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A Vecchiarelli

Publications and source records attributed to A Vecchiarelli.

At least 73 records · Page 4Linked to original sources
PubMed1990

T cell subsets and IFN-gamma production in resistance to systemic candidosis in immunized mice.

In addition to previous evidence for the roles of T cell-dependent immunity and delayed-type hypersensitivity in acquired resistance to systemic candidosis in mice, in the present study we have investigated the relative contributions of L3T4+ and Lyt-2+ lymphocytes in the protective immunity induced by vaccination with low virulence Candida albicans cells. We have also addressed the issue of the mode of Candida Ag recognition by specific T cells leading to cytokine release. Spleen cells from immunized mice produced high levels of IFN-gamma in vitro in response to Candida Ag, and this activity was abolished only by the combined treatment of the responder population with anti-L3T4 and anti-Lyt-2.2 mAb plus C. Positively selected L3T4+ and Lyt-2+ cells also produced IFN-gamma in vitro, provided accessory cells (plastic-adherent and Thy-1- Ia- splenocytes, respectively) were added to the lymphocyte-yeast cell cocultures. The production of IFN-gamma by purified L3T4+ and Lyt-2+ cells was inhibited by addition of the respective anti-class II and anti-class I H-2 antibody to the cultures. In vivo, administration of anti-L3T4, anti-Lyt-2.2 mAb or a combination of both significantly impaired the resistance of immunized mice to challenge with virulent C. albicans, as manifested by increased recovery of the yeast from the mouse kidneys. A similar effect was observed upon neutralization of endogenous IFN-gamma by treatment with rat mAb. These results suggest that both L3T4+ and Lyt-2+ T cells play a role in acquired immunity to systemic C. albicans infection, and that their activity may involve IFN-gamma-mediated stimulation of candidacidal mechanisms.

Animals↗
PubMed1989

Protective immunity induced by low-virulence Candida albicans: cytokine production in the development of the anti-infectious state.

A low-virulence, agerminative strain of Candida albicans (PCA-2) is able to confer a high degree of nonspecific protection against subsequent challenge with highly virulent microorganisms in mice. In an attempt to better define the effect of PCA-2 vaccination on the immune system and the nature of the mechanisms involved in this protective state, we evaluated the pattern and kinetics of production of selected cytokines in PCA-2-treated mice. Thus, granulocyte/monocyte colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin 1 (IL-1) were measured in the sera and spleen cell supernatants of vaccinated mice. In both cases, high levels of CSF, TNF, IL-1, and IFN were found 6 hr after PCA-2 infection and persisted for many days. There was always a correlation between the ability of PCA-2 to induce antimicrobial protection in vivo and its ability to cause cytokine production in vitro. Supernatants of splenocyte cultures from PCA-2-infected animals possessed macrophage-activating activity, as measured in microbiological assays. These data suggest an important involvement of cytokines in the nonspecific anti-infectious immunity induced by PCA-2, and also suggest a crucial role for IL-1 as an endogenous adjuvant in the initiation of the immune response to PCA-2.

Amphotericin B↗
PubMed1989

Immunosuppressive effect of cyclosporin A on resistance to systemic infection with Candida albicans.

We studied the influence of cyclosporin-A (Cy-A) on resistance of mice to systemic infection with Candida albicans. Cy-A clearly inhibited resistance to C. albicans. The effect was dose-dependent and time and route of administration of the drug were important. This immunodepressive effect was due, at least in part, to an impairment of polymorphonuclear leucocyte (PMNL) candidacidal activity, as demonstrated in vitro by a reduction of phagocytic and cytotoxic activity and in vivo by protection when PMNL from untreated mice were transferred into cyclophosphamide-treated hosts challenged with C. albicans. The decreased activity of PMNL could be partly restored by adoptive transfer of normal T-lymphocytes into Cy-A-treated mice, as well as by exposure of PMNL to gamma-interferon (IFN-gamma) in vitro.

Animals↗
PubMed1989

Role of L3T4+ lymphocytes in protective immunity to systemic Candida albicans infection in mice.

Protective immunity to lethal Candida albicans challenge in vivo and activation of splenic macrophages with highly candidacidal activity in vitro were detected in mice infected with low-virulence agerminative yeast cells of the variant strain PCA-2, at a time when a strong delayed-type hypersensitivity (DTH) reaction to C. albicans occurred in the footpads of PCA-2-treated mice. The DTH reaction was transferable with spleen cell populations from these animals, and enrichment of splenic lymphocytes in L3T4+ cells significantly increased the footpad swelling. The reactivity transferred by L3T4+ cells was a radiosensitive (2,500 rads in vitro) phenomenon that required collaboration with radioresistant, silica-sensitive syngeneic cells in the host and was inhibited by treatment of recipient mice with antibodies to the L3T4 antigen or murine gamma interferon. In vitro, the PCA-2-immune L3T4+ cells produced various lymphokine activities upon incubation with C. albicans, including gamma interferon and granulocyte-macrophage colony-stimulating factor. Anti-L3T4 monoclonal antibody treatment of PCA-2-infected mice significantly impaired their footpad reaction and resistance to C. albicans, as shown by increased recovery of yeast cells from the kidneys of anti-L3T4-treated mice. These results suggested that the mechanisms of anti-Candida resistance induced by PCA-2 may involve specific induction of a DTH response mediated by inflammatory L3T4+ T cells and lymphokine-activated phagocytic effectors. However, the survival rate of the PCA-2-immune mice challenged with C. albicans was not significantly modified by administration of the anti-L3T4 antibody, thus allowing for the conclusion that compensatory mechanisms lead to considerable anti-Candida resistance when the activity of L3T4+ cells is deficient.

Animals↗
PubMed1989

Modulation of anti-Candida activity of human alveolar macrophages by interferon-gamma or interleukin-1-alpha.

The fungicidal and bactericidal activities of human alveolar macrophages (AM) and peripheral blood monocytes (PBM) from 18 healthy volunteers were evaluated. The results showed that AM were able to phagocytize and kill Candida albicans, Pseudomonas aeruginosa, and Staphylococcus aureus. However, killing of the bacteria was already complete in 2 h, whereas killing of Candida required 4 to 6 h despite an early phagocytosis of yeast cells. The fungicidal activity of freshly collected AM and PBM was also tested after effector cell exposure to interferon-gamma (IFN-gamma), interleukin-1-alpha (IL-1 alpha), endotoxin lipopolysaccharide (LPS), or interleukin 2 (IL-2). It was found that treatment with IFN-gamma, IL-1 alpha, or LPS significantly augmented macrophage and PBM candidacidal activity, whereas the addition of IL-2 was ineffective. We also evaluated killing of C. albicans by AM cultured in vitro for different times. While phagocytosis was apparently unaffected, the candidacidal activity progressively decreased over the in vitro culture period, an effect that was largely reversed by cell exposure to IFN-gamma, IL-1 alpha, or LPS. In an experimental model in which mice infected with an agerminative C. albicans strain (PCA-2) resisted lethal microbial challenge, freshly harvested AM showed increased cytotoxic activity to Aspergillus fumigatus in vitro as well as enhanced IL-1 production. In conclusion, present data confirm the crucial role of AM in the surveillance of bacterial and fungal infections and indicate that treatment of these cells with IFN-gamma or IL-1 alpha is able to enhance their antimicrobial capability.

Adult↗
PubMed1989

Sarcoidosis: an alveolar macrophage disease?

The Authors focus on new functions of alveolar macrophages (AM) from patients with active pulmonary sarcoidosis. They show that sarcoid AM present a candidacidal activity higher than normal controls, probably due to an enhanced phagocytic efficiency. Furthermore, after LPS stimulation cultured sarcoid AM secrete larger amount of interleukin 1 (IL-1) and of tumor necrosis factor (TNF) than normal controls. In conclusion, a new key role is emerging for sarcoid AM: not only an antigen-presenting cell, but a cell with a great primitive potential in modulating the inflammatory process.

Bronchoalveolar Lavage Fluid↗
PubMed1988

Immunomodulation by a low-virulence, agerminative variant of Candida albicans. Further evidence for macrophage activation as one of the effector mechanisms of nonspecific anti-infectious protection.

Systemic infection of mice with a Candida albicans strain (PCA-2) incapable of yeast-mycelial conversion is known to activate host macrophages and confer protection against subsequent challenge with highly pathogenic cells of the same species or by other micro-organisms. In an attempt to define the relative contributions of different immune components to the protection mediated by PCA-2, we evaluated the effect of manipulations known to selectively deplete immune functions. By means of cytostatic drug or silica induced toxicity, it was possible to demonstrate that no crucial role in protection is played by cytotoxic T lymphocytes or B cells, nor by PCA-2 induced granulocytosis alone. The cells responsible for this effect were dacarbazine-resistant silica-sensitive macrophages whose activity in vivo paralleled the in vitro expression of splenic candidacidal activity. Macrophage activation by PCA-2 and increased anti-Candida resistance did not result from an immunological response mediated by T-dependent effectors, as these effects could be reproduced in athymic mice.

Adjuvants, Immunologic↗
PubMed1988

Immunomodulation by Candida albicans: crucial role of organ colonization and chronic infection with an attenuated agerminative strain of C. albicans for establishment of anti-infectious protection.

Intravenous inoculation of an attenuated agerminative strain of Candida albicans (PCA-2) of low virulence, but not of two other species of Candida of low virulence (C. parapsilosis and C. viswanathii) into CD2F1 mice conferred protection against the highly virulent microbes C. albicans CA-6, Staphylococcus aureus and Aspergillus fumigatus. To provide protection, a definite inoculum size (10(6) cells per mouse) resulting in organ colonization and establishment of a long-lasting chronic infection with PCA-2 was needed. An inoculum of 10(5) cells gave rise to transient kidney colonization whereas inocula greater than 10(6) cells led to acute septicaemia and eventual death. Chronic infection of mice following inoculation of 10(6) PCA-2 cells was accompanied by detectable mannoprotein antigen levels in the serum (30-70 ng ml-1) while specific antibodies did not appear until 14 d after inoculation, at which time low antimannan antibody was present (ELISA titre 1:40-1:80). Chronic infection was characterized by the presence in the kidneys of 2-3 x 10(6) c.f.u. of PCA-2 for at least 40 d after inoculation. Pharmacological modulation of the host through administration of either an anti-Candida drug, amphotericin B, or an immunosuppressive agent, cyclophosphamide, strongly supported the premise that the anti-infectious state conferred by PCA-2 'immunization' correlated with the maintenance of a sufficient number of PCA-2 in vivo. Protection was 'switched on' when 2-3 x 10(5) cells were present in the kidneys. It was maximal at a kidney count of 2-3 x 10(6) c.f.u. of PCA-2, and promptly declined when the number of PCA-2 cells in the kidney fell below 2 x 10(5). Mice chronically infected with PCA-2 had splenic macrophages with pronounced candidacidal activity in vitro. Modulation of the growth of PCA-2 in vivo, which determined activation or deactivation of the protective state, was paralleled by a similar modulation in macrophage activation, showing that in all cases resistance to virulent organisms persisted as long as macrophage activation was present. The results demonstrate that a critical in vivo antigenic load is crucial for the occurrence of resistance to infection and suggests that macrophages could be involved in this protection.

Adjuvants, Immunologic↗
PubMed1986

Evidence for macrophage-mediated protection against lethal Candida albicans infection.

Systemic infection of mice with a Candida albicans strain (PCA-2) incapable of yeast-mycelial conversion conferred protection against a subsequent intravenous challenge with the pathogenic strain of the parent organism, strain CA-6. Protection was nonspecific since it was also detected upon challenge of mice with Staphylococcus aureus. Moreover, the PCA-2 organisms had to be viable, their effects being most evident when they were given intravenously at a dose of 10(6) cells 7 to 14 days prior to microbial challenge. Thus, all mice pretreated with PCA-2 and challenged 14 days later with viable CA-6 cells lived through a 60-day observation period, whereas all control mice not treated with PCA-2 died within 3 days. In an attempt to correlate the immunostimulatory effects observed in vivo with possible modifications in in vitro functions, it was found that administration of PCA-2 was accompanied by an increase in the number of peripheral blood polymorphonuclear cells and by the activation in the spleen of cells with highly candidacidal activity in vitro. Moreover, the adoptive transfer of plastic-adherent cells from PCA-2-infected mice into histocompatible recipients conferred considerable protection against subsequent CA-6 challenge.

Amphotericin B↗
PubMed1986

Involvement of host macrophages in the immunoadjuvant activity of amphotericin B in a mouse fungal infection model.

We have recently reported the in vivo augmentation of resistance to experimental Candida albicans injection by amphotericin B in mice and have shown that this event is concurrent with the appearance in the spleen of a highly candidacidal cell population reactive in vitro against 51Cr-labeled yeast cells. In the present study we characterize these in vitro fungicidal effectors as macrophages and describe the conditions of amphotericin B treatment most suitable for inducing candidacidal activity. We also report that macrophages from intact mice can be activated in vitro to become cytotoxic against Candida. The possible mechanisms through which the amphotericin B activated macrophages exert their increased anti-Candida activity are also investigated.

Adjuvants, Immunologic↗
PubMed1985

In-vitro killing of Candida species by murine immunoeffectors and its relationship to the experimental pathogenicity.

Killing of yeast cells of several species of Candida by murine phagocytic cells was assessed in vitro by a radiolabel release microassay and measurement of colony forming units. The most effective candidacidal phagocytes, i.e. polymorphonuclear and bone marrow cells, were able to kill equally well cells of any species or isolate tested, given sufficient time (4 h) and an appropriate effector: target ratio. However, C. guilliermondii, C. krusei and C. parapsilosis were killed by polymorphonuclear and bone marrow cells much more promptly (1 h) and at a significantly lower effector:target ratio than C. albicans, C. tropicalis and C. viswanathii. Moreover, there were immune effectors such as peritoneal resident macrophages and, mostly, spleen cells which were practically ineffective against C. albicans and C. tropicalis but showed significant activity against C. guilliermondii, C. krusei and C. parapsilosis, even in mice immuno-depressed with cyclophosphamide. Three isolates of C. albicans, differing in the capacity to form germ tubes, also differed in mouse virulence: the germ-tube forming isolate was the most virulent. However, they showed an identical pattern of susceptibility to killing by mouse immunoeffectors, suggesting that virulence is probably not due to the resistance of hyphal cell to phagocytosis.

Animals↗
PubMed1985

Killing of yeast, germ-tube and mycelial forms of Candida albicans by murine effectors as measured by a radiolabel release microassay.

Candida albicans undergoes yeast to mycelial conversion under both in vivo and in vitro conditions but the relative pathogenicity of the two forms of growth is still unknown. By adapting a recently developed 51Cr radiolabel release assay, we have quantified the killing ability of different murine effector cell populations for the hyphal form of C. albicans. Up to 50% of specific 51Cr release from the mycelial form could be detected after incubation for only 1 h, with no requirement for opsonization, provided that appropriate effector: target cell ratios were used. The specific 51Cr release correlated well with viability, as assessed by dye exclusion tests, and with pathogenicity potential in cyclophosphamide-immunodepressed mice. Comparison of the activity of different murine effectors against yeast and hyphal forms showed that hyphal forms were killed by murine effectors to a similar, if not greater, extent than yeast forms. In particular, thioglycollate-induced murine polymorphonuclear neutrophils were able to kill hyphal cells extracellularly and without an opsonic requirement.

Animals↗