CD40 activation of B-CLL cells is associated with augmented intracellular levels of CD79b and increased BCR expression in a subset of patients.
Explore the source record for details and available documents.
Antigens, CD↗
Biomedical subjects
G Semenzato
Publications and source records attributed to G Semenzato.
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↗
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↗
Alveolar macrophage-T cell interactions during Th1-type sarcoid inflammation.
Sarcoidosis is an immunomediated, multisystem disorder of unknown cause(s) characterized by a heightened Th1 immune response that leads to an uncontrolled granuloma formation at sites of disease activity. The past few years have seen outstanding advances in the understanding of immunological and molecular events involved in the pathogenesis of this disease. The idea is that several cytokines and chemokines, which are secreted at sites of disease activity, participate in granuloma formation. This paper describes recent data that have clarified some of the events that govern the development of the hypersensitivity reaction during sarcoidosis. In particular, we will review recent evidence indicating that a complex relationship exists between the macrophage/lymphocyte cellular axis and the tissue networks of cytokines.
Chemokines↗
Identification of NKp80, a novel triggering molecule expressed by human NK cells.
The ability of NK cells to kill a wide range of tumor or virally infected target cells as well as normal allogeneic T cell blasts appears to depend upon the concerted action of multiple triggering NK receptors. In this study, using two specific monoclonal antibodies [(mAb) MA152 and LAP171], we identified a triggering NK receptor expressed at the cell surface as a dimer of approximately 80 kDa (NKp80). NKp80 is expressed by virtually all fresh or activated NK cells and by a minor subset of T cells characterized by the CD56 surface antigen. NKp80 surface expression was also detected in all CD3- and in 6 / 10 CD3+ large granular lymphocyte expansions derived from patients with lymphoproliferative disease of granular lymphocytes. In polyclonal NK cells, mAb-mediated cross-linking of NKp80 resulted in induction of cytolytic activity and Ca2+ mobilization. A marked heterogeneity existed in the magnitude of the cytolytic responses of different NK cell clones to anti-NKp80 mAb. This heterogeneity correlated with the surface density of NKp46 molecules expressed by different NK clones. The mAb-mediated masking of NKp80 led to a partial inhibition of the NK-mediated lysis of appropriate allogeneic phytohemagglutinin-induced T cell blasts, while it had no effect on the lysis of different tumor target cells, including T cell leukemia cells. These data suggest that NKp80 recognizes a ligand on normal T cells that may be down-regulated during tumor transformation. Molecular cloning of the cDNA coding for NKp80 revealed a type II transmembrane molecule of 231 amino acids identical to the putative protein encoded by a recently identified cDNA termed KLRF1.
Adult↗
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↗
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↗
Interstitial lung diseases: what next?
Explore the source record for details and available documents.
Humans↗
First report of the Italian register for diffuse infiltrative lung disorders (RIPID).
RIPID was established in 1998 as a joint project of the major Italian scientific societies for Respiratory Medicine, with the aim to create an Italian Register on diffuse infiltrative lung disorders that can provide the basis for epidemiological and clinical studies of adequate sample size. In the period from May 1998 to December 2000, 1,382 cases were submitted from 54 Centers in 15 regions of Italy, 54.2% males (mean age +/- SD 50.5 +/- 16.8 years) and 45.8% females (50.2 +/- 15.3 years). A current smoking habit emerges in 18% of subjects; former smokers and never-smokers represent 26% and 56% of the total case series, respectively. The most frequent disease registered is idiopathic pulmonary fibrosis (37.6%), followed in decreasing order by sarcoidosis (29.2%), and Langherans' cell hystiocytosis (6.6%). High resolution computed tomography (HRCT) was considered as the most important tool for final diagnosis in the majority of cases (74.4%); 39.4% of patients underwent transbronchial biopsies, 39.2% bronchoalveolar lavage (BAL). A surgical biopsy was performed in 20.5% of patients. A web site has been activated from December 2000 (www.pneumonet.it/ripid), allowing prompt access to all information and scientific material concerning the project and to an electronic form for data collection that can be completed on-line.
Adult↗
Genetic predisposition and pathogenetic mechanisms of interstitial lung diseases of unknown origin.
Understanding of the cellular and cytokine interactions associated with inflammation and fibrosis in interstitial lung diseases (ILDs) has increased substantially during the past few years. Presently, many agents are known to have the ability to induce ILDs, although only a small percentage of exposed individuals will develop the disease. In addition, the majority of ILDs are of unknown origin and many are labelled "idiopathic". Therefore, host susceptibility, genetic factors and, possibly, environmental cofactors may be important for the clinical expression of ILDs. The present review reports evidence of the genetic predisposition to develop ILDs of unknown origin, more specifically sarcoidosis, idiopathic pulmonary fibrosis (IPF), lymphangioleio-myomatosis and ILDs, in systemic sclerosis. For instance, for sarcoidosis and IPF several histocompatibility antigens have been associated with the development and/or the clinical presentation of the disease. Furthermore, there are also several types of ILD that are associated with inherited disorders, of which the tuberous sclerosis complex is only one example. This clearly indicates that pulmonary fibrosis can be influenced by genetic factors. Familial occurrence of sarcoidosis and IPF is also well known, although the exact modes of inheritance are debatable. Several studies have shown that extrinsic factors, such as single or multiple fibrosing agents, probably contribute to the development of clinical ILDs of unknown origin. It is probable that some of these studies deal with patients who do not have classical IPF, as recently defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus. Therefore, the true role of these extrinsic factors in the development of IPF, or even sarcoidosis, remains speculative. With the help of animal studies and, more specifically, by using knock-out mice, it may be possible in the near future to unravel at least some of the genes that are responsible for the increased susceptibility of the development of interstitial lung diseases.
Animals↗
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↗
Immune mechanisms in interstitial lung diseases.
Explore the source record for details and available documents.
Alveolitis, Extrinsic Allergic↗
HLA-Gm/kappam interaction in sarcoidosis. Suggestions for a complex genetic structure.
The aetiology of sarcoidosis is still unknown. Environmental exposures are believed to interact with genetic factors in determining the pattern of sarcoidosis presentation, progression and prognosis. The frequency of serological polymorphism of immunoglobulin G heavy chain (Gm) and kappa light chain (kappam) markers in 107 patients with biopsy-proven sarcoidosis and in 227 controls, and their interactions with histocompatibility leukocyte antigen (HLA) class I, II, and III markers, were studied. A "protective" effect of the Gm(3 5*) phenotype in the sarcoid group versus controls (p-value for number of specificities tested (p(c))=0.05, odds ratio 0.15) and a reduced frequency of Gm(3 23 5*) in patients with advanced chest radiographic stage (Chi-squared (two degrees of freedom)(chi2(2df) 17.61, p(c)=0.0058) were observed. With reference to epistatic interactions, the combination Gm(3 23 5*)/BfS had a "protective" effect towards stage II (chi2(2dt) 13.86, p(c)=0.043). Finally, correspondence analysis defined two clusters: HLA-DR4, C4BQ0, Gm(1, 3, 17 23 5*, 21, 28) and BfF associated with stage II, and HLA-DR3, C4AQ0, kappam(1) and Gm(3 23 5*) associated with stage I. These data further support the hypothesis that sarcoidosis results from an interplay of environmental factors and genes, each contributing to the susceptibility/resistance to and/or the clinical heterogeneity of the disease. In addition, these data provide the first evidence of an interaction between immunoglobulin G heavy chain/kappa light chain markers and histocompatibility leukocyte antigen class III genes in a disease.
Adult↗
Clinicopathological features of aggressive large granular lymphocyte leukaemia resemble Fas ligand transgenic mice.
Fas ligand triggers cell death after interaction with its receptor Fas. Altered expression of Fas has been associated with lymphoproliferation and autoimmune disorders in both mice and man. Apoptosis of lung and liver tissue is seen in Fas ligand transgenic mice. It is not known whether constitutive expression of Fas ligand can cause a similar human disease. Four patients with aggressive large granular lymphocyte (LGL) leukaemia involving lung and liver were studied. All four patients were severely ill with pulmonary involvement. Two patients presented with hypoxia and were oxygen dependent; the other two patients had severe pulmonary hypertension. Lung biopsies showed interstitial infiltration by leukaemic LGL. The infiltrating lymphocytes expressed both Fas and Fas ligand, whereas normal pneumocytes expressed only Fas. Similar findings were observed in liver biopsies from these patients. Features mimicking the pathological changes of graft-versus-host disease were observed, including pneumocyte apoptosis. All four patients had high levels of circulating Fas ligand. Successful treatment with oral methotrexate or 2-chlorodeoxyadenosine was associated with disappearance or marked reduction of circulating Fas ligand. These results suggest that dysregulated expression of Fas ligand can lead to human disease with pathological features resembling graft-versus-host disease.
Adult↗
New pathogenetic insights into the sarcoid granuloma.
Although the most important enigma of sarcoidosis, ie, its etiology, remains an unsolved problem, the past few years have seen remarkable advances in understanding general immunologic and molecular aspects of the mechanisms leading to granuloma formation in sarcoidosis. It is now clear that during the sarcoid inflammatory process several cytokines are secreted at sites of disease activity; in addition, high affinity receptors for cytokines participating in the granuloma development have been recently identified. This article provides a detailed description of recent data that have clarified cellular interactions governing the dynamics of granuloma formation in sarcoidosis. Together, these new results provide important insights that can refocus efforts at developing immunotherapeutic methods of inhibiting cytokine production at sites of granuloma formation.
Apoptosis↗
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↗