Serum interleukin-2 receptor as index of tumor burden in hairy cell leukemia.
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Biomarkers, Tumor↗
Biomedical subjects
F Vinante
Publications and source records attributed to F Vinante.
Shedding of the soluble form of the CD8 complex by CD8+/HLA-DR+ cells in HIV-1-infected patients.
High levels of the soluble form of the CD8 molecule (sCD8) are detectable in the serum of HIV-1-infected patients. To investigate the mechanisms accountable for the release of this molecule we evaluated the presence of sCD8 in the supernatants obtained from in vitro cultures of highly purified CD8 cells isolated from 20 HIV-1-infected patients. At resting conditions cultured CD8 cells from HIV-1-infected patients released low amounts of sCD8; no statistically significant differences were observed between unstimulated cultures from HIV-1-seropositive patients and from HIV-1-seronegative subjects at risk for HIV-1 infection or normal healthy controls. Following in vitro activation of highly purified CD8 cells with a series of stimulatory agents, including phorbol myristate acetate, phytohemagglutinin (PHA) and recombinant interleukin-2, CD8 cells of HIV-1-infected patients significantly increased the shedding of sCD8. By expressing the results of activation-related release index (ARRI = sCD8 levels detected in the cultures with stimulatory agent/sCD8 levels detected in the unstimulated cultures), significantly higher values were observed upon PHA stimulation in HIV-1-infected patients than in control subjects. In order to identify the cell subset responsible for the enhanced release of sCD8 by PHA-stimulated cultures, we correlated the amounts of sCD8 detected in the supernatants with the phenotypic profile of CD8+ cells recovered from the cultures. A significant relationship was demonstrated between the percentage of CD8+/HLA-DR+ lymphocytes and sCD8 levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Soluble molecules in lymphoproliferative disorders.
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Antigens, CD↗
Tumor necrosis factor-alpha and B-cell growth factor induce leukemic hairy cells to proliferate in vitro.
To clarify the mechanisms accounting for the hairy cell proliferation, in five patients with hairy cell leukemia (HCL), we evaluated the ability of neoplastic cells to proliferate in vitro in response to tumor necrosis factor-alpha (TNF-alpha), B-cell growth factor (BCGF), and interleukin 4 (IL-4). In addition, supernatants recovered from cultures of unstimulated hairy cells were tested for the capability to induce the proliferation of allogeneic hairy cells. We demonstrated that TNF-alpha and BCGF were able to induce the in vitro growth of hairy cells (stimulation index (SI) ranging, at different concentrations, from 1.6 to 10.7 and from 1.6 to 25.1 for TNF-alpha and BCGF, respectively). IL-4 did not show any proliferative effect on hairy cells. When unstimulated hairy cell supernatants were tested for the proliferative activity on allogeneic hairy cells, we demonstrated a low proliferative effect that was not inhibited by an anti-TNF-alpha antibody. Our findings demonstrate that unstimulated hairy cells proliferate in vitro in response to TNF-alpha and BCGF, thus suggesting that these cytokines could be involved in an autocrine model of cell proliferation.
Cell Division↗
[The immunophenotype in leukemia].
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Acute Disease↗
Serum levels of soluble CD30 molecule (Ki-1 antigen) in Hodgkin's disease: relationship with disease activity and clinical stage.
In all cases of Hodgkin's disease (HD) Reed-Sternberg (RS) cells express the CD30 antigen. It has been recently demonstrated that this molecule can be released from the cell membrane of CD30+ neoplastic cells in a soluble form (sCD30), detectable in culture supernatants and body fluids. In this paper we investigated by an immunoassay the serum levels of sCD30 in 58 patients with HD, in order to define the possible relationship of this molecule to the clinical and pathological findings. sCD30 molecule was found at detectable levels in 24 out of 50 patients (48%) with active disease, whereas it was always absent in control sera and in cases in complete remission. Among the patients with active HD, the incidence and mean values of detectable levels (+/- SEM) of sCD30 were higher in cases with progressive or relapsing disease (61.5%, mean 458 +/- 190 U/ml) as compared to those at presentation (43.2%, mean 116 +/- 33 U/ml). Among the cases at presentation, detectable levels were observed more often in patients with advanced stages (III + IV: 61%) and constitutional symptoms ('B': 61.5%) than in early stages (I + II: 26%) and without symptoms ('A': 33.3%). In addition, higher mean values were found in stages III + IV (182 +/- 60 U/ml) and in 'B' cases (208 +/- 73 U/ml) than in stages I + II (65 +/- 30 U/ml) or 'A' patients (64 +/- 26 U/ml). The above findings suggest a possible role for the sCD30 as a tumour marker in HD.
Adolescent↗
Increased serum levels of soluble IL-2 receptor, CD30 and CD8 molecules, and gamma-interferon in angioimmunoblastic lymphadenopathy: possible pathogenetic role of immunoactivation mechanisms.
Abnormal immunoreaction associated with increased cell activation phenomena might play a role in the pathogenetic events leading to the development of angioimmunoblastic lymphadenopathy (AILD). In the present study we investigated the serum levels of some soluble molecules related to cell activation in 24 patients with AILD at presentation. In particular, we measured by immunoenzymatic or immunoradiometric techniques the levels of the Tac peptide (sIL-2R), soluble CD30 (sCD30) and CD8 (sCD8) antigens, and gamma-IFN (gIFN). The results show that all the above molecules are increased as compared to normal controls, with a different pattern of increase for the different molecules. The sIL-2R levels were very high in all cases with no overlap between AILD and control samples (mean 6315 +/- 3374 U/ml, controls 271 +/- 112 U/ml, P less than 0.001). Very high values of the sCD30 antigen (722 +/- 895 U/ml) were detected in all cases but five, as opposed to the lack of detectable levels in controls. A significant increase of sCD8 (978 +/- 646 U/ml, controls 334 +/- 95 U/ml, P less than 0.01) and gIFN (329 +/- 236 U/ml, controls 97 +/- 43 U/ml, P less than 0.01) was also observed with some overlap between AILD samples and controls. The above findings further support the view that a condition of abnormally enhanced cell activation is likely to play a central role in the pathogenetic events leading to the composite clinicopathological picture of AILD.
Antigens, CD↗
Evaluation of serum levels of soluble interleukin-2 receptor in patients with chronic lymphoproliferative disorders of T-lymphocytes.
Serum levels of soluble interleukin-2 receptor (sIL-2R) have been evaluated in 33 patients with chronic lymphoproliferative disorders of T-lymphocytes, including 12 T-helper phenotype chronic lymphocytic leukemias (Th-CLL) and 21 lymphoproliferative diseases of granular lymphocytes (LDGL). All Th-CLL cases were negative for antibodies against type I human T-leukemia virus (HTLV-I). Serum levels of sIL-2R were significantly increased in patients with Th-CLL with respect to controls (P less than 0.02) and this increase was related to the clinical course of the disease. In fact, patients with rapidly progressive disease (mean survival, 11.6 +/- 3 months) showed significantly higher concentrations of sIL-2R than patients with less aggressive disease (mean survival, 39.5 +/- 5 months) (16,223 U/ml +/- 5612 versus 1447 U/ml +/- 817; P less than 0.05). A significant positive correlation was found between sIL-2R concentrations and the number of CD4-positive cells (r = 0.64; P less than 0.05). These data point to the possible use of sIL-2R levels as a marker of active malignancy in patients with Th-CLL. Patients with LDGL showed increased sIL-2R values (721 U/ml +/- 112) with respect to controls (334 U/ml +/- 28; P less than 0.005). However, the sIL-2R levels were lower than those detected in Th-CLL patients (P less than 0.05). Among the different correlations the authors tried to establish, the only observed difference was found between serum sIL-2R levels in the group of CD3+ LDGL patients with respect to CD3- LDGL cases (P less than 0.05).
Antigens, CD↗
Functional analysis of cytotoxic cells in patients with acute nonlymphoblastic leukemia in complete remission.
In the current study, we investigated the cytotoxic ability of peripheral blood mononuclear cells (PBMC) recovered from patients with acute nonlymphoblastic leukemia (ANLL) in complete remission (CR) against natural killer (NK)-sensitive, NK-resistant, autologous and allogeneic leukemic target cells taken at diagnosis. Our purpose was to define the role played by cytotoxic mechanisms in the control of leukemic cell growth in ANLL. Experiments were carried out at resting conditions and after in vitro activation with recombinant interleukin-2 (rIL-2) and anti-CD3 monoclonal antibody (moAb). At resting conditions, PBMC recovered from ANLL patients displayed a NK function that was not significantly different from controls (mean +/- standard error of the mean [SEM]: 21.9% +/- 3.9% versus control values of 27.5% +/- 2.9%; the P value was not significant [NS]), but they were unable to show cytotoxic activity against autologous and allogeneic leukemic cells. After in vitro boosting with rIL-2, PBMC were able to generate lymphokine activated killer (LAK) cells, as demonstrated by an increased killing of NK-resistant Daudi targets (16.3% +/- 2.7%). Although LAK activity was quantitatively lower than in control subjects (mean +/- SEM: 16.3% +/- 2.7% versus control values of 79.8% +/- 3.1%; P less than 0.001), it still exerted a cytotoxic effect against autologous and allogeneic leukemic cells. Similar results were obtained when anti-CD3 moAb was used as a stimulus in vitro. Our data suggest that nonspecific cytotoxic cells may be triggered to exert an in vitro cytotoxic effect on leukemic cells, which could possibly play a key role in vivo in the control of leukemic cell growth regulation.
Adult↗
Serum levels of soluble interleukin-2 receptors in acute and chronic viral hepatitis.
To analyze interleukin-2-dependent immunoregulatory function in hepatitis B virus infection and in other forms of viral hepatitis, levels of soluble interleukin-2 receptors (sIL-2R) were measured by an enzyme-linked assay in sera from patients with acute and chronic viral hepatitis of different etiology. Increased sIL-2R levels were detected in the early phase of acute hepatitis type A and type B, but not during acute non-A, non-B hepatitis. Among 46 patients with chronic hepatitis B virus infection, levels of sIL-2R were significantly increased only in cases with chronic active hepatitis, while they were about normal in chronic persistent hepatitis or in healthy carriers of the infection. These differences were independent of virus replication, being maintained when patients were stratified according to HBeAg/anti-HBe status and to serum HBV-DNA. Nine patients with chronic active hepatitis type B and high sIL-2R levels at presentation were followed prospectively for two to eight years, and in HBeAg-positive patients, the behavior of receptor levels closely paralleled disease activity. These results, which may reflect increased shedding of IL-2R by activated T lymphocytes in patients with active destruction of HBV infected hepatocytes, indicate the usefulness and potential prognostic importance of serum sIL-2R determination in patients with chronic viral hepatitis. Patients with chronic non-A, non-B hepatitis had much lower sIL-2R levels, although their liver disease was similar to hepatitis B cases, suggesting that different pathogenetic mechanisms operate in these patients.
Acute Disease↗
Increased levels of soluble CD8 molecule in the serum of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related disorders.
In this study we investigated the serological levels of the soluble form of the CD8 molecule (s-CD8) in 97 human immunodeficiency virus (HIV) seropositive patients. The control groups included 20 normal heterosexual subjects and 19 healthy seronegative subjects belonging to risk groups for AIDS. Our results show that patients with HIV infection have significantly higher levels of s-CD8 U/ml than the control groups. When the patients were further subdivided according to the Centers for Disease Control (CDC) classification, s-CD8 U/ml values were consistently increased in all HIV patients, irrespective of the CDC stages. No statistically significant correlation was found between the serological levels of s-CD8/ml and the absolute numbers of CD8 lymphocytes/mm3, in both HIV seropositive patients and control groups. Since in the more advanced stages of HIV infection (IV-A, IV-C1) the decrease in the absolute number of CD8+ cells was not followed by a decrease in s-CD8 levels, it is conceivable that an increased release and/or shedding of s-CD8 per cell might occur in these patients. In fact, when the results were expressed as s-CD8 units per CD8 positive cell (s-CD8/absolute number of CD8), the levels of s-CD8/cell were higher in patients belonging to the IV-A and IV-C1 CDC groups (1.94 U/cell +/- 0.33 and 3.39 U/cell +/- 0.5, respectively) compared to normal controls (P less than 0.001), HIV seronegative subjects at risk for AIDS (P less than 0.001), and the other patients' groups (II and III CDC groups, respectively, P less than 0.001 and P less than 0.001). The evidence herein provided that in patients with HIV infection s-CD8 levels are increased suggests a possible pathogenetic role of the cells involved in the release of this molecule.
AIDS-Related Complex↗
Serum levels of soluble CD8 are increased in patients with B chronic lymphocytic leukemia.
Serum levels of the soluble form of the CD8 (s-CD8) antigen were evaluated in the peripheral blood of 44 patients with B-CLL, using an enzyme-linked immunosorbent assay, and were correlated with clinical features and relevant hematological and immunological data. Increased values were observed with respect to normal age-matched controls (mean +/- S.E.M. 603 U/ml +/- 81 vs. 315 U/ml +/- 31, respectively; P less than 0.0001). This increase was observed in all stages of the disease, excluding stage 0 (mean 277 U/ml +/- 45). A general trend pointing to lower values overall in patients with less invasive disease was observed. In fact, the rank correlation test showed that the serum levels of s-CD8 correlate significantly with the WBC counts, the CD4/CD8 ratio, and also with the levels of serum immunoglobulins. On the contrary, no correlation was observed between s-CD8 levels and the absolute number of circulating CD8+ cells in individual cases. Therefore, the increase of s-CD8 is unlikely to be a mere expression of the increase of the CD8 cell number, but seems related to an increase of the activation phenomena involving the CD8+ T cell subset.
Antigens, Differentiation, T-Lymphocyte↗
Increased levels of soluble interleukin-2 receptor in non-Hodgkin's lymphomas. Relationship with clinical, histologic, and phenotypic features.
In this study the authors investigated the serum levels of the released soluble form of interleukin-2 receptor (sIL-2R) in patients with non-Hodgkin's lymphomas (NHLs). Data were evaluated in relationship to the morphologic and immunophenotypic heterogeneity of NHL at diagnosis and in progressive advanced diseases. Increased sIL-2R levels were found in most cases, when compared with levels observed in healthy controls. No obvious statistical correlation has been observed between sIL-2R values in different NHL subtypes as defined by current classifications. On the other hand, major significance was related to the extent of the disease. Very high values, comparable to those observed in hairy cell leukemia, were observed in a number of large cell NHLs complicating low-grade B-cell lymphoproliferations and in a single case of T-cell Kil+ NHL. The authors' findings suggest that the detection of sIL-2R in NHL may represent a good marker in improving risk assignment of single cases and/or for monitoring remissions and exacerbations during the treatment of cases with very high levels at diagnosis. Nevertheless, the observed overlap between groups on an individual case basis can render the clinical application of this marker problematic.
B-Lymphocytes↗
Serum levels of soluble interleukin-2 receptor in hairy cell leukaemia: a reliable marker of neoplastic bulk.
In hairy cell leukaemia (HCL), the strong membrane expression of the Tac antigen, corresponding to the p55 chain of the interleukin-2 receptor (IL-2R), is associated with the presence in the serum of high levels of a soluble form of the same molecule (sIL-2R). Previous observations that therapy-induced clinical and haematologic improvement in HCL is accompanied by a progressive decrease of sIL-2R suggest a possible correlation between sIL-2R levels and tumour burden. To verify this hypothesis, we monitored the variation of sIL-2R values in 13 non-splenectomized HCL patients admitted for treatment with recombinant interferon alpha-2. The data were correlated with the estimated weight of bone marrow (BM) and spleen infiltration, which in these patients almost entirely account for the tumour mass. The regression analysis test showed a direct correlation between sIL-2R values and both BM neoplastic involvement (r = 0.63) and spleen tumour mass (r = 0.76). In addition, the correlation was further improved (r = 0.86) when sIL-2R values were correlated with the total neoplastic mass, as calculated by the sum of spleen and BM neoplastic tissue weight. These data indicate that the detection of sIL-2R in HCL is a reliable non-invasive marker of tumour burden, which can be regarded as an additional useful tool for monitoring treatment response.
Adult↗
Increased serum levels of soluble interleukin-2 receptor in patients with systemic lupus erythematosus and rheumatoid arthritis.
In this study we investigated the serum levels of a released soluble form of the interleukin-2 receptor (sIL-2R) in 42 patients with rheumatoid arthritis and in 12 cases of systemic lupus erythematosus. Data were evaluated in relationship to the clinical phase and compared with those observed in normal controls (N = 56) and in osteoarthritis (N = 7). Increased levels were observed in both rheumatoid arthritis (mean +/- SE, 604 +/- 49 U/ml) and systemic lupus erythematosus (1438 +/- 481 U/ml). These values were significantly higher than in control (256 +/- 15 U/ml; P less than 0.001) and in osteoarthritis (298 +/- 33 U/ml; P less than 0.001) groups. In addition, the highest values were associated with the active phases of both rheumatoid arthritis (active vs inactive, 771 +/- 78 vs 451 +/- 39 U/ml; P less than 0.001) and systemic lupus erythematosus (active vs inactive, 2108 +/- 489 vs 499 +/- 75 U/ml; P less than 0.001). Our findings suggest that the detection of sIL-2R in rheumatoid arthritis and in systemic lupus erythematosus may represent a good marker of disease activity, which indirectly indicates the ongoing activation and/or proliferation of immunoreactive cells which are involved in the pathogenetic events of these autoimmune conditions.
Acute Disease↗
Natural killer cell function and lymphoid subpopulations in acute non-lymphoblastic leukaemia in complete remission.
A long term follow-up study has been undertaken in 33 patients with acute non-lymphoblastic leukaemia (ANLL) in order to establish whether a correlation exists between the clinical course and the immunologic pattern of lymphoid subpopulations. Peripheral blood lymphoid cells have been investigated longitudinally (each 1 to 4 months) during complete remission (CR), by morphologic, phenotypic and functional analyses. Particular attention has been paid to the evaluation of the natural killer (NK) cell compartment, by the detection of cells expressing an NK-related phenotype and by NK in vitro assay. Among the patients so far evaluable, 20 relapsed (R) and 10 are long survivors in CR 'off therapy' (LS). The most relevant finding was represented by statistically higher values of NK activity observed in LS vs. R patients (P less than 0.01). The removal of adherent cells before the NK assay, performed to investigate the possible inhibitory effect on NK function played by the macrophage component, abolished this difference, due to a selective increase of NK function in the R group. The longitudinal study revealed that NK activity tended to decrease in individual patients who subsequently relapsed. These data suggest a possible role of NK cells in the relapse control of ANLL, although it cannot be excluded that the low level of NK activity observed in the R group is the result of impending relapse rather than its cause.
Adolescent↗
Origin of the soluble interleukin-2 receptor in the serum of patients with hairy cell leukemia.
High levels of soluble IL-2 receptor (sIL-2R) are detectable in the serum of HCL patients. To determine the cell source of this molecule, we evaluated the presence of sIL-2R in the supernatants obtained from in vitro cultures of leukemic (hairy cell, HC) and non-leukemic lymphocytes from six untreated HCL patients and from an additional four patients under therapy with rIFN-alpha 2. We demonstrated that cultured HCs at resting conditions were able to spontaneously release the sIL-2R, whereas control enriched B cells did not. This phenomenon was present only when culturing HCs recovered from patients observed at the time of diagnosis but was not observed during treatment with rIFN-alpha 2. Following activation in vitro with a series of different stimulatory agents including BCGF, phorbol myristate acetate, and anti-human IgM antibody, cultured HCs increased their capability to shed the IL-2R molecules. On the other hand, the release of sIL-2R from enriched T cell populations from HCL patients did not significantly differ from the value obtained in controls. Taken together, these findings provide evidence that leukemic B cells represent the main source of sIL-2R in HCL patients and further emphasize the importance of evaluating this parameter as a relevant marker for monitoring the effectiveness of rIFN-alpha 2 therapy.
Adult↗
Immunologic abnormalities in angioimmunoblastic lymphadenopathy.
In this study we describe the results of phenotypic, serologic, and functional analyses performed in nine patients with angioimmunoblastic lymphadenopathy (AILD). The study investigates the nature of the T-cell defects which seem to represent a consistent feature in this disease. The study, based on the analysis of T-cell subsets with monoclonal antibodies and on functional in vitro tests, showed the following main abnormalities: reduction of the absolute number of circulating T-cells; inversion of the CD4/CD8 ratio, both in the peripheral blood and in the involved lymph nodes; high percentages of activated T-cells (CD8+/HLA-DR+); defective T-cell response in vitro to the PHA mitogen; and minimal helper and enhanced in vitro suppressor functions. Some of these immunologic dysfunctions are also observed in acquired immune deficiency syndrome (AIDS) which has in common with AILD several clinical features. However, no evidence of HTLV-III infection could be demonstrated in our patients with AILD.
Acquired Immunodeficiency Syndrome↗