Lorella Morosato

High serum level of the soluble form of CD30 molecule in the early phase of HIV-1 infection as an independent predictor of progression to AIDS.

ObjectiveTo determine the serum levels of the soluble form of the CD30 (sCD30) activation molecule in the early phase of HIV-1 infection, and to investigate the possible correlation with evolution to AIDS. MethodssCD30 values were determined by an enzyme-linked immunosorbent assay (ELISA) on serum samples collected at the time of the first evidence of HIV-1 infection in 110 individuals with a median follow-up of 56 months (range, 12–88 months), at the A1 (74 cases) or A2 (36 cases) stages of the 1993 revised Centers for Disease Control and Prevention classification. The data were evaluated using established clinical and immunological parameters, including circulating CD4+ T-cell count. The controls were 110 blood donors and 51 HIV-1 -negative subjects belonging to groups at risk for HIV-1 infection. ResultsElevated sCD30 levels ( 20 U/ml) were found in 83.6% of HIV-1 -infected cases and in 47% of at-risk seronegatives. Data analysis revealed that HIV-1-infected patients with higher sCD30 levels (>35 U/ml) experienced faster disease progression (P = 0.0002). This was also the case in patients at the earliest stage (A1) of HIV infection (P = 0.0027). In these latter cases the predictive value of sCD30 was independent of the initial absolute number of circulating CD4+lymphocytes. ConclusionsSerum levels of sCD30 are increased in the large majority of patients in the early phase of HIV-1 infection and represent an indicator of progression to AIDS independent of other prognostic parameters.

Progressive polarization towards a T helper/cytotoxic type-1 cytokine pattern during age-dependent maturation of the immune response inversely correlates with CD30 cell expression and serum concentration

In order to investigate the T cell cytokine profile during age‐dependent maturation of the immune response, we evaluated the cytokine expression of CD4+ and CD8+ circulating cells by flow cytometric single‐cell analysis after non‐specific stimulation in vitro in different age groups of normal individuals, from cord blood to adulthood. Moreover, we correlated these lymphocyte cytokine patterns with the expression/release of CD30, a member of the tumour necrosis factor (TNF) receptor superfamily, which has been suggested to be related to the T helper/cytotoxic (Th(c))2‐type immune responses, in order to verify this association in vivo, in non‐pathological conditions. The results showed a progressive increase of circulating Th(c)1‐type, interferon‐gamma (IFN‐γ)‐ and/or IL‐2‐producing T cells along with ageing and, conversely, a stable number, although higher than in cord blood samples, of CD4+/IL‐4+ T cells in the post‐natal groups. In addition, serum levels of soluble CD30 (sCD30) and numbers of circulating CD4+/CD30+ and CD8+/CD30+ T cells were significantly higher in children aged < 5 years in comparison with those found either in cord blood or in blood from both older children and adults. These data support the concept of a progressive polarization of the Th(c) cell cytokine profile towards the Th(c)1 pattern during age‐dependent maturation of the immune response. Moreover, the peak of CD30 expression/release in early infancy before the Th(c)1 shifting occurs, although not associated with a significant increase of circulating IL‐4+ T cells, raises the question of the possible relationship in vivo between CD30 and Th(c)2‐type immune responses.

High serum level of soluble CD30 in acute primary HIV-1 infection

CD30 has been suggested to play a role in HIV infection. In this study the serum concentration of soluble CD30 (sCD30) was determined by an ELISA essay on samples collected from patients with acute primary HIV‐1 infection during the acute phase (n = 17) and after seroconversion (n = 13). sCD30 during acute infection was consistently elevated (137.58 ± 120.33 versus 6.4 ± 5.4 U/ml (mean ± s.d.) in normal controls; P < 0.0001) and decreased after seroconversion (49.1 ± 66.17 U/ml; P = 0.0018 compared with acute infection). This trend mirrored the disappearance of detectable levels of HIV antigen in the blood, resulting in a direct correlation between sCD30 and HIVAg values (P = 0.002). These data suggest that the high levels of sCD30 observed during the peak concentration of HIVAg in acute primary HIV infection might reflect the high rate of viral replication.

ICAM‐1 tissue overexpression associated with increased serum levels of its soluble form in Hodgkin's disease

Summary. We investigated ICAM‐1/CD54 tissue immunoreactivity and serum levels of its soluble form (sICAM‐1) in patients with Hodgkins disease (HD) at diagnosis. ICAM‐1 was strongly expressed in involved tissues, and sICAM‐1 serum levels were higher in HD (79 patients) than in controls (P < 0 · 01), and in patients with more advanced or more active disease (stages III ± IV vI ± II: P= 0 · 002; stage ‘B’v‘A’: P <0 · 0001; ‘bulky’disease v non‐‘bulky’: P= 0 · 042). We suggest that tissue ICAM‐1 overexpression leading to increase of circulating sICAM‐1 may interfere with the lymphocyte adhesion machinary thus contributing to the well‐known immune derangement of HD.

Serum levels of p55 and p75 soluble TNF receptors in adult acute leukaemia at diagnosis: correlation with clinical and biological features and outcome

The tumour necrosis factor (TNF)/TNF‐receptor (TNFR) complex plays a role in the growth of leukaemic cells. We retrospectively investigated the relationship between pre‐treatment serum concentration of soluble TNFR (p55‐ and p75‐sTNFRs) and outcome in adult acute myeloid (AML 82 cases) and lymphoid (ALL 44 cases) leukaemia. Both sTNFRs were significantly higher in AML (p55‐sTNFR 4.53 ± 3.7, median 3.75; p75‐sTNFR 6.51 ± 5.25 ng/ml, median 4.72) and ALL sera (3.31 ± 1.5, median 2.95; 5.30 ± 2.3 ng/ml, median 4.56, respectively) than in controls (1.89 ± 0.5, median 1.98; 2.22 ± 0.8 ng/ml, median 2.37) (P < 0.01 for both sTNFRs). Fresh leukaemic cells expressed p55‐ and p75‐sTNFRs, which were modulated and released into the supernatant (SN) following short‐term in vitro culture, suggesting that in vivo sTNFRs were also leukaemia‐derived. Whereas no correlation was observed between sTNFRs and outcome in ALL, in AML higher p55‐sTNFR levels (> 3.75 ng/ml) were associated with shorter disease‐free survival (DFS) (P = 0.006) and overall survival (OS) (P = 0.0004). At multivariate analysis p55‐sTNFR was the most significant predictor of DFS (P = 0.006) and OS (P < 0.001). Our data suggest that the prognostic significance of p55‐sTNFR in AML could be related to relevant biological features of AML blasts.

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)

Soluble interleukin-2 receptor in hairy-cell leukemia: a reliable marker of disease.

SummaryThe CD25 molecule, which corresponds to the p55 α chain of the interleukin-2 receptors, is strongly expressed by neoplastic cells in hairy-cell leukemia and is released in large amounts in the soluble form which is detectable in serum. In order to assess the reliability of the soluble interleukin-2 receptor as a disease marker in the management of patients with hairy-cell leukemia, we investigated serum levels in 35 untreated patients and in 2 patients with the hairy-cell leukemia variant. In 21 of 35 patients soluble receptor levels were also monitored during and after recombinant interferon-α therapy. Clinical and hematological parameters were also assessed. Soluble interleukin-2 receptor levels were extremely high at the time of diagnosis in patients with typical hairy-cell leukemia [32,722±27,001 vs. 331±145 units/ml in controls (mean±SD)], but not in patients with the leukemia variant. A progressive decrease in soluble interleukin-2 receptor levels paralleled the clinical response to treatment, although normal values were never detected, even in patients who achieved an apparent complete remission. After recombinant interferon-α discontinuation, disease recurrence was accompanied by a progressive increase to pre-treatment soluble receptor levels. Overall, a close correlation was found between soluble interleukin-2 receptor values and total tumor burden (r=0.84,P<0.001). On the basis of these data, soluble interleukin-2 receptor should be regarded as a key marker in the management of patients with hairy-cell leukemia.

Circulating levels of soluble CD23 reflect clinical and biological features of leukemic B-cell chronic lymphoproliferative disorders

SummaryOne hundred and twenty-four sera, from patients with various leukemic B-cell chronic lymphoproliferative diseases were investigated at diagnosis by ELISA for their soluble CD23 content. Immunophenotyping was carried out in all patients, and in a selected subset the mean number of membrane-bound CD23 molecules per cell was also investigated. Seventy-three patients had typical B chronic lymphocytic leukenia, 41 leukemic B-cell disorders with atypical morphological and/or immunophenotypic features, 5 had low-grade follicular cell lymphoma in the leukemic phase, and 5 had splenic lymphoma with villous lymphocytes Soluble CD23 levels were significantly higher than in normal sera (mean±SD: typical B chronic lymphocytic leukemia 3,650±4,654 U/ml, atypical B chronic lymphocytic leukemia 3,440±4,671 U/ml, follicular cell lymphoma 3,200±1,511 U/ml, splenic lymphoma with villous lymphocytes 8,236±7,294 U/ml, controls 137±128 U/ml;P<0.001). More advanced Rais stages were related to higher soluble CD23 levels (P<0.01), both in typical and atypical B chronic lymphocytic leukemias, the highest levels and the best correlation with the absolute number of circulating CD19+ cells (r=0.50) being observed in the typical form. The number of membrane-bound CD23 molecules per cell was significantly higher in typical than in atypical B chronic lymphocytic leukemias (mean number 156,727±94,668 vs. 12,010±10,643,P<0.001). Our data suggest that soluble CD23 levels correlate with the clinical and biological features of leukemic B-cell lymphoproliferative disorders.

High Serum Levels of Soluble Interleukin-2 Receptor and Absence of Detectable Levels of Soluble CD30 Molecule: A Specific Diagnostic Combination for Hairy Cell Leukemia

Hairy cell leukemia (HCL) is almost constantly characterized by the presence of very high levels of a soluble form of the interleukin-2 receptor (sIL-2R). Since several other hematologic neoplasias also display very high levels of sIL-2R, this feature cannot be considered specific for HCL. On the other hand, most of the above hematologic disorders are also characterized by the presence of detectable levels of the soluble CD30 molecule (sCD30). In the present study we investigated the sera from 22 patients with HCL for the presence of detectable circulating levels of sCD30 in combination with the detection of sIL-2R. In this report we demonstrate that the high serum levels of sIL-2R found in all HCL patients were never associated with the presence of sCD30. Since this pattern is unlikely to be found in neoplastic conditions other than HCL, we suggest that the combined serum determinations of sIL-2R and sCD30 be used as a reliable additional tool for the diagnosis of HCL.

Correlation between clinical features and circulating levels of soluble intercellular adhesion molecule-1 in Hodgkin's disease

SummaryPrevious reports have suggested soluble intercellular adhesion molecule-1 as a marker of disease activity in Hodgkins disease. In the present study we investigated serum levels of intercellular adhesion molecule-1 at diagnosis in 104 patients with Hodgkins disease and in 77 of these patients following the achievement of complete remission (within 12 months of diagnosis). Mean serum levels at diagnosis were significantly higher in patients than in controls (P<0.0001) and were related to advanced stages of disease (P=<0.0001) presence of “B” symptoms (P<0.0001), abnormality of laboratory indexes (P<0.0001), erythrocyte, sedimentation rate values (r=0.41,P<0.0001) and serum levels of soluble interleukin-2 receptor α chain (r=0.51,P<0.0001). Mean values in complete remission were significantly lower than at diagnosis (P=0.003). Lower mean values at diagnosis were detected in 30 patients with advanced disease who attained complete remission, compared with 6 patients who failed to attain complete remission with standard treatment. We conclude that in Hodgkins disease, high serum levels of soluble intercellular adhesion molecule-1 are detectable at presentation and strictly correlate with some clinical features. Response to treatment is paralleled by reduced serum levels. Larger prospective studies are needed to evaluate the possible prognostic significance of serum levels of soluble intercellular adhesion molecule-1 at diagnosis.