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Biomedical subjects

A Vecchiarelli

Publications and source records attributed to A Vecchiarelli.

At least 55 records · Page 3Linked to original sources
PubMed1995

Downregulation by cryptococcal polysaccharide of tumor necrosis factor alpha and interleukin-1 beta secretion from human monocytes.

The regulation by Cryptococcus neoformans encapsulation of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) production by human monocytes was investigated. By using encapsulated and acapsular C. neoformans, we demonstrated that both strains induce cytokine production, although the acapsular strain was a better stimulator than the thinly encapsulated strain. The cytokine levels produced by cells stimulated by the two strains were lower and followed a different kinetic than those stimulated by lipopolysaccharide (LPS). Purified capsular polysaccharide inhibits TNF-alpha secretion induced by LPS or acapsular C. neoformans. In contrast, no regulator effect on IL-1 beta was observed when LPS was used. The secretory response of these cytokines follows different pathways of macrophage activation; in fact, complete inhibition of TNF-alpha does not affect IL-1 beta production and vice versa. These data indicate that purified capsular polysaccharide of C. neoformans could contribute to the in vivo progress of cryptococcosis by suppressing cytokine production of macrophages and suggest that a therapeutic approach to address the suppressive effect of cryptococal polysaccharide could be devised.

Adult↗
PubMed1994

Cytokine regulation of low-affinity IgE receptor (CD23) on monocytes from asthmatic subjects.

The regulation of CD23 expression (Fc epsilon RII) by cytokines on monocytes from normal subjects, asymptomatic and acute asthmatics was investigated. CD23 was weakly expressed on cells from controls, but was significantly enhanced in the two groups of asthmatics. The addition of IL-4 on monocytes induced an increase of CD23 expression in cells from controls and asthmatics. Interferon-gamma (IFN-gamma) did not modulate CD23 expression in asthmatics or control subjects, while high doses of IL-6 (2000 U/ml) enhanced CD23 expression on cells from asthmatics or controls. In vitro stimulation of monocytes with Timothy grass pollen allergen did not enhance CD23 receptor in asthmatics with a positive skin test to this pollen. We speculate that CD23 expression in asthmatics is markedly enhanced by Th2-dependent cytokines, such as IL-4 and IL-6. Thus, the regulation of Th2 cell activation by anti-cytokine therapy could have an important effect on the down-regulation of CD23 on monocytes, and in shifting a Th2 subpopulation into a Th1 subpopulation by blocking Th2-dependent cytokines.

Adolescent↗
PubMed1994

Encapsulation of Cryptococcus neoformans regulates fungicidal activity and the antigen presentation process in human alveolar macrophages.

Our previous studies have shown that unstimulated alveolar macrophages (AM) play a predominant role as antigen-presenting cells in Cryptococcus neoformans infections, while the function as effector cells seems to be of minor relevance. The present study focuses on the role of encapsulation of C. neoformans on fungicidal activity and the antigen presentation process of AM. Fungicidal activity in unstimulated AM occurs to a higher degree when the acapsular strain is employed, but this is impaired compared with other natural effectors, such as peripheral blood monocytes (PBM) and polymorphonuclear (PMN) cells. Cryptococcus-laden AM also induce a higher proliferative response in autologous CD4+ lymphocytes when the acapsular strain is used compared with encapsulated yeast. The enhanced blastogenic response is, in part, ascribed to an augmented IL-2 production by T cells. In addition, higher levels of interferon-gamma (IFN-gamma), but not IL-4, are produced by the responding T cells, when the acapsular strain is used compared with the encapsulated yeast. Moreover, IFN-gamma is able to induce fungicidal activity in AM against the encapsulated yeast and augments killing activity of the acapsular strain. This phenomenon is not mediated by nitric oxide production, but is correlated with an enhancement of fungicidal activity of cytoplasmic cationic proteases. We speculate that encapsulation of C. neoformans could down-regulate the development of the immune response mediated by Cryptococcus-laden AM at lung level.

Adult↗
PubMed1994

Role of human alveolar macrophages as antigen-presenting cells in Cryptococcus neoformans infection.

The contribution of human alveolar macrophages (AM) from normal subjects in Cryptococcus neoformans infection was investigated. AM were able to efficiently phagocytize the fungus after opsonization, but killing activity did not occur at an effector-to-target ratio of 10:1 in a 6-h incubation since there was an inhibition of phagosome-lysosome fusion. Moreover, the role of AM as antigen-presenting cells was investigated. Cryptococcus-laden AM were co-cultured with autologous T lymphocytes and lymphoproliferation was determined; a massive blastogenic response of alpha/beta TCR-bearing T lymphocytes was observed. The response started after 1 day of co-culture and was triggered and regulated by IL-1 produced by AM in response to C. neoformans. Finally, the antigen-presentation process was associated with HLA class II DR molecules. This finding suggests that AM play a key role in the lung as antigen-presenting cells and, through the secretion of IL-1, regulate proliferation and activation of T lymphocytes, which are important in mediating pulmonary clearance. We speculate that in immunodepressive conditions, the impairment of AM functions could contribute to the spread of C. neoformans infection from the lung.

Adult↗
PubMed1994

Macrophage activation by N-acetyl-cysteine in COPD patients.

The effect of in vivo and in vitro N-acetylcysteine (NAC) treatment on destructive activity of macrophages against Candida from COPD patients has been evaluated. Patients received NAC (600 mg) or placebo orally 3 times a day for 15 days and bronchoalveolar lavage (BAL) fluid and peripheral blood were collected before and at the conclusion of treatment. In our system, NAC treatment was not able to modulate antifungal activity of alveolar macrophages, peripheral blood monocytes (PBM), and polymorphonuclear leukocytes. On the contrary, in vitro NAC treatment at appropriate doses (10 micrograms/ml) significantly enhanced antifungal activity of PBM from COPD patients. This phenomenon is mediated by augmented phagocytic activity and phagosome-lysosome fusion. The lack of correlation between in vivo and in vitro studies could be ascribed to differences in the intracellular concentration of the drug that in vivo does not reach levels capable of inducing macrophage activation. We speculate that in COPD patients who undergo long-term NAC treatment, appropriate schedules and doses of the drug could augment resistance against microbial infections which are often life-threatening in these patients.

Acetylcysteine↗
PubMed1994

Systemic infection with Herpes bovis virus 2 evokes a biphasic immune response in the mouse.

We evaluated the effects of systemic infection by Herpes bovis virus 2 (HBV-2) on a murine experimental system. We provide evidence that such infection is lethal for the immunocompromised but not for the immunocompetent mouse in which a biphasic immune response is elicited. In particular, 1 day post-infection, we observed a rapid transient depression induced by the virus, as documented by a decrease in peripheral leukocyte counts, mitogenic spleen cell response and resistance to a secondary microbial challenge. Later, HBV-2 infection boosted cytokine secretion and enhanced antimicrobial and antitumoral activities by the splenic district. In conclusion, our experimental model discloses some immunological aspects underlying the complex host-virus interaction.

Animals↗
PubMed1993

Low-dose streptozotocin-induced diabetes in mice. I. Course of Candida albicans infection.

Diabetic patients are highly susceptible to microbial and fungal infections. To better understand the immune mechanisms underlying the diabetic host-parasite relationship, we studied the course of systemic infection with Candida albicans in mice with low-dose streptozotocin-induced diabetes. For this purpose, we used a low-pathogenic strain of C. albicans, PCA-2, which causes a chronic infection in the intact host. Injection of PCA-2 cells into diabetic mice caused a lethal acute infection. The levels of interferon-gamma (IFN-gamma) determined in sera and splenocyte culture supernatants from diabetic mice were significantly higher than those in control mice. Moreover, splenic macrophages from diabetic mice were functionally activated relative to normal macrophages, as evaluated by significantly augmented C. albicans killing in vitro. However, when diabetic mice were infected with PCA-2, IFN-gamma levels dropped dramatically to undetectable levels during the first week of infection and there was a marked decrease in macrophage activation. These data suggest that the levels of IFN-gamma production early in infection might have a crucial role in generating the susceptibility of diabetic mice to infection.

Animals↗
PubMed1993

Low-dose streptozotocin-induced diabetes in mice. II. Susceptibility to Candida albicans infection correlates with the induction of a biased Th2-like antifungal response.

We have previously found that the development of fatal disseminated candidiasis correlates with the detection of a strong Th2 response, while protective antifungal immunity is associated with a predominant Th1 response. In the present study we verified the hypothesis that an altered antifungal Th response could be responsible for the high susceptibility of diabetic mice to systemic Candida albicans infection. Outbred CD1 mice rendered diabetic with multiple low doses of the pancreatic islet beta-cell toxic, streptozotocin, develop a fatal systemic infection when injected with low-virulence C. albicans cells. Progressive disease was found to be associated with the presence in the serum of IgA, IgE, and IgG1 Candida-reactive specific antibodies, absent footpad reactions, and elevated production in vitro of the Th2 cytokines IL-4, IL-6, and IL-10 but not the Th1 cytokine IFN-gamma. Both the Th2 and Th1 (IL-2 and IFN-gamma) cytokines were produced in vitro by CD4+ lymphocytes from noninfected diabetic mice that, in addition, showed a noticeable footpad reaction to Candida antigens. Thus, it appears that a perturbation in the anticandidal T helper responses resulting in the induction of a biased Th2-like antifungal response renders diabetic mice highly susceptible to systemic C. albicans infection.

Animals↗
PubMed1993

Inhibition of candidacidal activity of polymorphonuclear cells by alveolar macrophage-derived factor from lung cancer patients.

Culture supernatants of alveolar macrophages (AM) from lung cancer patients are able to inhibit the candidacidal activity of polymorphonuclear cells (PMN) in vitro. This phenomenon is ascribed to a factor secreted in the culture medium by unstimulated AM from tumor-bearing patients, but not from normal subjects. The inhibitor does not apparently affect the phagocytic activity of PMN, but the superoxide release during phagocytosis is significantly impaired when cells are pretreated with supernatants containing the factor. The secretion of the inhibitor seems to be restricted to the pulmonary compartment of lung cancer patients, since culture supernatants of peripheral blood monocytes (PBM) from the same subjects are not capable of depressing the candidacidal activity of PMN. The AM-derived factor is not inactivated after exposure to heat (60 degrees C) and when supernatants are analyzed by HPLC, the inhibitory activity is recovered in the fractions corresponding to a low molecular weight (800 D). In conclusion, AM from lung cancer patients are able to produce a factor capable of inhibiting the antimicrobial activity of PMN. This could account, at least in part, for the enhanced susceptibility to local infections observed in lung cancer patients.

Biological Factors↗
PubMed1993

Mechanism of intracellular candidacidal activity mediated by calcium ionophore in human alveolar macrophages.

In the present study, we investigated the effect of in vitro treatment with calcium ionophore (A23187) on candidacidal activity of human alveolar macrophages (AM) from normal subjects. In vitro incubation of AM with A23187 results in a significant dose-dependent enhancement of candidacidal activity. The availability of Ca2+ and Mg2+ ions in the culture medium is crucial for phagocytosis and killing to occur, but appears irrelevant for the binding between Candida albicans and AM. Enhancement of the killing effect mediated by A23187 does not correlate with increased phagocytic activity; in fact, the availability of ions is required for the phagocytic event, but an increase of cations does not correlate with enhancement of this activity. On the contrary, the augmentation of killing activity correlates with increased production of superoxide anion. Moreover, soluble material endowed with candidacidal activity has been extracted from cytoplasmic granules of AM both unstimulated and following A23187 treatment in vitro. Indeed, the granules extracted contain cationic proteases and, when isolated from stimulated cells, appear to be significantly more cytotoxic for C. albicans with respect to those obtained from unstimulated AM. In conclusion, the results reported here show that the phagocytic and killing events are ion dependent and the enhancement of intracellular candidacidal activity mediated by A23187 in AM is correlated with an augmented anti-Candida activity of cation-activated proteases.

Adult↗
PubMed1993

Ligation of the lymphocyte homing receptor CD44 triggers T-helper and cytolytic functions of human T cells.

We show that antibodies to the CD44 molecule trigger proliferation of human CD3+/CD4+ T-cell clones. Such effect is IL2-dependent, as shown by IL2 production induced by anti-CD44 mAb and by inhibition of cell proliferation in the presence of anti-IL2 antibodies or cyclosporin A (CsA). Moreover, anti-CD44 mAb triggered human cytolytic CD4+ and CD8+ TCR alpha/beta+ clones, and V delta 1 or V delta 2 TCR Y/delta+ clones to lyse Fc-gamma-R+ P815 cells and to release granule trypsin-like esterase enzymes. Anti-CD44 mAb-triggered proliferation and cytotoxicity were blocked by the PTK-inhibitor, genestein. In addition, ligation of the CD44 molecule induced tyrosine phosphorylation of proteins identical, by molecular weight, to those phosphorylated following anti-CD3 mAb-stimulation. Notably, anti-CD44 mAb does not induce tyrosine phosphorylation of a 21 kD protein (the phosphorylated zeta chain of the TcR molecular complex) typically observed upon anti-CD3 mAb stimulation.

Antibodies, Monoclonal↗
PubMed1992

Effect of corticosteroid treatment on interleukin-1 and tumour necrosis factor secretion by monocytes from subjects with asthma.

Peripheral blood monocytes (PBM) may be activated in asthmatic patients, a condition usually reverted by corticosteroid (CS) treatment. In the present research we have evaluated the spontaneous or lipopolysaccharide (LPS)-induced production of interleukin 1 (IL-1) and tumour necrosis factor (TNF) by PBM obtained from 14 asthmatic subjects during an asthmatic attack and after 1 week of CS treatment. The control group included 20 healthy volunteers. PBM obtained during severe asthma showed a pattern of IL-1 and TNF secretion similar to that of normal subjects. After CS treatment, IL-1 levels did not change significantly in comparison to baseline values, while LPS-induced TNF production was apparently related to the degree of airway obstruction after CS treatment. In fact, TNF production by PBM from CS-responsive subjects was significantly decreased in comparison to the levels determined before CS treatment, while PBM from CS-resistant subjects produced the same cytokine levels regardless of CS treatment. The present study suggests that the determination of LPS-induced TNF secretion by PBM could be used to confirm the effectiveness of CS treatment in asthma.

Adrenal Cortex Hormones↗
PubMed1992

Changes in interleukin-1 and tumor necrosis factor production by peripheral blood monocytes after specific bronchoprovocation test in occupational asthma.

The pathogenetic mechanisms of occupational asthma (OA) due to low-molecular-weight compounds have been poorly defined, and further studies are required to clarify the role of immunologic mechanisms in OA. Until now cellular mechanisms have been less investigated than humoral ones. We have evaluated interleukin-1 (IL-1) and tumor necrosis factor (TNF) production by peripheral blood monocytes (PBM), and peripheral T-cell subpopulations in 22 subjects with possible OA before and after specific bronchoprovocation test (SBPT). After SBPT, three subjects had an immediate reaction, seven a late reaction, and two a dual reaction. Ten subjects had no asthmatic reaction to SBPT. Spontaneous release of IL-1 from PBM did not change significantly after SBPT. TNF activity was increased 48 h after SBPT in immediate reactions and 72 h after SBPT in late-dual reactions. These results suggest that exposure to occupational agents may induce activation of PBM with increased spontaneous release of cytokines, such as TNF.

Adult↗
PubMed1992

Prediction of pulmonary immunodeficiency in chronic bronchitis by cutaneous hypoergy to multitest.

Multitest (Pasteur Mérieux) is a plastic disposable device used to assess delayed cutaneous hypersensitivity (DCH) to seven antigens. Hypoergy to Multitest is believed to reflect a status of compromised cell-mediated immunity. Among the many possible pathogenic factors of chronic bronchitis, immunodepression has been little investigated. Indeed, whether lower immunodefence is the cause or the consequence of chronic bronchitis is still a subject of debate. The aim of the study was to evaluate DCH in a large group of patients with chronic obstructive pulmonary disease (COPD) and in a control group, in order to relate DCH (expressed as score, mm) to clinical and functional impairment. One hundred patients with COPD in stable conditions and not undergoing treatment with immunomodulating drugs (mean age, yr, M +/- SD: 66.1 +/- 6.5) and 40 normal controls in the same age range were admitted to the study. Evaluated parameters were: symptoms scores, physical examination, lung function tests and Multitest. Fifty-three percent of the COPD patients were hypoergic compared with 14% of controls. The Multitest score was 10 +/- 10 (mm M +/- SD) in COPD compared with 17 +/- 9 in controls. The Multitest score was significantly related to age (r = -0.45) in the control group, but not in COPD patients. DCH to only three of the seven antigens may predict a response to Multitest, with a sensitivity of 90%.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

In vitro production of tumor necrosis factor by murine splenic macrophages stimulated with mannoprotein constituents of Candida albicans cell wall.

Mannoprotein components from Candida albicans were investigated for their ability to induce production of tumor necrosis factor (TNF) by cultured splenocytes from naive or Candida-infected mice. Two chromatographically separated mannoproteins preparations, designated F1 and F2, were as able as the heat-inactivated Candida cells to induce the production of TNF from splenocytes of naive animals. In addition, they caused a significant augmentation of basic TNF secretion by splenocytes of Candida-infected animals. Experiments using plastic and/or nylon wool adherence, as well as treatments with antibodies depleting T or NK cells, consistently indicated that most if not all TNF was produced by splenic macrophages. In cultures of splenocytes from Candida-infected mice, mannoprotein addition also stimulated interferon-gamma (IFN-gamma) production by Thy 1.2 positive cells. Depletion of these cells or addition of anti-IFN-gamma antibodies abolished IFN production and reduced TNF secretion by adherent cells to the levels found in the cultures of mannoprotein-stimulated spleen cells from naive mice. These data add further evidence to the immunomodulatory properties possessed by some cell wall constituents of the human commensal microorganism C. albicans and suggest that IFN-gamma is endowed with a regulatory role in TNF production by mouse macrophages in vitro.

Animals↗
PubMed1991

Defective candidacidal activity of alveolar macrophages and peripheral blood monocytes from patients with chronic obstructive pulmonary disease.

We investigated the in vitro candidacidal activity of alveolar macrophages (AM) and peripheral blood monocytes (PBM) from normal subjects or from patients with chronic obstructive pulmonary disease (COPD) displaying defective skin test delayed-type hypersensitivity (DTH) reactivity to seven antigens including Candida albicans. The results showed that cells from patients with COPD were significantly less effective than cells from control subjects in the killing of C. albicans. To explore whether the observed functional impairment could be reversed, interferon-gamma (IFN-gamma) was added to AM and PBM from patients with COPD, alone or in the presence of lipopolysaccharide (LPS) as a suboptimal stimulus. The cells were cultured for 24 h and then assayed for anti-Candida activity. After IFN-gamma treatment, the fungicidal activity of cells from patients with COPD was comparable to that of unstimulated AM or PBM from healthy donors. Treatment with IFN-gamma plus LPS resulted in a further enhancement in the killing of C. albicans. To gain more insight into the mechanisms involved in the modulation of killing, we evaluated the possible stimulating activity of IFN-gamma plus LPS treatment on the secretion of tumor necrosis factor (TNF) and interleukin-1 (IL-1), two cytokines produced by activated macrophages and capable of stimulating natural effectors. The results showed that IFN-gamma plus LPS can indeed stimulate TNF and IL-1 secretion by AM and PBM from patients with COPD. Therefore, a precise role can reasonably be ascribed to these soluble factors in the observed augmentation of candidacidal activity as ascertained by treatment with IFN-gamma plus LPS.

Aged↗