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Biomedical subjects

M Massaia

Publications and source records attributed to M Massaia.

At least 37 records · Page 2Linked to original sources
PubMed1997

Hypernatremic dehydration in the elderly on admission to hospital.

Dehydration is the most common cause of fluid and electrolyte disturbances in the elderly. This condition is related to the lack of increase in water intake in the presence of an increased fluid loss. The aim of this study was to evaluate the prevalence of hypernatremic dehydration in elderly patients admitted to the hospital. We retrospectively studied 2,894 subjects admitted to the acute ward of the Geriatric Section of the Department of Medical and Surgical Disciplines of the University of Torino from January 1990 to July 1995. Among them 84 (2.9%) patients, mean age 77.3 +/- 9.8 years, had serum sodium levels and blood urea nitrogen greater than 145 mEq/L and 25 mg/dL respectively with serum creatinine below 3 mg/dL. The prevalence of hypernatremic dehydration increases with age. Only 1.6% of the subjects under 65 years old are affected by this condition, against 5.3% of those over 85 years. The mortality rate observed during hospitalization is 29.8%. Mortality is positively related to serum sodium levels. We found mortality rates of 33.3% and 71.4% respectively in subjects with serum sodium levels from 151 to 153 mEq/L and in those with values over 154 mEq/L. Both serum sodium levels and age are independent risk factors for mortality (O.R. 1.31 and 1.07 respectively).

Aged↗
PubMed1996

Selective induction of CD73 expression in human lymphocytes by CD38 ligation: a novel pathway linking signal transducers with ecto-enzyme activities.

CD73 is a glycosyl phosphatidylinositol (GPI)-anchored purine salvage enzyme (ecto-5'-nucleotidase (ecto-5'-NT), E.C. 3.1.3.5) whose expression on lymphocytes is dependent on their differentiation state and function. CD73 behaves as an agonistic molecule in signaling via the CD3/TCR and CD2 pathways and is associated with CTL generation, IgG production, and activation of resting naive CD8+ T cells. CD73 deficiency has been reported in a variety of patients with impaired T and/or B cell function. Thus, CD73 holds promise as a molecular target for intervention in the immune system, but the mechanisms regulating its expression are largely unknown. The aim of this study was to gain insight into the regulation of CD73 expression in human lymphocytes. CD38, another cell surface differentiation Ag with ecto-enzyme activities (NAD+ glycohydrolase, ADP-ribosyl cyclase, and cyclic ADP-ribose (cADPR) hydrolase), was found to specifically induce CD73 expression in T and B cell lines as well as in normal adult T and NK cells, cord blood T cells, and thymocytes. CD38 cross-linking induced a rapid export to the cell surface of pre-formed CD73 derived from an intracellular pool and not from de novo biosynthesis. This translocation was dependent on protein tyrosine kinase (PTK) activity and lasted approximately eight hours, after which CD73 was removed from the cell surface by enzymatic cleavage. CD73 was not induced by other agents that activate T cells and CD73 was the only GPI-anchored molecule up-regulated by CD38 ligation out of six analyzed. These results document a novel pathway in human lymphocytes leading from CD38 ligation to CD73 expression, which may result in the rapid acquisition of new functions, including increased purine salvage, increased sensitivity to Ag-induced activation, and the generation of adenosine (Ado) for Ado receptor signaling.

5'-Nucleotidase↗
PubMed1996

Clinical and immunological studies in advanced cancer patients sequentially treated with anti CD3 monoclonal antibody (OKT3) and interleukin-2.

CD3 engagement has been used as a surrogate for antigen-specific stimulation to trigger T cell effector functions. Exogenous IL-2 has been used to prolong and amplify CD3-induced T cell activation. Previous studies have been shown that CD3 reactivity is increased in cancer patients with preactivated (> 10% HLA-DR+) T cells in the peripheral blood. In this study, we report 9 courses of a single infusion of anti-CD3 mAb (OKT3) followed by continuous infusion of intermediate dose IL-2 in 4 cancer patients [2 multiple myeloma (MM), 1 B-cell lymphoma (NHL), 1 metastatic melanoma (ME)] with advanced disease and > 10% HLA-DR+ T cells in the peripheral blood. An increase of lymphocytes, equally distributed between CD4+ and CD8+ subsets, was observed during treatment. Activation was phenotypically documented by the emergence of CD25+ cells in the peripheral blood. Unexpectedly, functional studies [including proliferation to mitogens (PHA, OKT3) and cytotoxicity assays (NK and LAK activities)] did not parallel phenotypic data and a slight decrease of all functions was observed after OKT3 and IL-2 treatment. OKT3 and IL-2 infusions were well tolerated and no limiting toxicity was observed. The treatment did not revert tumor progression in the 2 patients with progressive disease (NHL, ME) and had only minimal effects in the 2 MM patients with stable disease. These data indicate that the sequential administration of OKT3 and IL-2 had no anti-tumor activity in this small series of patients with advanced cancer who were selected for treatment because of an increased number of HLA-DR+ T cells in the peripheral blood. A discrepancy was observed between the emergence of CD25+ T cells and the clinical outcome.

Antibodies, Monoclonal↗
PubMed1995

Dysregulated Fas and Bcl-2 expression leading to enhanced apoptosis in T cells of multiple myeloma patients.

We have previously reported the presence of activated (HLA-DR+) T cells in multiple myeloma (MM) patients. These cells produce high amounts of interleukin (IL)-2 and interferon (IFN)-gamma and generate a potent antiplasma cell activity after appropriate in vitro stimulation, but they are unable in vivo to hold in check the disease. Activated T cells are highly susceptible to apoptosis, a form of programmed cell death involved in the modulation of immune responses and regulated by molecules such as Fas (CD95) and bcl-2. The aim of this study was to determine the expression of Fas and bcl-2 antigens and the susceptibility to apoptosis in T cells of MM patients. Fas+ cells were significantly higher, whereas bcl-2+ cells were significantly lower in MM patients than in the controls. MM patients with the highest number of HLA-DR+ T cells showed the highest Fas and the lowest bcl-2 expression. Two-color cytofluorometric analysis confirmed in individual cells that HLA-DR+ T cells coexpressed Fas and lacked bcl-2. Susceptibility to apoptosis was then investigated to evaluate the consequence of dysregulated Fas and bcl-2 expression. The percentage of apoptotic cells after incubation in medium alone (spontaneous apoptosis) or in the presence of methylprednisolone (MP) or anti-Fas monoclonal antibody (triggered apoptosis) was significantly higher in MM and mainly restricted to HLA-DR+ T cells. Spontaneous apoptotosis was reverted by exogenous IL-2. In conclusion, MM T cells have a dysregulated expression of Fas and bcl-2 antigens that is associated with an enhanced susceptibility to apoptosis. These data may unravel a novel mechanism by which activated MM T cells are weakened in their ability to exert an effective antitumor activity in vivo.

Antigens, Surface↗
PubMed1995

CD3-induced T-cell activation in the bone marrow of myeloma patients: major role of CD4+ cells.

A large expansion of activated T cells (CD3+CD25+) with the potential to act as anti-tumour effector cells is inducible in multiple myeloma (MM) patients by culturing bone marrow mononuclear cells (BMMCs) with the anti-CD3 monoclonal antibody (mAb) OKT3. The aim of this study was to provide a greater characterization of CD3-activated T cells. On day 6, most T cells coexpressed the CD11a, CD18, CD54, CD45R0 antigens and consisted of activated (CD25+) CD4+ and CD8+ cells in nearly equal proportions. Kinetics studies showed that CD4+CD25+ cells proliferated more rapidly and peaked earlier than CD8+CD25+ cells. When experiments were performed with purified subpopulations by removing CD4+ cells (resulting in CD8+ BMMCs) or by removing CD8+ cells (resulting in CD4+ BMMCs). T-cell activation and autologous plasma cell decrease were observed in CD4+ BMMCs only. Transwell cultures showed that CD4 help was necessary to make CD8+ BMMCs susceptible to CD3 stimulation. Relevant amounts of IL-2 were found in the supernatants of CD4+ BMMCs cultures, whereas no secretion of IL-4 was detected, indicating a Th1-like profile of CD3-activated CD4+ cells. These data indicate that CD4+ cells proliferate earlier and provide optimal help to induce the subsequent expansion of CD8+ cells after CD3 stimulation of MM BMMCs. Adequate stimulation of CD4+ cells is therefore essential in any strategy aiming to recover T-cell-mediated immunity in MM.

Bone Marrow↗
PubMed1995

Reversible bronchial hyperresponsiveness induced by OK-T3/IL-2 administration in a patient with multiple myeloma.

Severe bronchial hyperresponsiveness to methacholine developed after intravenous therapy with OK-T3 and IL-2 in a patient with multiple myeloma, in whom no factors known to be associated with bronchial hyperresponsiveness were present. A substantial increase and activation of peripheral T-lymphocytes was observed after immunotherapy. Bronchial responsiveness and lymphocyte subsets both returned to normal baseline values 2 months after the patient was shifted to subcutaneous low dose administration of IL-2. The strict association between peripheral T-lymphocytes activation and the development of bronchial hyperresponsiveness suggests a causal relationship.

Antibodies, Monoclonal↗
PubMed1995

T cells in multiple myeloma: is this a reliable population to count on as antitumor effector cells?

Multiple Myeloma (MM) is still a long way from being cured. Disease evolution has been associated with a number of phenotypic and functional alterations in T cells, indicating that a progressive deterioration of cellular immunity might facilitate the negative outcome. Despite these correlations, specific interactions between tumor and T cells have been demonstrated indicating that a population liable to be exploited as antitumor effector cells exists in vivo. This review aims at recording some evidence obtained in our laboratory demonstrating that MM T cells, despite the variety of their alterations, can still generate potent antitumor activity. Adequate stimulation, however, is required to exploit this ability.

Animals↗
PubMed1995

Usefulness of frequency analysis of cytotoxic T-lymphocytes precursors (CTL-p) for selection of HLA matched unrelated marrow donors.

A child with Sanfilippo syndrome and 5 potential unrelated marrow donors were typed serologically, tested in mixed lymphocyte reaction and typed by restriction fragment length polymorphism analysis in attempt to find a suitable donor. All donors were found to be identical with the recipient, however, these studies were not conclusive in identifying the best match donor. Therefore, recipient-donor pairs were examined by HLA-DR oligotyping. In addition we have studied the potential of cytotoxic T-lymphocytes precursors (CTL-p) analysis as a means of selection for matched unrelated donors. Low frequencies (1/10(5)) of pretransplant CTL-p correlated with oligotyping identity in all donor-recipient pairs evaluated. In one case oligotyping disclosed a previously unrecognized HLA-DRB1 disparity. This resulted in high frequencies of CTL-p (1/35,000). Based on this experience we can argue that CTL-p analysis may be used as an additional tool for selection of compatible unrelated marrow donors.

Bone Marrow Transplantation↗
PubMed1994

Serum levels of tumour necrosis factor-alpha in patients with B-cell chronic lymphocytic leukaemia.

Serum levels of tumour necrosis factor-alpha (TNF-alpha) have been evaluated in the peripheral blood of 91 patients with B-cell chronic lymphocytic leukaemia (B-CLL), and have been correlated with the clinical stage (according to Rai's staging system) and relevant haematological and immunological data. Increased values were detected, compared to 36 normal age-matched controls (36 pg/ml +/- 5 versus 0.11 pg/ml +/- 0.08; P < 0.05). An increase of TNF-alpha serum levels was observed in all stages including stage 0, with a progressive increase in relation to the stage of the disease. A significant relationship between serum TNF-alpha levels and the number of circulating monocytes (P < 0.002) and an inverse correlation with the level of the haemoglobin (P < 0.001) was established, as defined by the Pearson's correlation test. In contrast, no correlation was observed between TNF-alpha serum levels and the other parameters taken into account, including the white blood cell and platelet counts, the absolute number of peripheral blood (PB) lymphocytes, CD5+ B lymphocytes, CD57+ lymphocytes, serum levels of lactic dehydrogenase, total serum immunoglobulins and the serum levels of IgG, IgA and IgM. These data suggest that, in addition to the B-CLL neoplastic cells, the PB monocytes may be involved in the release of TNF-alpha.

Aged↗
PubMed1994

Correlation between disease activity and T-cell CD3 zeta chain expression in a B-cell lymphoma.

The T-cell receptor (TCR)/CD3 complex is the surface molecule responsible for the highly specific response to foreign antigens, including tumour-associated antigens. and correlations have been observed with disease status. Recently, low amounts of CD3 gamma and CD3 zeta chains in the CD3/TCR complex have been reported in long-term tumour-bearing mice as a possible mechanism for the impaired T-cell responses. In this study we report a B-cell lymphoma in which T-cell CD3 zeta expression correlated with disease activity.

CD3 Complex↗
PubMed1993

Rapid generation of antiplasma cell activity in the bone marrow of myeloma patients by CD3-activated T cells.

We have recently shown that peripheral blood T cells of multiple myeloma (MM) patients are very susceptible to stimulation of the T-cell receptor/CD3 complex with anti-CD3 monoclonal antibodies (MoAbs). CD3 stimulation is currently under clinical investigation as a nonspecific approach to boost antitumor effector mechanisms. The aim of this study was to determine whether the hyperreactivity of MM T cells to CD3 stimulation could be exploited to generate antitumor activity. Bone marrow mononuclear cells (BMMCs) from 65 MM patients were stimulated with the anti-CD3 MoAb OKT3 and the effect of this stimulation on autologous T cells and plasma cells was evaluated. The number of CD3+ CD25+ cells on day 6 was significantly higher in MM than the controls (30 normal individuals) (P = .001). Kinetic studies showed that 3H-thymidine incorporation peaked on day 3 and that the T-cell expansion peaked on days 5 and 6. In MM, T-cell activation markedly affected the survival of autologous plasma cells; their number in OKT3-treated cultures was significantly lower than in unstimulated cultures (P < .0001). T-cell activation and plasma cell decrease were not observed when T cells were removed from BMMC preparations. MM produced significantly higher levels of interferon-gamma (P = .005) and tumor necrosis factor-beta (P = .001), but lower levels of tumor necrosis factor-alpha (P < .001) than normal individuals. Interferon-gamma only was partially involved in CD3-induced plasma cell killing. Transwell cultures showed that the main mechanism by which CD3+ CD25+ cells affected plasma cells was direct cell-to-cell contact rather than cytokines. In conclusion, T cells in MM BMMCs possess distinct features in terms of susceptibility to CD3 stimulation and cytokine production compared with normal bone marrow T cells that can be exploited to generate antiplasma cell activity.

Antibodies, Monoclonal↗
PubMed1992

Immunologic characteristics of fibrillary glomerulonephritis.

IgG and IgA immune complexes, mononuclear phagocytic system function, interleukin-2 (IL-2) production by peripheral blood lymphocytes (PBL), serum-soluble IL-2 receptors, tumor necrosis factor, beta 2-microglobulin and IL-1 beta, HLA-DNA polymorphisms, immuno-isoelectrofocusing, phenotype of PBL, lymphocyte cytotoxicity, activation of lymphokine-activated killer cells and natural killer cell activity were evaluated in 8 patients with tubular/fibrillary glomerulonephritis (GN). No common serologic, immunologic or immunogenetic features suggestive of plasma cell dyscrasias were found. No elements to state whether these GNs represent a new entity or just atypical forms of known GN were found.

Adolescent↗
PubMed1992

Constitutive production of tumor necrosis factor-alpha in hairy cell leukemia: possible role in the pathogenesis of the cytopenia(s) and effect of treatment with interferon-alpha.

PURPOSE: In view of the pleomorphic role cytokines play in human lymphoproliferative disorders, we investigated the possible involvement of tumor necrosis factor-alpha (TNF) in hairy cell leukemia (HCL). PATIENTS AND METHODS: The levels of TNF were measured in the serum of untreated patients, and in the culture supernatants of unstimulated and stimulated enriched hairy cells (HC). Furthermore, the presence of TNF mRNA transcripts in HC was analyzed. The possibility that HC could inhibit the in vitro growth of normal erythroid progenitors via the release of TNF was also investigated. Finally, in an attempt to correlate the circulating levels of TNF with the course of the disease, these were retested during and after treatment with interferon-alpha (IFN). RESULTS: Significantly increased levels of TNF were found in the sera of untreated HCL patients compared with normal control sera were seen from patients with other diseases (P less than .001), with values greater than 10 pg/mL in 21 of 42 samples tested. A significant decrease (P less than .01) of TNF levels was recorded following IFN-2a administration in 16 cases with detectable pretreatment serum levels of TNF. In two cases, an increase in TNF values was associated with persistence or progression of disease. The likelihood that the circulating levels of TNF were caused by the pathologic cells is supported by the evidence that purified HC may release TNF spontaneously. The values can be markedly increased following in vitro activation with the phorbol ester 12-0-tetradecanoylphorbol-13 acetate (PMA), with B-cell growth factor (BCGF), and, to a further extent, with the combination of PMA and BCGF. Furthermore, the constitutive mRNA for TNF was found in seven of eight HC samples analyzed. Although supernatants of enriched HC, were capable of reducing the growth of normal bone marrow erythroid progenitors by 50%, duplicate experiments using an anti-TNF antibody produced an almost complete disappearance of the inhibitory effect. CONCLUSION: The results of this study suggest that TNF plays an important role in the pathogenesis of the cytopenia(s) characteristically associated with HCL.

Adult↗
PubMed1991

Detection of hyperreactive T cells in multiple myeloma by multivalent cross-linking of the CD3/TCR complex.

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.

Aged↗
PubMed1991

Dipyridamole in vitro suppresses the generation of T-cell cytotoxic functions: synergistic activity with cyclosporine.

The pharmacological activity of dipyridamole has been related to its ability to increase intracellular cAMP. Elevated cAMP concentrations can tone down T-cell effector functions. The aim of this study was to evaluate the dipyridamole effect in vitro on the generation of alloreactive cytotoxic and lymphokine-activated killer cells in normal T-cell subpopulations. Dipyridamole suppressed T-cell cytotoxic functions in a dose-dependent way. The kinetics of suppression showed that dipyridamole prevented the first step of cytotoxicity, i.e. activation of the lytic program following allogeneic or interleukin-2 stimulation. The ability of dipyridamole to interact with the immunosuppressive activity of cyclosporine was also investigated. By itself, cyclosporine suppressed the generation of alloreactive cytotoxicity, but not the generation of lymphokine-activated killer cells. A synergistic immunosuppressive activity between dipyridamole and cyclosporine was observed on the generation of alloreactive cytotoxic T lymphocytes.

Cell Cycle↗