence of CD3 and CD8 antigen expression after IL-2 therapy was caused by an increase in CD3-CD8+ cells, detectable as a low-density CD8+ subset. This study shows that cytotoxic activity of in vivo IL-2-activated killer cells is predominantly, but not exclusively, mediated by CD3-CD56+ lymphocytes, partially coexpressing the CD8 antigen and lacking the expression of CD16 antigens.
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PMID:Cytotoxic activity and phenotypic characteristics of lymphocyte subsets after therapy of cancer patients with interleukin-2. 187 92

A continuous cell line was established from the blood of a patient (HH) with an aggressive cutaneous T-cell leukemia/lymphoma who lacked antibodies to human T lymphotrophic virus, type I. The immunophenotype of the cultured cells was CD2+, CD3+, CD4+, CD5+, CD8-, DR+ and CD25- (Tac, IL-2 receptor alpha chain). Southern-blot hybridization analysis of T-cell-receptor beta chain DNA demonstrated the same rearrangement in freshly isolated blood cells and cultured cells, indicating that the cell line was derived from the patient's malignant clone. Since cultured T-cells grew in complete medium without added IL-2, we investigated whether HH cells could be producing and responding to IL-2 in an autocrine fashion. However, no IL-2 was detectable in supernatant from the cell line, while antibodies to IL-2, or to the IL-2 receptor alpha or beta chains did not inhibit cell growth. In addition, no mRNA message for IL-2 was detectable in these cells. The results appear to exclude an autocrine IL-2-dependent mechanism of cell growth for this T-cell line. Although cultured HH cells lacked detectable IL-2 receptor alpha chain, they did show increased proliferation to exogenous IL-2. Binding studies with 125I-IL-2 demonstrated an intermediate affinity receptor for IL-2, KD = 1.7 nM, with 6400 binding sites per cell, suggesting the presence of an IL-2 receptor beta chain. Consistent with these findings 125I-IL-2 cross-linking studies demonstrated a single receptor calculated to be 75 kDa. Also, the beta chain of the IL-2 receptor was detected by immunofluorescence using specific monoclonal antibodies (MAbs). Nanomolar concentrations of an IL-2-diphtheria toxin fusion protein inhibited cellular protein synthesis, an effect abrogated by native IL-2. These findings indicate that the IL-2 receptor beta-chain was functional. This novel mature T-cell line may be useful in studies of IL-2 receptor regulation and in analysis of the mechanism of T-cell leukemogenesis.
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PMID:Establishment of an IL-2 independent, human T-cell line possessing only the p70 IL-2 receptor. 187 69

Because T cell-derived cytokines may affect the functioning of eosinophils, we have investigated the capacity of human eosinophils to respond to IL-2. IL-2 was a potent chemoattractant with ED50 of 10(-12) M with eosinophils from all normal and eosinophilic donors tested. The monoclonal antibodies anti-Tac and TU27 against p55 (Tac/CD25) and p75 receptor subunits, respectively, each inhibited IL-2-dependent eosinophil migration. The molar potency of IL-2 and the inhibitory activity of each of the above antibodies suggest that high affinity heterodimeric IL-2 receptor complexes mediated the migration responses of eosinophils to IL-2. Binding of monoclonal antibody against p75 was not detectable by flow cytometry, and high affinity binding sites for 125I-IL-2 were below the limits of quantitation on eosinophils from individuals with eosinophilia. Expression of p55 (Tac/CD25) by eosinophils, without requirement for in vitro activation, was demonstrable by flow cytometry, radioimmunoprecipitation, and Northern blotting for mRNA. Surface expression of p55 on eosinophils from normal or eosinophilic individuals increased during culture for 24-48 h with a biologic activity purified from stimulated U937 cells and to a lesser extent with granulocyte-macrophage CSF or lymphocyte chemoattractant factor but not with nine other cytokines. These studies indicate that blood eosinophils respond to IL-2 and identify one mechanism whereby activation of T lymphocytes may influence the function of eosinophils.
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PMID:Human eosinophils express functional interleukin 2 receptors. 188 72

In a phase I/II dose escalation study performed at our institution, a total of 14 advanced metastatic cancer patients received between 4 and 16 weeks of subcutaneous recombinant interleukin-2. Doses were escalated at weekly intervals, starting at 1.8 million IU/m2/day up to a maximum dose of 14.4 million U/m2 daily. When comparing patients with (n = 4) and without (n = 7) prior chemotherapy on day 0 (i.e., before rIL-2), both patient groups exhibited Tac IL-2 receptor (CD25) positive peripheral blood lymphocytes at equal levels of positivity (8%). In contrast, 4-week systemic treatment with subcutaneous rIL-2 at escalating dose levels revealed a significant difference in the up-regulation by interleukin-2 of CD25 cell surface receptor. Thus, after 4 consecutive weeks of treatment, patients without previous chemotherapy showed a mean CD25 positivity of peripheral blood lymphocytes at 38%, as compared with 22% in patients who did receive prior chemotherapy (p less than 0.05). These data suggest that chemotherapy pretreatment may have a significant effect on biological response to rIL-2 in vivo.
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PMID:Diminished expression of interleukin-2 receptors in vivo after prior chemotherapy in advanced cancer patients receiving recombinant interleukin-2. 191 Jun 21

Twenty-three monoclonal antibodies (MAbs) against the IL-2 receptor alpha-chain (CD25) were evaluated as ricin A-chain immunotoxins for the treatment of Hodgkin's disease. Primary screening used an indirect assay in which the cells were treated with the test antibody followed by a Fab' immunotoxin against mouse immunoglobulin. This screening identified 5 MAbs which inhibited protein synthesis in L540 Hodgkin cells by 50% at a concentration (IC50) of 6 x 10(-11) M or less: RFT5 gamma 1, RFT5 gamma 2a, B-B10, B-F2 and B-G3. These MAbs were then linked directly to deglycosylated ricin A-chain (dgA) and were confirmed to have potent and specific toxicity for L540 cells. The immunotoxins had the following potency order: RFT5 gamma 1 greater than RFT5 gamma 2a greater than B-B10 greater than B-F2 greater than B-G3. The most effective immunotoxin, RFT5 gamma 1.dgA, had an IC50 value of 7 x 10(-12) M, which is the same as that of whole ricin. In vivo, a single intravenous injection of 48 micrograms of RFT5 gamma 1.dgA, RFT5 gamma 2a.dgA, B-B10.dgA or B-F2 induced lasting complete remissions in 78, 66, 50 and 44%, respectively, of nude mice bearing subcutaneous solid L540 tumours of 0.7 cm diameter. Two tumours which regrew after B-B10.dgA treatment were re-established in tissue culture. Both had reduced sensitivity to B-B10.dgA in vitro but not to immunotoxins recognizing different antigens on Hodgkin cells. The MAbs that produced the most potent immunotoxins, RFT5 gamma 1, RFT5 gamma 2a and B-B10, had no significant cross-reactivity with normal human tissues outside the lymphoid system as judged from indirect immunoperoxidase staining of frozen sections. By contrast, B-F2 strongly stained normal human renal tubules.
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PMID:Immunotoxins constructed with anti-CD25 monoclonal antibodies and deglycosylated ricin A-chain have potent anti-tumour effects against human Hodgkin cells in vitro and solid Hodgkin tumours in mice. 191 43

Different immunotherapy regimens using s.c. recombinant interleukin-2 (rIL-2) were studied in 76 patients with progressive metastatic renal carcinoma, malignant melanoma, colorectal cancer, B-cell lymphoma, or Hodgkin's disease. To assess the immunomodulatory capacity of rIL-2, we measured serum levels of soluble interleukin-2 (sIL-2) receptors, gamma-interferon, tumor necrosis factor-alpha, and various lymphocyte subsets expressing the CD25 Tac IL-2 receptor and the CD56 natural killer (NK) associated antigen. Additionally, we measured serum antibodies specific to rIL-2 in order to evaluate immunogenicity of rIL-2. In all patients, a significant increase in sIL-2 receptor levels could be observed when comparing values on day 0 and after one treatment course. Patients developing a neutralizing anti-rIL-2 antibody exhibited significantly lower serum sIL-2 receptor levels than patients without antibody. Soluble IL-2 receptors correlated with the percentage of CD25 IL-2 receptor-positive peripheral blood lymphocytes. Both soluble and cell surface IL-2 receptors exhibited a significant increase during rIL-2 therapy but did not correlate with the percentage of CD56-positive peripheral blood lymphocytes. Measurement of treatment-induced secondary cytokines showed significant increases in gamma-interferon serum levels in a proportion of patients tested, although with considerable interindividual variability. No significant increase in mean tumor necrosis factor-alpha levels was observed during rIL-2 treatment in vivo. The percentage of CD56-positive NK cells correlated with the clinical outcome of rIL-2 therapy. Thus, partial or complete responders had an increase from a mean of 20% NK cells prior to therapy up to a mean of 40% after the first treatment course. In contrast, patients with progressive disease had a mean of 22 and 24% NK cells before and after treatment, respectively.
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PMID:Biological monitoring of low-dose interleukin 2 in humans: soluble interleukin 2 receptors, cytokines, and cell surface phenotypes. 193 92

Soluble CD8, soluble CD4, soluble CD25 (IL-2 receptor), beta 2-microglobulin and the cytokine tumour necrosis factor-alpha (TNF-alpha) were measured in sera from patients with common variable immunodeficiency (CVI). Levels of soluble CD8, soluble CD25 and beta 2-microglobulin but not of soluble CD4 and TNF-alpha were raised significantly above levels in normal sera. Sera from patients with X-linked agammaglobulinaemia, who are also antibody deficient, did not show this marked elevation. The raised levels of soluble CD8, soluble CD25 and beta 2-microglobulin in CVI, correlated with the extent of the defects in the B lymphocytes assessed in vitro, as well as with the clinical severity of the disease. The selective release of these molecules into sera may indicate that abnormal cellular activation occurs in most CVI patients. It is also possible that the raised levels of these soluble molecules play a part in the immunodeficiency.
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PMID:Raised serum levels of CD8, CD25 and beta 2-microglobulin in common variable immunodeficiency. 193 93


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