CD40 activation of B-CLL cells is associated with augmented intracellular levels of CD79b and increased BCR expression in a subset of patients.
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Antigens, CD↗
Biomedical subjects
L Trentin
Publications and source records attributed to L Trentin.
The raft marker GM1 identifies functional subsets of granular lymphocytes in patients with CD3+ lymphoproliferative disease of granular lymphocytes.
The raft marker GM1 is expressed at very low levels at the plasma membrane of resting T cells (GM1dull). In vitro T-cell activation induces synthesis of this lipid, which is then expressed at very high levels (GM1bright) at the membrane of activated/effector cells. By flow cytometry and confocal microscopy, we analyzed the expression and organization of GM1 in a series of 15 patients with CD3+ lymphoproliferative disease of granular lymphocytes (LDGL). We found that GM1bright GL were detectable in fresh blood samples obtained in all LDGL patients, although the range of brightly stained cells was extremely variable. This distinctive in vivo pattern has never been shown in T lymphocytes from healthy individuals or in patients with different chronic T or B lymphoproliferative disorders or active infectious diseases. The low number of cycling cells detected in LDGL patients was always included within the GM1bright GL population. Interestingly, GM1bright GL were demonstrated to contain a higher amount of IFN-gamma as compared to GM1dull GL. These findings allow to distinguish subsets of GL at different levels of activation within the monoclonal CD3+ population. The GM1bright GL subset is likely to be responsible for the renewing of GL and thus for maintaining chronic proliferation.
Aged↗
Surface expression of squamous cell carcinoma antigen (SCCA) can be increased by the preS1(21-47) sequence of hepatitis B virus.
A variant of the serpin squamous cell carcinoma antigen (SCCA) has been identified as a hepatitis B virus binding protein and high expression of SCCA has recently been found in hepatocarcinoma. Since HBV is involved in liver carcinogenesis, experiments were carried out to examine the effect of HBV preS1 envelope protein on SCCA expression. Surface and intracellular staining for SCCA was assessed by FACS analysis. Preincubation of HepG2 cells and primary human hepatocytes with preS1 protein or with preS1(21-47) tetrameric peptide significantly increased the surface expression of SCCA, without modification of its overall cellular burden, suggesting a surface redistribution of the serpin. An increase in HBV binding and internalization was observed after pre-incubation of the cells with preS1 preparations, compared to cells preincubated with medium alone. Pretreatment of cells with DMSO, while not influencing SCCA basal expression, was responsible for an increase in the efficiency of HBV internalization and this effect was additive to that obtained after incubation with preS1 preparations. In conclusion, the HBV preS1(21-47) sequence is able to induce overexpression of SCCA at the cell surface facilitating virus internalization, while the increased efficiency of HBV entry following DMSO addition is not mediated by SCCA.
Antigens, Neoplasm↗
Ifosfamide and cyclophosphamide: effects on immunosurveillance.
Ifosfamide (IF) and cyclophosphamide (CTX) are chemotherapeutic agents frequently used in the treatment of human malignancies. These drugs can exhibit a bimodal mechanism of antitumor action with cytotoxic and immunomodulatory effects when associated with adoptive immunotherapy. In human peripheral blood lymphocytes, IF irreversibly inhibits the proliferative response to interleukin-2 in a dose-dependent manner and may also induce the phosphorylation of HSP27 by depleting glutathione. CTX promotes discrete cytokine profiles upregulating the expansion of Th1 cells, and this may be important to increase cellular immune response. The data presented in this report indicate that treatment regimens of CTX and IF may be used according to the tumor immunogenicity.
Adjuvants, Immunologic↗
Cxcr3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection.
The attraction of T lymphocytes into the pulmonary parenchyma represents an essential step in mechanisms ultimately leading to lung allograft rejection. In this study we evaluated whether IP-10 (CXCL10), a chemokine that is induced by interferon-gamma and stimulates the directional migration of activated T cells, plays a role in regulating the trafficking of effector T cells during lung allograft rejection episodes. Immunohistochemical examination showed that areas characterized by acute cellular rejection (grades 1 to 4) and active obliterative bronchiolitis (chronic rejection, Ca) were infiltrated by T cells expressing CXCR3, i.e., the specific receptor for CXCL10. In parallel, T cells accumulating in the bronchoalveolar lavage of lung transplant recipients with rejection episodes were CXCR3+ and exhibited a strong in vitro migratory capability in response to CXCL10. In lung biopsies, CXCL10 was abundantly expressed by graft-infiltrating macrophages and occasionally by epithelial cells. Alveolar macrophages expressed and secreted definite levels of CXCL10 capable of inducing chemotaxis of the CXCR3+ T-cell line 300-19; the secretory capability of alveolar macrophages was up-regulated by preincubation with interferon-gamma. Interestingly, striking levels of CXCR3 ligands could be demonstrated in the fluid component of the bronchoalveolar lavage in individuals with rejection episodes. These data indicate the role of the CXCR3/CXCL10 interactions in the recruitment of lymphocytes at sites of lung rejection and provide a rationale for the use of agents that block the CXCR3/CXCL10 axis in the treatment of lung allograft rejection.
Bronchiolitis Obliterans↗
High levels of soluble tumor necrosis factor superfamily receptors in patients with hepatitis C virus infection and lymphoproliferative disorders.
BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with a variety of extrahepatic disorders that may relate to direct or indirect effects of virus infection. Increased levels of soluble forms of tumor necrosis factor (TNF) receptors I and II, found in lymphoproliferative and infectious diseases, can interfere with TNF induced apoptotic cell death. The aim of the present study was to evaluate soluble TNF family receptors levels in lymphoproliferative disorders associated with HCV infection. METHODS: One hundred and forty-nine subjects were studied, including 120 anti-HCV positive patients (60 without lymphoproliferative manifestations, 47 with type II cryoglobulinemia and 13 with low-grade B-cell non-Hodgkin's lymphoma (B-NHL)) and 29 anti-HCV negative subjects (19 with low-grade B-NHLs and ten normal controls). RESULTS: Soluble forms of TNF receptor I, TNF receptor II and Fas were significantly higher in HCV positive patients compared with normal controls. The highest levels were found in patients affected by type II cryoglobulinemia or HCV positive lymphoplasmacytoid lymphomas (LP-NHLs), while HCV positive patients without type II cryoglobulinemia or with other B-NHLs had lower values (P < 0.01). CONCLUSIONS: Among HCV infected individuals, very high levels of soluble TNF receptors are significantly associated with type II cryoglobulinemia and LP-NHLs, suggesting that they may be involved in these proliferative disorders.
Adult↗
Knowledge and attitudes of Italian medical staff towards the approach and treatment of patients in pain.
This study is part of the project, "Towards a Pain-Free Hospital," which aims at improving the approach and treatment of the patient in pain. The objective of the study was to evaluate the knowledge and attitudes of doctors and nurses on the wards of a 1000-bed general hospital located in a rather densely-populated, industrialized area of Italy regarding the following topics: attention paid to pain, the use of analgesic drugs, and pain in children. In total, 669 nurses and 225 doctors completed a 16-item questionnaire evaluating knowledge and beliefs about pain. The overall percentage of correct answers was 61% (9.7/16). The score varied among the different wards and ranged from 48% (7.8/16) to 76% (12.3/16). Physicians scored 65% and nurses 59% (p < 0.001). The percentage of correct answers varied widely among the different items (from 30% to 96%). From these results, we conclude that there are still significant knowledge deficits and erroneous beliefs that may hamper treatment of the patient in pain. These results will help in conducting educational programs aimed at improving pain treatment in the different departments of the hospital.
Adult↗
Antiapoptotic effects of IL-15 on pulmonary Tc1 cells of patients with human immunodeficiency virus infection.
In the early phases of human immunodeficiency virus (HIV) disease a T-cell alveolitis sustained by cytotoxic T lymphocytes (CTL) with anti-HIV activity occurs in the lung. With the progression of HIV disease, pulmonary CTL become infected and their cytotoxic activity declines. To investigate the potential causes leading to this phenomenon, we evaluated T cells obtained from the bronchoalveolar lavage (BAL) of 18 HIV-infected patients with T-cell alveolitis. BAL T cells were CD45R0+/CD8+ defined as Tc1 cells because they expressed cytoplasmic interferon gamma (IFN-gamma) and were CXCR3+/IL-12Rbeta2+. Furthermore, they bore the interleukin (IL)- 15 receptor, Fas antigen, and tumor necrosis factor receptor (TNFR) type II. When cultured for 24 h highly purified BAL T cells showed an excessive spontaneous apoptosis; after activation with anti-CD3 or ionomycin, the proportion of T cells undergoing cell death increased. Interestingly, we found a direct relationship between the predisposition to undergo spontaneous apoptosis and the levels of Fas expression by BAL T cells. Alveolar macrophages (AMs) expressed high levels of IL-15 which paralleled the intensity of T-cell infiltration in most patients. The predisposition of CD8 T cells to undergo cell death was downregulated by the incubation with IL-15; the protective effect of the cytokine was dose-dependent. Nonetheless, AMs also expressed proapoptotic molecules, including membrane TNF-alpha (mTNF-alpha). Based on these observations it may be suggested that an excessive, spontaneous, and activation-induced apoptosis of pulmonary lymphocytes may be observed in HIV lung and that AMs are major regulators of T-cell homeostasis.
Adult↗
Telomerase activity and clinical progression in chronic lymphoproliferative disorders of B-cell lineage.
The activation of telomerase, which specifically occurs in neoplastic cells to avoid telomere attrition at each cell division, is a necessary event in tumorigenesis. The evidence that telomerase is also present in normal B cells at different levels according to their differentiation and activation state makes the study of telomerase activity in B cell tumors particularly interesting. This review summarizes data concerning telomerase activity in chronic lymphoproliferative disorders of B-cell lineage (B-CLD), making suggestions regarding B-cell development and B-cell tumor histogenesis. The role of telomerase activity as a potential prognostic marker, as well as a target of new antineoplastic strategies is discussed.
B-Lymphocytes↗
B7 costimulatory molecules from malignant cells in patients with b-cell chronic lymphoproliferative disorders trigger t-cell proliferation.
BACKGROUND: B7 family molecules are involved in T-B-cell communications after interaction with their ligands CD28 and CD152. They play a key role in costimulatory mechanisms and during antigen presentation by efficient antigen presenting cells. B7 molecules are usually absent or expressed at low intensity on B lymphocytes from healthy subjects. In this study, the authors addressed the questions of whether B7 molecules are expressed and modulated in vitro on malignant B lymphocytes from patients with chronic lymphoproliferative diseases of B-cell type and whether they are able to trigger allogenic T-cell reactions. METHODS: Malignant B cells from the peripheral blood of 32 patients with B-cell chronic lymphocytic leukemia, mantle cell lymphoma, hairy cell leukemia, and its variant form were investigated for the expression of B7 molecules on the cell surface and for the ability to trigger allogenic T lymphocytes in different experimental conditions. RESULTS: Flow cytometry analysis demonstrated that freshly isolated malignant B cells express B7 molecules and that their expression may be up-regulated by the in vitro triggering of the CD40 molecule. Furthermore, freshly isolated malignant B cells induce allogenic T-cell proliferation. The in vitro triggering of malignant B lymphocytes by CD40, alone and in combination with interleukin-4, elicits a strong allogenic T-cell proliferation. This T-cell proliferation is related mainly to the presence of B7 molecules on malignant and normal B lymphocytes. CONCLUSIONS: These findings indicate that malignant B cells are efficient antigen presenting cells. It might be suggested that vaccination with pulsed malignant B cells themselves or dendritic cells with in vitro preactivated tumor B cells may represent an alternative therapeutic approach in these patients to generate an antilymphoma T-cell response in vivo.
Adult↗
Analysis of TNF-receptor and ligand superfamily molecules in patients with lymphoproliferative disease of granular lymphocytes.
In 21 patients with lymphoproliferative disease of granular lymphocytes (LDGL), we investigated the expression and the function of molecules belonging to TNF-receptor and TNF-ligand superfamilies (CD30/CD30L; CD40/CD40L; CD27/CD70; Fas [CD95]/FasL[CD95L]). Fourteen patients were characterized by a proliferation of granular lymphocytes (GLs) expressing the CD3(+)CD16(+) phenotype, whereas 7 cases showed the CD3(-)CD16(+) CD56 +/- phenotype. Our data show that both CD3(+) and CD3-GLs are preferentially equipped with CD30, CD40, CD40L, CD70, and CD95 antigens; this pattern is usually associated with the lack of CD27 and CD30L antigens expression. CD95L was demonstrated in the cytoplasm in 14 of 21 cases by flow cytometry, but a definite signal was demonstrated in all cases studied using polymerase chain reaction analysis. On functional grounds, a stimulatory activity on rIL-2 mediated redirected-cytotoxicity against Fcgamma+ P815 targets was demonstrated with anti-CD30, CD40, CD40L, CD70, CD95, and CD95L mAbs, although resting cells were unable to exhibit significant redirected-cell lysis. The addition of anti-CD30, CD30L, CD40, CD40L, CD95, and CD95L mAbs did not show any significant effect on cell proliferation at resting conditions or after rIL-2 stimulation, whereas anti-CD70 mAb mediated cell proliferation in 6 of 10 cases tested. This figure was not related to an increase in apoptotic cells, as investigated by Annexin-V expression. Our data indicate that both CD3(+) and CD3(-) GLs are equipped with different costimulatory antigens, supporting the concept that these cells are in vivo activated and suggesting that these molecules might play a role in the cytotoxic mechanisms of GLs. (Blood. 2000;96:647-654)
Adult↗
CXC chemokines IP-10 and mig expression and direct migration of pulmonary CD8+/CXCR3+ T cells in the lungs of patients with HIV infection and T-cell alveolitis.
The recruitment of cytotoxic T lymphocytes (CTL) is considered to be the major tool for the clearance of HIV from the lower respiratory tract. In this study we evaluated the pathophysiologic role of two lymphotactic CXC chemokines (IP-10 and Mig) in the lung of HIV-infected patients. These chemokines stimulate the directional migration of activated T cells and interact with a specific receptor (CXC receptor 3, CXCR3). Lymphocytes recovered from the bronchoalveolar lavage (BAL) of HIV-infected patients with high intensity T-cell alveolitis were CD8+ T cells expressing high levels of CXCR3 and IFN-gamma, a phenotype that is characteristic of Tc1 cells. Pulmonary T cells expressing CXCR3 exhibited a high migratory capability in response to IP-10 and Mig. Alveolar macrophages recovered from patients with T-cell alveolitis bore the IFN-gamma-inducible proteins IP-10 and Mig. A positive correlation was demonstrated between IP-10, Mig, and IL-15 expression by alveolar macrophages. Interestingly, macrophages isolated from the lung of HIV-infected patients with T-cell alveolitis secreted definite levels of CXCR3 ligands capable of inducing T-cell chemotaxis. Taken together, our data suggest that chemotactic ligands that bind CXCR3 contribute significantly to the accumulation of HIV-specific CTL in the lung.
Adult↗
[The predictive lidocaine test in treatment of neuropathic pain].
BACKGROUND: In daily practice, the intravenous lidocaine drip has been introduced as a predictive test for subsequent oral treatment with adjuvant drugs (anti-depressants, channel blockers and anti-convulsants). Our aim is the assessment of the correlation between the test response and the effectiveness of the consequent oral drug therapy. METHODS: 183 inpatients (central and peripheral neuropathic pain), treated between 1996-1997, were retrospectively checked. The trial was conducted as follows: a VAS reading > 5 was taken; a subsequent continuous i.v. lidocaine drip was given, at a dose of 4 mg/kg, in saline solution; a VAS reading was taken before (VAS 0), every 5 minutes, and at the end of the drip (VAS 1); the results of the drip were to be considered positive where pain relief was > or = 50%; irrespective of test results, all patients were given a different follow-up drug therapy; a VAS reading was taken one month after the drug therapy (VAS 2). RESULTS: Eighty-five patients (90%), responders to lidocaine, had a pain relief and 71 patients (85%), no responders to lidocaine, did not have improvement by taking oral drugs. CONCLUSIONS: In agreement with a other authors, we also noted that there was a statistically significant correlation between the results obtained and the therapy prescribed; the usefulness of a lidocaine drip as routine procedure to predict the therapeutic response of neuropathic pain to adjuvant analgesics is underlined.
Adult↗
CD8 T-cell infiltration in extravascular tissues of patients with human immunodeficiency virus infection. Interleukin-15 upmodulates costimulatory pathways involved in the antigen-presenting cells-T-cell interaction.
Interleukin (IL)-15 regulates the proliferative activity of the CD8(+) T-cell pool in human immunodeficiency virus (HIV)-infected patients, thereby contributing to the maintenance of the CD8(+) T-cell-mediated immune response against HIV in extravascular tissues, including the lung. However, the effects of IL-15 on antigen-presenting cells (APC) during HIV infection are still unclear. In this study, we evaluated whether IL-15 regulates the macrophage stimulatory pathways governing inflammatory events that take place in the lung of patients with HIV infection. As a first step we evaluated the in vitro effects of IL-15 on lung macrophages retrieved from the respiratory tract of eight normal subjects. Although macrophages from uninfected individuals expressed the IL-15 binding proteins (IL-15Ralpha and the common gammac) at resting conditions, they did not express IL-15 messenger RNA (mRNA). However, a 24-hour stimulation with IL-15 induced the expression of interferon-gamma (IFN-gamma) and IL-15 itself, suggesting a role for this cytokine in the activation of the pulmonary macrophage pool during inflammation. As a confirmation of the role of IL-15 in this setting, at resting conditions, alveolar macrophages of patients with HIV infection and T-cell alveolitis expressed IL-15, IFN-gamma, and IL-15 binding proteins; showed an upmodulation of costimulatory molecules, B7 and CD72, which are involved in the APC of macrophages; and behaved as effective accessory cells because they elicited a strong proliferation of T cells. The accessory effect was inhibited by pretreatment with anti-CD72, anti-B7 (CD80 and CD86), and anti-IL-15 monoclonal antibodies (MoAb). We then investigated the relationship between IL-15 and the expression of costimulatory molecules by macrophages. A 24-hour stimulation of IL-15Ralpha+/gammac+ macrophages with IL-15 upregulated the expression of CD80 and CD86. The evidence that IL-15 upregulates the expression of coligands that favor the contact between T cells and APC, per se, triggers T-cell activation and proliferation and acts as a chemoattractant for T cells, suggests that IL-15 plays a key role in Tc1-mediated defense mechanisms taking place in extravascular tissues of patients with HIV disease.
Adult↗
Detection of identical T-cell clonotype expansions in both the donor and recipient after allogeneic bone marrow transplantation.
Using phenotypic, functional and molecular techniques, this study was performed to compare the complexity of the T-cell receptor repertoire of a bone marrow transplanted patient with that of his HLA-matched related donor, both of whom developed a chronic lymphocytosis sustained by CD3+CD8+CD57+CD16-CD56- granular lymphocytes 3 years after transplantation. Although Southern blot analysis revealed the presence of extra bands in both subjects, thus indicating the presence of at least one clonal T-cell population, the study of the different T-cell receptor Vbeta (TCRBV) usage did not demonstrate discrete overexpression of any TCRBV segments. On the contrary, heteroduplex analysis of TCRBV transcripts suggested the presence of oligoclonal T-cell expansions in the two subjects. Cloning and sequencing studies demonstrated that T-cell clones expressing identical TCRBV chains were expanded both in the donor and in the recipient. Furthermore, clones with similar, but not identical, junctional regions were also found in the two subjects. These data indicate that, at the time of the graft, a few cells with a monoclonal/oligoclonal pattern that were present in the donor were transferred to the recipient, where they may have found the same environmental in vivo conditions and/or the antigenic pressure favouring their abnormal expansion.
Adult↗
Telomerase activity in chronic lymphoproliferative disorders of B-cell lineage.
The progressive shortening of telomeres at each cell division is a key mechanism in controlling cell proliferative capacity. The activation of telomerase, a reverse transcriptase that extends telomere length, potentially leads to unlimited cell proliferation, and is believed to play a critical role in the neoplastic process. High levels of telomerase activity have been demonstrated in almost all solid tumours; however, little data is available concerning its expression in chronic B-cell neoplasms. By using a quantitative polymerase chain reaction-based method we quantified telomerase activity in normal B lymphocytes, and in various B-cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and hairy cell leukaemia (HCL). Compared to normal B cells, which expressed very low levels of telomerase activity, malignant cells from most of the patients showed a significant increase in telomerase activity, with highest values observed in HCL samples. Moreover, among the CLL and HCL cases, significantly higher levels of telomerase activity were found in patients with progressive disease at 1 year follow-up versus patients with stable disease. These data suggest that telomerase activity might correlate with disease progression.
Aged↗