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Biomedical subjects

M Scudeletti

Publications and source records attributed to M Scudeletti.

At least 37 records · Page 2Linked to original sources
PubMed1996

IL2 triggers a tumor progression process in a melanoma cell line MELP derived from a patient whose metastasis increased in size during IL2/INFalpha biotherapy.

Human melanomas may express both in vivo and in vitro functional IL-Rs and may be expected to directly respond to injected IL2. This may generate biological situations which may be favourable for the patient, but also for tumor progression. Here, we analyse the latter hypothesis. MELP is a melanoma cell line derived from a patient whose metastasis increased in size during IL2/IFN alpha biotherapy [correction of biotheraphy]. These cells have been characterized in vitro for their phenotype and for their sensitivity to IL2. In vitro MELP cells express an IL2-R alpha(+) beta(+) gamma(-) phenotype and IL2 treatment induces the acquisition of new functional characteristics represented (i) by the increased surface expression of two markers of metastatic evolution (ICAM-1 and CD44); (ii) by the stable induction of the IL2-R gamma with the appearance of functional IL2-R beta complex, which are also recognized by GM-CSF; (iii) by the inhibition of transcription of a regulatory cytokine such as IL6; (iv) by a differential effect of IL6 on CD44 surface expression in MELP cells treated or not with IL2 (MILG cells); (v) by the acquisition of faster growth rates and appearance of piling up and multilayer cellular organization; (vi) by the development of rapidly growing tumors in nude mice. IL2 induces in MELP cells a tumor progression process that could mimic the metastatic evolution observed in vivo during biotherapy. Therefore, MELP phenotype may help to define a subset of patients in which IL2 therapy may trigger unfavourable evolution.

Adult↗
PubMed1996

MEL-P, a GM-CSF-producing human melanoma cell line.

A human melanoma cell line, MEL-P, expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and its specific receptor was newly established from a primary nodular lesion of a patient with a particularly unfavourable prognosis. Cytogenetic, immunophenotypic, cytokine and intercellular adhesion molecule (ICAM)-1 production analyses confirmed that this cell line was similar to the fresh melanoma cells from which it had been established. MEL-P constitutes a valuable model for the study of multistep tumour progression and the role of biologically active GM-CSF production in human malignant melanoma. Our results show a decreasing expression of HLA class I molecules during in vitro culture, when GM-CSF secretion attains the highest levels, and a constantly high production of ICAM-1. The inhibitory effect of GM-CSF antisense treatment on cellular growth might suggest the presence of an autocrine mechanism. On the whole, these data are consistent with the possible involvement of high GM-CSF production in the metastatic competence of melanoma cells through the autocrine mechanism of growth and/or the activation of other migration-related molecules by its local production in metastatic invasion.

Adult↗
PubMed1996

Prednisone increases apoptosis in in vitro activated human peripheral blood T lymphocytes.

Glucocorticoid hormones (GCH) regulate, through the apoptotic process, the negative selection of immature T cells in the thymus. Because apoptosis seems to occur also in the maintenance of peripheral tolerance, we have investigated whether GCH may induce apoptosis in human mature lymphocytes. Peripheral blood lymphocytes (PBL) or peripheral CD4(+) and CD8(+) T cell subsets were cultured in the presence of phytohaemaglutinin (PHA) or PHA and prednisone (PDN) at 10(-3)-10(-12)M concentrations for 72, 96 and 120h. Cell cycle and membrane antigen expression were evaluated by flow cytometry and DNA degradation was detected by agarose gel electrophoresis. PDN blocks PBL growth in the G1 phase of cell cycle and inhibits both IL-2 receptor (IL-2R) expression and IL-2 secretion. Apoptosis is clearly increased by PDN in PHA-activated human PBL, and the apoptotic effect of PDN is stronger on CD8(+) than on CD4(+) T lymphocytes. All these effects are dose- and time-dependent. The addition of exogenous IL-2 did not rescue lymphocytes from PDN-increased apoptosis. These results show that PDN increases apoptosis in mature activated human peripheral blood lymphocytes, suggesting a possible role of GCH in the maintenance of immune tolerance at post-thymic level.

Adult↗
PubMed1996

Serum HLA class I antigen levels in allogeneic bone marrow transplantation: a possible marker of acute GVHD.

The levels of serum HLA class I antigens were determined at weekly intervals up to 5 weeks in 46 patients who had undergone allogeneic BMT. In patients with GVHD grade I or with GVHD grade I and fever of unknown origin (FUO), serum HLA class I antigen levels did not change during the observation period. In patients with GVHD grade II-IV serum HLA class I antigen level significantly increased in the week before the onset of GVHD, was maximal at the onset of GVHD and then persisted unchanged in the following 2 weeks. In patients with GVHD grade I or GVHD grade II-IV and infections whose onset coincided with that of acute GVHD a significant increase of serum HLA class I antigen level was found 2 weeks after the onset of the infectious episode. An increase of serum HLA class I antigen level was also found before the onset of repetitive GVHD grade II-IV episodes as well as during and after infectious episodes whose onset occurred after the onset of acute GVHD. The mean +/- s.d. concentrations of serum HLA class I antigens during GVHD grade II-IV episodes (9.4 +/- 3.4 micrograms/ml) and 2 weeks after the onset of infectious episodes (7.1 +/- 1.6 micrograms/ml) are significantly (P < 0.01 and P < 0.05, respectively) higher than that found 2 weeks before the onset of GVHD (3.0 +/- 0.5 micrograms/ml). The results of the present investigation suggest that measurement of serum HLA class I antigen level may be a possible marker to detect an acute GVHD following BMT.

Acute Disease↗
PubMed1996

[The immunological activity of corticosteroids].

Corticosteroids are among the most used anti-inflammatory and immunosuppressive drugs. The most recent reports have shown that the corticosteroids: A) modulate the lymphocyte recirculation and induce a lymphocyte depletion mainly regarding to the CD4 cells. B) Inhibit several lymphocyte activities, as well as their capacity to secrete cytokines and their clonal expansion under activating conditions. C) Induce apoptosis in primed T cells. D) Modulate the synthesis and activity of nuclear factors AP1 and NFkB. Moreover several data suggest that the molecular manipulations of cortisol, performed with the aim of improving its therapeutic efficiency, might change its capacity to bind the cytoplasmic receptor and/or generate CTS/CTS-R compounds that have different capacity to migrate through the nuclear membrane and/or to activate the nuclear responsive elements inducing different biologic responses.

Adrenal Cortex Hormones↗
PubMed1995

CD4+ Th0 cell clones, isolated from a metastatic lymph node of a melanoma patient, possess cytolytic function.

In the present study T lymphocytes isolated from a metastatic lymph node (T-LNL) of a melanoma patient have been cloned. In the attempt to verify whether T-LNL may acquire in vitro functional activities in the absence of tumour-associated antigens, they were cloned utilizing allogenic lymphocytes as feeder cells. Nineteen clones generated from T-LNL proved to be CD4+ and, among these, five were able to kill autologous and allogeneic human melanoma cells in HLA-class-II-restricted way. On the basis of their cytokine production, these CD4+ cytolytic T-LNL clones were shown to belong to the Th0 subset and three of them expressed the V beta 17 chain of the T cell receptor. These results suggest the presence of melanoma-specific but functionally inactive lymphocytes with T cell receptor oligoclonality in the lymph node environment. These specific T cells may acquire in vitro the capacity to kill autologous and allogeneic tumours without any induction by autologous melanoma cells.

CD4-Positive T-Lymphocytes↗
PubMed1995

Behavior of soluble HLA class I antigens in patients with chronic hepatitis C during interferon therapy: an early predictor marker of response?

Soluble HLA class I antigens (sHLA-I), beta 2-microglobulin (beta 2-mu) and alanine aminotransferase (ALT) serum levels have been evaluated in 16 patients affected by chronic hepatitis C treated for six months with recombinant interferon-alpha (rIFN-alpha, 3 MU three times a week). The predictor role of sHLA-I and ALT modifications with respect to the response to rIFN-alpha therapy was also evaluated. Six patients responded (group 1), five patients relapsed followed in initial responses (group 2), and five did not respond to rIFN-alpha treatment (group 3). The baseline serum levels of sHLA-I and beta 2-mu were significantly higher in all three groups of HCV-positive patients with respect to HCV-negative controls (P < 0.05). A significant increase of sHLA-I serum level with respect to baseline value (P < 0.001) was observed in group 1 patients after two weeks of rIFN-alpha treatment. sHLA-I serum level then decreased, although remaining steadily and significantly increased with respect to baseline (P values ranging from 0.05 to 0.01) in the following five months and then returned to baseline one month after the end of rIFN-alpha administration. No significant variations of beta 2-mu serum levels were detected throughout the observation period. In group 1 patients ALT serum levels significantly decreased after two weeks of rIFN-alpha treatment (P < 0.001) and then remained in the normal range throughout the observation period. In the other two groups of patients no relevant variations of sHLA-I and beta 2-mu serum levels were found during and after rIFN-alpha therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Interferons up-regulate with different potency HLA class I antigen expression in M14 human melanoma cell line. Possible interaction with glucocorticoid hormones.

The relative potency of interferon alpha (IFN alpha), interferon beta (IFN beta), and interferon gamma (IFN gamma) in inducing the expression of HLA class I antigens, as well as their capacity to counteract the inhibition induced by glucocorticoid hormones on HLA class I antigen expression, were analysed in the human melanoma cell line M14, both at membrane and at mRNA level. The data obtained indicate that (a) IFN enhance with different potency (IFN gamma > IFN beta > IFN alpha) the expression of HLA class I antigens in M14 cells, (b) prednisone inhibits HLA class I antigen expression, (c) glucocorticoid hormones, when associated with IFN alpha or IFN gamma, inhibit the HLA class I enhancement induced by IFN alone, and, finally, (c) the association between 1 microM prednisone or 1 microM deflazacort and IFN beta seems to potentiate the enhancing capacity of IFN on the expression of HLA class I molecules at the mRNA level. These findings, if confirmed, might indicate that IFN and glucocorticoid hormones are not mutually exclusive in the management of human melanoma.

Drug Synergism↗
PubMed1995

Increased serum concentration of soluble HLA-DR antigens in HIV infection and following transplantation.

HLA class I and class II antigens circulate in serum as soluble molecules. Increased concentrations of soluble HLA class I molecules have been demonstrated in viral diseases, in rejection episodes following organ transplantation and in graft versus host disease. To explore the possibility of a variation of the serum concentrations of soluble HLA class II molecules in the same pathologic conditions we developed a double determinant immune assay that detects whole soluble HLA-DR molecules (sHLA-DR). The mean level of sHLA-DR antigens in sera from 23 healthy individuals was 0.64 +/- 0.72 microgram/ml. Elevated serum concentrations of sHLA-DR molecules were detected in sera from HIV infected patients in CDC2/3 and in CDC4 C1 stages (2.0 +/- 1.7 micrograms/ml and 4.6 +/- 1.7 micrograms/ml, respectively), in sera from patients affected by acute rejection after liver transplantation (5.3 +/- 3.7 micrograms/ml) and in sera from patients affected by severe acute graft versus host disease following bone marrow transplantation (8.8 +/- 3.1 micrograms/ml). The increase of sHLA-DR molecules in these sera significantly correlated with the elevation of soluble HLA class I antigens (P = 0.0004). The reported data suggest that both soluble HLA class I and class II molecules serum levels increase during viral infections and strong immune reactions and could suggest the involvement of these molecules in immunoregulation.

Bone Marrow Transplantation↗
PubMed1994

Immune cell circulating subsets are affected by gonadal function.

Influence on the immune system activity by sex hormones has been widely reported. Fertile women are proner to the onset of autoimmune diseases than men, but this increased susceptibility disappears after menopause. The hormonal changes are very likely to be responsible for this event, but precise correlations between sex hormone levels and immune functions have not been defined. For this reason we have analyzed phenotype and natural cytotoxicity of peripheral blood lymphocytes (PBL) from 35 women in menopause, comparing them with the same parameters of 28 fertile and 8 postmenopausal women and correlating them with the hormonal pattern of each group. We have also considered 8 women with premature menopause. Hormonal levels have been detected by radioimmune assays, while PBL phenotype has been studied by immunofluorescence and FACS analysis. The natural killer (NK) cell activity has been calculated on the basis of a chromium release assay. Postmenopausal women showed a reduction of the number of total lymphocytes (1650 +/- 215 cells/mmc) in comparison to fertile women (2081 +/- 200 cells/mmc, P < 0.01). The decrease mainly involved B and CD4+ T lymphocyte subpopulations (P < 0.05 and P < 0.01, respectively). Women with premature menopause had lower percentage of CD4 lymphocytes (34% vs 47%, P < 0.01) and higher percentage of CD8 (30% vs 22%, P < 0.02) and NK cells (32% vs 14%, P < 0.009) than fertile women of the same age. The percentage of circulating lymphocytes expressing HLA class II antigens also resulted as being increased (22% vs 9%, P < 0.01). The number of total, CD2, CD4 T lymphocytes, B and NK cells correlated positively with LH and negatively with FSH serum levels (P < 0.05 and P < 0.002, respectively). PRL positively influenced CD2, CD4 and B lymphocyte numbers (P < 0.001). FSH and 17 beta-estradiol inversely affected CD8 and B lymphocyte numbers (P < 0.005 and P < 0.02, respectively). In conclusion, the increase of FSH and the decrease of PRL levels appear to be involved in the reduction of B and CD4 T lymphocytes thus lowering the risk for the onset of autoimmune diseases during and after menopause. Generalized activation of the immune system (raised expression of HLA class II antigens) with elevated numbers of cytotoxic subpopulations (CD8 and NK lymphocytes) is present in women affected by premature menopause suggesting the involvement of autoimmune dysregulation in the pathogenesis of this syndrome.

Adult↗
PubMed1994

Increased level of serum HLA class I antigens in HIV infection. Correlation with disease progression.

Analysis of (sHLA-I) antigens in a large number of HIV-positive subjects found a significant increase of their level, but did not detect any change in their molecular profile. Monitoring at yearly intervals for four years of the sHLA-I antigen level in 14 HIV-positive subjects with a normal sHLA-I antigen level at study entry showed a significant correlation between progressive increase of sHLA-I antigen level and disease progression. Furthermore, a Kaplan-Meier plot of the frequency of development of AIDS in 34 patients whose cases were followed for 7 years showed that sHLA-I antigen level is a strong predictor of progression to AIDS. Its predictive value is comparable to that of serum beta 2-mu level, greater than that of serum neopterin, and lower than that of CD4+ T-cell percentage. The predictive value of sHLA-I antigen level in combination with serum beta 2-mu level, neopterin level, or CD4+ T-cell percentage is greater than that of each individual variable. These results suggest that measurement of the sHLA-I antigen level may provide useful prognostic information in HIV-positive subjects.

CD4 Lymphocyte Count↗
PubMed1994

HLA class-I-soluble antigen serum levels in liver transplantation. A predictor marker of acute rejection.

The serum levels of sHLA-I have been determined in 16 patients following liver transplantation. sHLA-I levels did not show remarkable variations in six patients without evidence of transplant-related complications. sHLA-I levels strongly increased in 10 patients undergoing acute rejection episodes. In these patients, an average 20% daily increase of sHLA-I levels was detected on the 6 days preceding and on the 2 days following the rejection episode. A fast decrease of sHLA-I levels was observed in seven patients following treatment of acute rejection with anti-CD3 mAb. The serum level of sHLA-I antigens positively correlated with ALT serum level and inversely correlated with PT. The determination of sHLA-I in serum may therefore be proposed as a useful marker in the monitoring of patients following liver transplantation. The increase of sHLA-I antigens may predict the onset of acute rejection whereas their decrease may be related to a good response of acute rejection to immunosuppressive treatment.

Adult↗
PubMed1993

Immunotherapy with intralesional and systemic interleukin-2 of patients with non-small-cell lung cancer.

Eight patients affected by non-small-cell lung cancer were treated with intralesional and systemic recombinant IL-2 (rIL-2) injection with the aim of activating both tumour-infiltrating lymphocytes and circulating cytotoxic or killer cells. The schedule of treatment was as follows: a daily fine-needle transparietal intralesional rIL-2 injection (1 x 10(5) Cetus units) from day 1 to day 5 and systemic rIL-2 infusion (1 x 10(5) Cetus units kg-1 day-1) from day 6 to day 10. One to four cycles of treatment were received by each patient. Clinical and immunological evaluations were performed (a) before treatment, (b) following the intralesional rIL-2 administration, (c) 1 h after the beginning of rIL-2 infusion and (d) at the end of the systemic rIL-2 infusion. No complete remission was achieved, two patients showed a partial remission, three resulted in stable disease and three patients progressed. Natural killer and lymphokine-activated killer cell activity dramatically decreased 1 h after the beginning of rIL-2 infusion and increased at the end of treatment. A progressive increase of circulating CD8+ and HLA class II+ T cells as well as of CD8+ T cell clones, most of which displayed NK activity, was recorded following rIL-2 infusion. Present data indicate that (a) the local administration of rIL-2 coupled with systemic rIL-2 infusion may be suggested as an alternative approach for the immunotherapy of lung cancer, (b) rIL-2 induces different immunological modifications according to the route and the time of its administration and (c) rIL-2 administration increases the amount of circulating immune cells with potential antitumour activity.

Carcinoma, Non-Small-Cell Lung↗