PubMed Health⌕ Search

Biomedical subjects

A Vecchiarelli

Publications and source records attributed to A Vecchiarelli.

At least 37 records · Page 2Linked to original sources
PubMed1999

Neutrophils from patients with advanced human immunodeficiency virus infection have impaired complement receptor function and preserved Fcgamma receptor function.

Interleukin (IL)-8 production by human polymorphonuclear leukocytes (PMNL) to Cryptococcus neoformans is related to complement activation. Generation of the bioactive fragments C3a and C5a is responsible for IL-8 release. IL-8 production was analyzed in response to C. neoformans by PMNL from persons with early- and late-stage (>400 and <200 CD4 cells/mm3, respectively) human immunodeficiency virus (HIV) infection who were at high risk for cryptococcosis. IL-8 release by PMNL from persons with early-stage infection and from healthy donors was similar; however, PMNL from persons with late-stage HIV infection had significantly impaired IL-8 production, which correlated with reduced IL-8 response to C3a and C5a proteins and decreased CD88 expression. Addition of murine monoclonal antibody (MAb) 18B7 promoted phagocytosis and restored IL-8 release consistent with integrity of FcgammaRIII. These results provide evidence for a selective defect in CD88 expression on PMNL from persons with late-stage HIV infection. However, Fcgamma receptor expression in PMNL appears to be intact and allows MAb to glucuronoxylomannan to positively influence PMNL function.

Adult↗
PubMed1999

A new azole derivative of 1,4-benzothiazine increases the antifungal mechanisms of natural effector cells.

The most widely used drug for treatment of candidiasis is fluconazole (FCZ). Recently, a new derivative of 1,4-benzothiazine, compound FS5, was developed. FS5 had an appreciable protective effect against murine candidiasis. The present study was designed to dissect the antifungal mechanisms triggered by FS5 and to establish whether this compound could enhance the antimicrobial abilities of natural effector cells. The results show that intraperitoneal injection of FS5 in mice (i) induced an increase in circulating neutrophil levels comparable to that observed in FCZ-treated mice; (ii) enhanced phagocytosis and the killing activities of macrophages (Mphis) isolated from the spleen or peritoneal cavity, with the latter effect correlating with induction of nitric oxide synthesis and production by Mphis; and (iii) increased the levels of expression and synthesis of tumor necrosis factor alpha. These results suggest that the compound-induced synthesis of antimicrobial and proinflammatory molecules by heterogeneous Mphi populations is part of the beneficial effect of FS5 exerted against murine candidiasis.

Animals↗
PubMed1998

Polycyclic aromatic hydrocarbons enhance the production of phorbol 12-myristate 13-acetate-induced superoxide ions in human monocytes.

Monocytes, separated from peripheral blood, preincubated with a mixture of polycyclic aromatic hydrocarbons (PAHs) show an enhanced production of superoxide ions (O2-.) when the cells are stimulated with phorbol 12-myristate 13-acetate (PMA, direct activator of protein kinase C). When opsonized-zymosan is used as a stimulus (receptor-dependent stimulus), no enhanced production of O2-. is observed. Superoxide production increases dose dependently up to a PAH concentration of 5 microg/ml. Although the effect was rather small (125-145% of the control value), it was significant and reproducible. Similar enhancing activity was also observed in the production of hydrogen peroxide (H2O2) excluding an inhibitory effect of PAHs on the enzyme superoxide dismutase (SOD). Since the effect is related to the concentration of PMA and in the absence of stimulus, the O2-. is undetectable in both the control and in the PAHs-treated cells, it is concluded that the over production of O2-. is due to an increased activity of the NADPH oxidase.

Carcinogens, Environmental↗
PubMed1998

Cryptococcus neoformans differently regulates B7-1 (CD80) and B7-2 (CD86) expression on human monocytes.

To induce a specific response in primary resting T cells, two signals must be provided by antigen-presenting cells (APC). The first antigen-specific signal is mediated by formation of the T cell receptor major histocompatibility complex molecule ternary complexes. The second signal is delivered by interaction of either B7-1 or B7-2 expressed by APC with CD28 or CTLA-4 on T cells. In this study, we examined the modulation of B7-1 and B7-2 molecules on human monocytes exposed to encapsulated or acapsular Cryptococcus neoformans or Candida albicans. In our experimental system, C. albicans or acapsular C. neoformans are able to induce B7-1 expression while the encapsulated yeast is a poor stimulator. A modest increase of B7-2 expression was also observed after monocyte treatment with acapsular C. neoformans or C. albicans, while the encapsulated yeast was ineffective in inducing B7-2 molecules. Kinetic analysis showed the maximum expression of B7-1 after 24 to 48 h. Addition of the opsonic IgG1 mAb 2H1 to monocytes and C. neoformans significantly increased B7-1, but not B7-2, expression. The contribution of B7-1 and B7-2 co-stimulatory (CS) molecules to cryptococcal-specific T cell activation was analyzed and a substantial inhibition of T cell proliferation was observed. In this study we provide the first demonstration of fungal interference in the regulation of CS molecules. Our results suggest a potential mechanism for poor inflammatory responses observed in C. neoformans infections.

Antigen Presentation↗
PubMed1998

Azole derivatives of 1,4-benzothiazine as antifungal agents.

A series of azole derivatives of 1,4-benzothiazine 7-14 was synthesized and evaluated for the in vitro and in vivo activity against Candida albicans. Secondary alcohol 10 and its ether derivative 13 showed very good efficacy against systemic candidiasis in a murine experimental model.

Animals↗
PubMed1998

Cryptococcus neoformans and Candida albicans regulate CD4 expression on human monocytes.

This study examined the capability of Candida albicans and Cryptococcus neoformans to modulate CD4 expression on human monocytes. C. albicans and an acapsular strain of C. neoformans induced higher levels of CD4 expression than encapsulated strains. Purified glucuronoxylomannan did not regulate CD4 expression on monocytes, but down-regulation of CD4 expression compared with stimulation by acapsular C. neoformans alone was observed when glucuronoxylomannan was used in combination with acapsular C. neoformans. The ability of opsonic factors to facilitate fungal-mediated CD4 overexpression suggests that binding or internalization (or both) of the yeast cells is a critical event. Protein synthesis was required, excluding redistribution of the intracellular pool of CD4 receptors to the cellular surface as the sole possible mechanism. Results demonstrate a new effect of fungi on professional phagocytic cells and raise the possibility that modulation of CD4 could influence gp120-mediated human immunodeficiency virus entry.

CD4 Antigens↗
PubMed1998

Human immunodeficiency virus type 1 envelope protein gp120 impairs intracellular antifungal mechanisms in human monocytes.

The key to success of fungal opportunistic pathogens in the immunocompromised host is related to survival inside phagocytic cells, which represent the first line of defense against microorganisms. The contribution of human immunodeficiency virus-1 recombinant envelope protein gp120 on effector functions of peripheral blood monocytes (PBM) against Candida albicans was investigated. gp120 binds CD4 receptors on PBM while not affecting the access of the fungus into the lysosome compartment. However, gp120 reduces the antifungal capacity of PBM. This phenomenon correlates with impaired oxygen-dependent antimicrobial machinery and reduced ability of phagolysosome acidification. The maintenance of phagolysosomal pH at approximately 6.2 restricts antimicrobial properties of the enzyme that work at a low pH, as evidenced by reduced antifungal capability of lysosomal protein extracted from gp120-treated PBM. These findings highlight gp120 perturbation of intracellular antimicrobial mechanisms of phagocytic cells and suggest a new aspect for gp120 in impairing immune functions.

AIDS-Related Opportunistic Infections↗
PubMed1998

Encapsulation of Cryptococcus neoformans with glucuronoxylomannan inhibits the antigen-presenting capacity of monocytes.

This report examines the effect of the major capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), on the antigen-presenting capability of human monocytes treated with acapsular cells of C. neoformans. We found that pretreatment of acapsular cryptococci with GXM downregulates, in a dose-dependent manner, the antigen-presenting capacity of monocytes, leading to reduced proliferative T-lymphocyte responses. Similar levels of suppression occurred when monocytes were exposed to encapsulated cryptococci or acapsular cryptococci that were pretreated with GXM. The magnitude of the T-cell response correlated with the ability of monocytes to ingest the yeast. Supernatant fluids from cocultures of monocytes and T cells cultured with encapsulated cryptococci contained higher levels of interleukin-10 (IL-10) than supernatant fluids of cells with acapsular cryptococci. Addition of anti-IL-10 monoclonal antibodies to the incubation medium of monocytes and T cells cultured with encapsulated cryptococci restored proliferative T-cell responses to levels observed during culture with acapsular cryptococci. Finally, treatment of monocytes with encapsulated cryptococci or GXM-treated acapsular cryptococci suppressed expression of class II major histocompatibility complex (MHC) molecules in a manner consistent with previous reports of IL-10-mediated suppression of class II MHC molecules and suppression of proliferative T-cell responses. These results suggest a link between GXM encapsulation, increased IL-10 synthesis by monocytes, decreased expression of class II MHC molecules on monocytes, and reduced proliferative T-cell responses.

Antigen Presentation↗
PubMed1998

Specific antibody to Cryptococcus neoformans alters human leukocyte cytokine synthesis and promotes T-cell proliferation.

Addition of a monoclonal antibody which binds the Cryptococcus neoformans capsule to suspensions of human monocytes, T lymphocytes, and cryptococcal cells (i) enhances interleukin-1beta (IL-1beta), tumor necrosis factor alpha, and IL-2 production; (ii) reduces IL-10 secretion; and (iii) promotes T-cell proliferation. The ability of specific antibody to influence cytokine production and lymphoproliferation suggests a mechanism by which humoral immunity can influence cell-mediated immunity.

Antibodies, Fungal↗
PubMed1998

Involvement of C3a and C5a in interleukin-8 secretion by human polymorphonuclear cells in response to capsular material of Cryptococcus neoformans.

In a previous paper we demonstrated that human polymorphonuclear cells (PMN) in the presence of normal human serum (NHS) secrete proinflammatory cytokines in response to Cryptococcus neoformans or its major capsular component, glucuronoxylomannan (GXM). The hypothesis that activation of the complement system could be responsible for the observed phenomenon is supported by the fact that encapsulated and acapsular C. neoformans isolates are activators of the complement system and, in particular, large encapsulated isolates are powerful activators. In the present study we demonstrate that (i) interleukin-8 (IL-8) release in response to acapsular or encapsulated strains of C. neoformans is significantly reduced in the presence of heat-inactivated serum rather than NHS and is completely abrogated in the absence of human serum; (ii) GXM-induced IL-8 release is strictly dependent on the presence of NHS, is inhibited by specific antibodies to either C3a and C5 complement components, and is completely abrogated by the combined use of these antibodies; (iii) the addition of purified C3a and C5a directly stimulates IL-8 release by PMN; and (iv) monoclonal antibody to GXM in combination with GXM or encapsulated C. neoformans potentiates IL-8 release by PMN. These data shed light on the mechanism involved in GXM-induced IL-8 secretion by PMN, provide an additional potential role for complement in the control of C. neoformans infections, and suggest a complex interplay between the complement system, humoral immunity, and cytokine regulation.

Cells, Cultured↗
PubMed1997

Monocyte dysfunction in patients with acquired immunodeficiency syndrome (AIDS) versus Cryptococcus neoformans.

In the present study we investigated the response of monocytes from AIDS patients, susceptible to cryptococcosis (<200 CD4 cells/microl), against Cryptococcus neoformans. Different patterns of response were observed in these cells compared to cells from healthy donors. In particular, fungicidal activity versus this fungus was impaired; this phenomenon could be due to the difficulty of monocytes to internalize C. neoformans in the presence of an intact complement system. Impairment of complement receptor type 3 and direct involvement of this receptor in phagocytosis of C. neoformans were found in monocytes from AIDS patients, which may account for the difficulty in phagocytosis of the fungus. Also, superoxide anion production was dramatically reduced in monocytes from AIDS patients. An increase of spontaneous tumor necrosis factor (TNF) production was evidenced after in vitro addition of C. neoformans. However, this did not activate the antifungal capacity of monocytes from AIDS patients. Moreover, cryptococcus-laden monocytes from AIDS patients were able to induce only a weak response of autologous T-lymphocytes. Hence, monocyte dysfunction could play a part in the progression of cryptococcosis in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Regulatory role of exogenous IL-10 in the development of immune response versus Cryptococcus neoformans.

The most important event involved in host defence against Cryptococcus neoformans is the development of an adequate cell-mediated immune response. IL-10, abundantly produced during AIDS progression, could be a negative factor that affects the T cell response through its own immunosuppressive action on antigen-presenting cells. To determine whether this cytokine affects the course of immune response against C. neoformans, we added exogenous IL-10 to cultured Cryptococcus-laden monocytes plus T lymphocytes. The data from this study confirmed the down-regulatory effect of exogenous IL-10 on monocytes and expanded the known inhibitory role to include an increase of the deleterious effect due to capsular material of C. neoformans on (i) lymphoproliferation, (ii) down-regulation of MHC class II molecules, (iii) inhibition of IL-2 mRNA expression and protein secretion by T lymphocytes. These results indicate that the presence of IL-10 in AIDS patients, due to the progression of disease, could represent a pivotal problem contributing to augment the pathogenic effect of C. neoformans.

Antibodies, Fungal↗
PubMed1997

Effect of airborne particulate extracts on monocyte oxidative metabolism.

Alveolar macrophages lie on the air side of the alveolar-capillary barrier of the lung. They originate from circulating monocytes and are an important first-line host defense against inhaled microorganisms. In monocytes and macrophages, phagocytosis is associated with an increase in O2 consumption and superoxide anion (O2-) generation, that is, "the respiratory burst". O2- is the precursor of highly reactive, oxygen-derived free radicals that are used to kill potential pathogens. Although it is well known that airborne particulate matter inhibits the phagocytic activity of alveolar macrophages, very little is known about the effect of airborne particulate extracts on the respiratory burst. In this study, monocytes isolated from the peripheral blood were incubated for 2 hr at 37 degrees C with increasing concentrations of particulate extract and then stimulated for 30 min with phorbol 12-myristate 13 acetate (PMA) or with Zymosan. The released O2- was measured by the superoxide dismutase inhibitable reduction of cytochrome C. The results cleary showed that, at a particulate concentration of 0.17 mg/mL, the production of O2- was reduced to 22% and 40% of the control values when the cells were stimulated with PMA and Zymosan, respectively. Concomitantly, there was a release of LDH in the supernatant (50% of the total), indicating that a large proportion of cells were damaged by the treatment with the environmental pollutants, and some cytosolic components were released from the cells. Giemsa staining of the treated monocytes revealed the presence of many cells with a dispersed cytosol; the nucleus, although not destroyed, had a different shape. It was suggested that the airborne particulate matter has a toxic effect that induces the disintegration of the plasma membrane. Cytosolic factors (proteins and coenzymes) necessary for O2- production leak from the cells and superoxide generation is therefore reduced. It remains to be determined whether this phenomenon also occurs in vivo.

Air Pollutants↗
PubMed1996

Inhibition of fungicidal activity of polymorphonuclear leukocytes from HIV-infected patients by interleukin (IL)-4 and IL-10.

OBJECTIVE: To investigate the effect of human recombinant interleukin (hrIL)-4 or hrIL-10 on the functional status of polymorphonuclear leukocytes (PMNL) from normal subjects and HIV-infected patients. DESIGN: In an in vitro system we studied the effect of hrIL-4 or hrIL-10 on phagocytosis, fungicidal activity and superoxide anion production by PMNL. METHODS: PMNL were treated in vitro with hrIL-4 or hrIL-10 or their combination for 6 h and then candidacidal activity was evaluated in a colony-forming unit inhibition assay. Superoxide anion generation by PMNL was measured in the presence or absence of preopsonized zymosan or Candida albicans. RESULTS: Treatment in vitro with hrIL-4 or hrIL-10 of PMNL for 6 h was able to impair candidacidal activity of neutrophils in both normal or HIV-infected patients. The inhibitory effect was time- and dose-dependent and was more evident in PMNL from HIV-infected subjects, and reflected in these latter cells a decrease of superoxide anion generation. The impairment of candidacidal activity in PMNL from HIV-infected patients was accompanied by survival of the yeasts shown by budding formation into phagosomic organelles of cytokine-treated PMNL. CONCLUSIONS: Our data highlight new biological effects of IL-4 and IL-10 evidenced by suppressed effector function of neutrophils; this phenomenon is emphasized in HIV-infected patients suggesting a role for these cytokines in mediating increased susceptibility to microbial infection during AIDS progression.

Adult↗
PubMed1996

Purified capsular polysaccharide of Cryptococcus neoformans induces interleukin-10 secretion by human monocytes.

In this study, we demonstrated that purified capsular polysaccharide of Cryptococcus neoformans is a potent inducer of interleukin-10 (IL-10) secretion by human monocytes. Endogenous IL-10 was involved in regulating tumor necrosis factor alpha and IL-1beta secretion by human monocytes in response to encapsulated C. neoformans strains. Our results suggest a new immunosuppressive effect exerted by glucuronoxylomannan through the induction of IL-10, a potent downregulator of proinflammatory cytokines.

Anti-Bacterial Agents↗
PubMed1996

Capsular polysaccharide of Cryptococcus neoformans induces proinflammatory cytokine release by human neutrophils.

Human polymorphonuclear leukocytes from normal subjects produced proinflammatory cytokines in response to stimulation with Cryptococcus neoformans yeast cells. The cytokines released after stimulation of neutrophils included interleukin-1beta (IL-1beta), IL-6, IL-8 and tumor necrosis factor alpha. The magnitude of the cytokine response was related to the yeast capsule size. Cells of a large-capsule isolate stimulated release of greater amounts of cytokine than did a thinly encapsulated isolate, which, in turn, stimulated release of greater amounts of cytokine than an acapsular isolate. Cytokine release was also stimulated by supernatant fluids from cryptococcal cells that were preincubated with 10% human serum, suggesting the generation of a soluble mediator. The major capsular polysaccharide, glucuronoxylomannan, stimulated release of tumor necrosis factor alpha, IL-1beta, and IL-8 in a dose-dependent fashion. These results differ from previous studies of cytokine secretion by human monocytes in several important respects, including the importance of encapsulation in stimulation of cytokine secretion and the ability of purified glucuronoxylomannan to induce cytokine secretion.

Cryptococcus neoformans↗
PubMed1995

Beneficial effect of recombinant human granulocyte colony-stimulating factor on fungicidal activity of polymorphonuclear leukocytes from patients with AIDS.

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration on the functional status of polymorphonuclear leukocytes (PMNL) in neutropenic AIDS patients was investigated. PMNL destructive activity against Candida albicans or encapsulated or acapsular Cryptococcus neoformans was significantly impaired with respect to control subjects before rhG-CSF treatment. After subcutaneous administration of rhG-CSF (5 micrograms/kg), neutrophil counts increased 3- to 11-fold in 24 h and returned to baseline within 96 h. PMNL fungicidal activity showed significant enhancement 48-72 h after rhG-CSF administration that decreased to baseline within 96 h. Enhanced rhG-CSF-mediated destructive activity strictly correlated with augmented superoxide anion production by PMNL. These findings suggest that therapeutic use of rhG-CSF at appropriate schedules in neutropenic AIDS patients could decrease the risk of infection or, in association with antibiotic therapy, more rapidly resolve the occurring infections.

Acquired Immunodeficiency Syndrome↗