Biomedical subjects

E Jirillo

Publications and source records attributed to E Jirillo.

At least 19 recordsLinked to original sources

PubMed1999

Use of intranasal IL-12 to target predominantly Th1 responses to nasal and Th2 responses to oral vaccines given with cholera toxin.

We have investigated the effects of IL-12 and cholera toxin (CT) on the immune response to tetanus toxoid (TT) given by intranasal or oral routes. CT inhibited IL-12-induced IFN-gamma secretion both in vivo and in vitro. Intranasal administration of IL-12 to mice nasally immunized with the combined vaccine of TT and CT resulted in increased TT-specific IgG2a and IgG3 Abs, while IgG1 and IgE Ab responses were markedly reduced. This shift of the CT-induced immune response toward Th1 type was associated with TT-specific CD4+ T cells secreting IFN-gamma and reduced levels of Th2-type cytokines (i.e., IL-4, IL-5, IL-6, and IL-10). In contrast, intranasal IL-12 enhanced the CT-induced serum IgG1 and IgE Ab responses in mice given the combined vaccine orally. IFN-gamma secretion by TT-specific CD4+ T cells was also enhanced; however, Th2-type cytokine responses were predominant. Mucosal secretory IgA responses to oral or nasal vaccines were not affected by intranasal IL-12. Thus, intranasal IL-12 delivery influences Th cell subset development in mucosal inductive sites that are dependent on the route of vaccine delivery.

Administration, Intranasal↗

PubMed1999

IL-12 is an effective adjuvant for induction of mucosal immunity.

We addressed the effects of two cytokines, IL-6 and IL-12, derived from APCs, for the development of mucosal IgA Ab responses following their nasal delivery with the protein vaccine tetanus toxoid (TT). Mice treated nasally with IL-6 and TT showed higher TT-specific serum IgG (mainly IgG1 and IgG2b) Ab responses than did control mice, but exhibited no IgE and negligible secretory IgA (S-IgA) Ab responses. In contrast, IL-12 administered nasally with TT not only induced sharp increases in TT-specific serum IgG (mainly IgG1 and IgG2b) and IgA, but also elevated mucosal S-IgA Ab responses. Coadministration of IL-6 and IL-12 with TT did not enhance the mucosal or serum Ab responses over those seen with IL-12 alone. TT-specific CD4+ T cells from mice given TT with IL-6 or IL-12 produced higher levels of IFN-gamma, IL-6, and IL-10 than did those from control mice, but only negligible levels of IL-4 and IL-5. In summary, both intranasal IL-6 and IL-12 induced serum Abs that protected mice from systemic challenge with TT, whereas only IL-12 induced mucosal S-IgA Ab responses. The significance of IL-12-induced Th1-type responses for regulation of both mucosal and systemic immunity is discussed.

Adjuvants, Immunologic↗

PubMed1998

Spontaneous and Fas-induced apoptotic cell death in aged neutrophils.

On the basis of the strict analogies between polymorphonuclear cell (PMN) alterations in the aging and depressed functional capacities displayed by apoptotic PMN, we investigated the possible occurrence of age-associated changes in neutrophil apoptosis, either spontaneous or induced by Fas antigen (CD95) activation. In both cases, old subjects exhibited a time course kinetics of neutrophil apoptosis, as assessed by morphologic and quantitative DNA fragmentation analysis, which overlapped that observed in the young. These findings were confirmed by DNA ladder analysis, showing a progressive increase in DNA cleavage products in cells cultured in medium alone or added with agonistic anti-Fas IgM (CH-11) monoclonal antibodies (mAbs), after 12 and 6 hr of incubation, respectively. Aged purified neutrophils constitutively expressed CD95, at levels similar to those observed in the young. Moreover, although we failed to detect Fas ligand expression on PMN surface, treatment of cell cultures with antagonistic anti-Fas IgG1 (ZB4) mAbs determined a significant inhibition of spontaneous apoptosis in neutrophils from both groups of subjects, thus suggesting that the Fas/Fas ligand system is in fact involved in such an event. The results indicate that the overall intrinsic mechanisms regulating neutrophil cell death are not affected by age. Yet aged neutrophils showed a diminished capacity to be rescued by proinflammatory mediators, such as granulocyte-monocyte colony-stimulating factor, granulocyte colony-stimulating factor, and bacterial lipopolysaccharide, following Fas activation. This may hamper the accumulation of functionally active cells in inflammatory areas in vivo, thus contributing to the increased susceptibility of elderly individuals to life-threatening infections.

Aged↗

PubMed1998

The influence of Helicobacter pylori eradication on the gastric mucosal content of epidermal growth factor, transforming growth factor-alpha, and their common receptor.

BACKGROUND: The relationship between the expression of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) and that of their receptor (EGF-R) in the Helicobacter pylori-infected gastric mucosa has not been completely elucidated. The aim of this study was to examine the interplay between H. pylori colonization and gastric mucosal growth factor content. METHODS: By means of a solid-phase enzyme-linked immunosorbent assay EGF, TGF-alpha, and EGF-R levels and interleukin-1beta (IL-1beta) content, which is considered a marker of chronic inflammation, were evaluated in the antral mucosa of 24 H. pylori-positive patients before and 8 weeks after eradication therapy. RESULTS: After therapy H. pylori was eradicated in 19 patients. The eradication was accompanied by a significant decrease in IL-1beta content and an increase in EGF and TGF-alpha levels. On the other hand, in the five patients in whom the bacterium was not eradicated EGF, TGF-alpha, and EGF-R levels were quite similar to those assayed before therapy, whereas IL-1beta content was still high. CONCLUSIONS: These results suggest that H. pylori exerts an inhibitory effect on the mucosal expression of EGF and TGF-alpha, which are likely involved in the gastric mucosa repair process.

Adult↗

PubMed1998

Impairment of phagocytic and T-cell-mediated antibacterial activity and plasma endotoxins in patients with untreated gastrointestinal cancer.

BACKGROUND: Cancer patients have multiple immune deficits, and mediators, such as prostaglandins, transforming growth factor-beta, and interleukin (IL)-10, may play a role in the pathogenesis of these immune dysfunctions. METHODS: Fifty-six patients with gastrointestinal cancer (11 gastric cancer, 7 papilla of Vater cancer, and 38 colorectal cancer) were enrolled for this study, before starting conventional treatments. Phagocytosis and killing exerted by polymorphonuclear cells and monocytes, peripheral blood mononuclear cell absolute numbers, T-cell-mediated antibacterial activity, serum levels of IL-10 and interferon (IFN)-gamma, and plasma bacterial endotoxin concentration were evaluated. RESULTS: Data show an impaired phagocytic and T-cell-mediated antibacterial activity in all cancer patients, whereas only in subjects with gastric cancer were IFN-gamma serum levels reduced. Circulating endotoxins were detected in 17 patients. CONCLUSIONS: In untreated gastrointestinal cancer patients the capacity of phagocytes and T-cells to clear pathogens is reduced. This dysfunction may increase the risk of becoming infected and may account for the presence of endotoxin in 30% of patients.

Adult↗

PubMed1998

Soluble (s) CD14 and plasmatic lipopolysaccharides (LPS) in patients with chronic hepatitis C before and after treatment with interferon (IFN)-alpha.

CDI4 is a monocyte/polymorphonuclear cell receptor for lipopolysaccharide (LPS)-LPS Binding Protein (LBP), which mediates most of the toxic effects exerted by such a bacterial component in the host. Here, we provide evidence that sCD14 and interferon (IFN)-gamma serum levels are significantly higher in chronic hepatitis C (CH-C) patients than those detected in normal donors. On the other hand, CD4+/CD8+ antibacterial activity is depressed, thus facilitating entry of bacteria into the host. Of note, all these immune parameters are not modified by in vivo IFN-alpha administration over a period of one year. Finally, after 12 months of IFN-alpha treatment number of CH-C patients with detectable levels of plasmatic LPS increased, thus indicating a continuous release of LPS into the host and also suggesting a putative pathogenetic role for sCD14 LPS-LBP complex in subjects affected by CH-C virus infection.

Adult↗

PubMed1998

Immunoresponsiveness in chronic hepatitis C patients: correlation between tissue and serum findings.

In the present study, intrahepatic CD8+ lymphocyte infiltrates as well as HLA class I and CD54 (ICAM-1) antigen expression at both tissue and serum levels were evaluated in 54 untreated patients with chronic hepatitis C stratified on the basis of histological diagnosis (Chronic Persistent Hepatitis/Chronic Lobular Hepatitis -CPH/CLH- and Chronic Active Hepatitis -CAH-: 22 and 32 subjects, respectively). The relationships between soluble HLA-I (sHLA-I) and ICAM-1 (sICAM-1) serum levels and their membrane-bound counterparts, CD8+ liver infiltration and serum alanine aminotransferase (ALT) were also studied. A strong HLA-I and CD54 tissue expression, associated to the presence of CD8+ cell infiltrates in necro-inflammatory areas, and elevated sHLA-I and sICAM-1 serum amounts were observed in all patients. At the same time, no difference was found at tissue level between the two groups of patients with respect to the mean scores of HLA-I and CD54 expression, while CAH subjects displayed a significantly higher CD8 periportal and lobular reactivity in comparison to the other subset. Serological assays outlined higher values of circulating HLA-I molecules in CPH/CLH patients and higher sICAM-1 levels in the CAH group. Finally, a negative correlation was found between sHLA-I and ALT in CAH subjects while, in all patients, sICAM-1 positively correlated with both CD8 tissue infiltration and ALT. Our findings confirm the occurrence of an immune activation status during chronic hepatitis C and suggest that sHLA-I molecules might play a down-modulating role on immunoresponsiveness of these patients.

Adult↗

PubMed1998

Stress, neuropsychiatric disorders and immunological effects exerted by benzodiazepines.

Psychoneuroimmunology is a growing scientific field which deals with the mutual interplay between nervous and immune systems. In this framework, many data have demonstrated that cytokines (CKs) derived from the periphery are able to cross the blood brain barrier and act upon the central nervous system (CNS) [e.g., the hypothalamic-pituitary-adrenal axis (HPAA)], thus regulating several physiological functions (thermoregulation, sleep, appetite) or damaging the nervous tissue, when released in exaggerated amounts. On the other hand, nervous cells, such as astrocytes and microglial cells also generate proinflammatory CKs which may be detrimental for the CNS. The neuromodulating CK network can be triggered by microorganisms and/or their products (i.e. bacterial endotoxins), but also stressful life events may activate the HPAA, thus affecting the immune system function. This review will place emphasis on some clinical conditions, such as phobia and migraine without aura (MWA), characterized by anxiety disorders. Patients affected by these neuropsychiatric alterations exhibit multiple functional deficits of phagocytes and T lymphocytes which allow penetration of various pathogens into the host. This is also supported by the detection of circulating bacterial endotoxins and the evidence of both spontaneous and induced exaggerated release of proinflammatory CKs in phobic and MWA patients. The possible iatrogenic effects of benzodiazepines (BDZ) on the immune system have been evaluated by in vitro and in vivo studies. In this respect, it emerges that diazepam exerts an inhibitory function on the immune system, while alprazolam behaves as an immunoenhancer. The presence of central and/or peripheral BDZ receptors on immune cells seems to be the key mechanism responsible for the immunomodulation exerted by these drugs.

Adjuvants, Immunologic↗

PubMed1998

Modulation of cytoskeleton assembly capacity and oxidative response in aged neutrophils.

Several reports have emphasized that aged polymorphonuclear cells (PMN) exhibit an impairment of superoxide anion (O2-) generation when triggered with formyl-methionyl-leucine-phenylalanine (FMLP) in comparison to the younger counterpart. Since microfilaments and microtubules are involved in PMN-mediated functions, in a group of old donors we assessed the effects of either actin stabilizing and disrupting agents, i.e. phalloidin and cytochalasin B, or microtubule stabilization or disruption by taxol and colchicine, respectively, on FMLP-triggered neutrophil oxidative responsiveness. Results show that phalloidin treatment, at a concentration ranging from 10(-6) to 10(-8) M, gave rise to an inhibition of O2- release by aged PMN, while the same effect was seen in similarly treated young cells at a concentration of 10(-7) M only. On the contrary, cytochalasin B pretreatment led to an enhancement of O2- generation in both young and aged neutrophils, even if to a lower extent in the latter group. At the same time, taxol at 10(-8) M strength inhibited young cell responsiveness, while no effects were induced by colchicine treatment. Quite interestingly, elderly neutrophil function was negatively modulated by both microtubule affecting compounds. Altogether, these findings suggest the possible relevance of cytoskeletal affecting compounds in the modulation of FMLP-stimulated O2- release during senescence.

Actins↗

PubMed1997

In vitro production of tumor necrosis factor-alpha, interleukin-6 and interleukin-8 from normal human peripheral blood mononuclear cells stimulated by Rhodococcus equi.

The capability of heat-killed Rhodococcus equi organisms to induce in vitro release of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8 from normal human mononuclear cells as well as the secretion kinetics of these inflammatory cytokines over a 48 h period were evaluated. Results show that normal human mononuclear cells are efficiently triggered to secrete TNF-alpha, IL-6 and IL-8 following R. equi stimulation according to a different kinetics. In particular, release of IL-B was already maximally expressed after 2 h of stimulation, while TNF-alpha amounts progressively increased in a time-dependent fashion. Finally, IL-6 secretion reached peak levels as soon as 18 h of incubation. Taken together, these data point out that monocyte-derived cytokines may play an important role in the immunological control of R. equi infection in immunocompetent people.

Cells, Cultured↗

PubMed1997

Oral but not parenteral interleukin (IL)-12 redirects T helper 2 (Th2)-type responses to an oral vaccine without altering mucosal IgA responses.

Our past studies have shown that the mucosal adjuvant cholera toxin (CT) induces T helper type 2 (Th2) responses with systemic IgG1, IgE and mucosal secretory IgA (S-IgA) antibodies (Abs). In this study, recombinant murine IL-12 (rmIL-12) was given either parenterally or orally to mice orally immunized with tetanus toxoid (TT) and CT to determine whether this cytokine could redirect the CT-induced Th2-type responses and what effect this shift would have on S-IgA Ab responses. Intraperitoneal administration of rmIL-12 shifted TT-specific responses toward Th1-type and resulted in CD4+ T cells producing IFN-gamma and IL-2 with markedly reduced levels of Th2-type cytokines. This cytokine profile was accompanied by increased delayed-type hypersensitivity (DTH) and shifts in serum IgG1 to IgG2a and IgG3 anti-TT Ab responses. Further, serum IgE and S-IgA Ab responses were markedly reduced by parenteral IL-12. When IL-12 complexed to liposomes was given orally both shifts to IgG2a and IgG3 and low IgE Abs again occurred concomitant with enhanced serum IFN-gamma and DTH responses. Interestingly, oral rmIL-12 did not result in significant levels of serum IL-12 nor altered S-IgA Ab responses and resulted in higher levels of some Th2-type cytokines both in vitro and in vivo when compared with parenteral IL-12. Our results show that the shifts in systemic immune responses with intact S-IgA Abs which occur after oral delivery of IL-12-liposomes are due to cytokine effects in the Peyer's patches and suggest new strategies for the targeted manipulation of Th1- and Th2-type responses to mucosal vaccines.

Administration, Oral↗

PubMed1997

Expression and function of the early activation antigen CD69 in murine macrophages.

CD69, a member of the natural killer cell gene complex family of signal transducing receptors, represents one of the earliest activation antigens in human and murine lymphocytes. In contrast, human monocytes may express CD69 in a constitutive fashion. We have evaluated the expression and function of CD69 in murine bone marrow-derived macrophages. CD69 expression as determined by flow cytometry was not constitutive but was induced by stimulation with interferon-gamma (IFN-gamma) plus bacterial lipopolysaccharide (LPS) or tumor necrosis factor a (TNF-alpha). Stimulation with LPS alone was equally effective. Infection with the protozoan parasite Leishmania did not induce CD69 expression nor influence CD69 up-regulation by IFN-gamma plus LPS. Induction of CD69 expression was significantly inhibited in the presence of prostaglandin E2 or dibutyryl-cAMP. Stimulation of macrophages with anti-CD69 monoclonal antibody in the presence of IFN-gamma induced both nitric oxide production and TNF-alpha release. Moreover, anti-CD69 stimulation of Leishmania-infected macrophages resulted in elimination of the intracellular parasite. These results suggest that CD69 is an activation antigen for murine macrophages and may serve as a signaling receptor for an as yet uncharacterized ligand.

Animals↗

PubMed1997

In-situ immunophenotyping study of hepatic-infiltrating cytotoxic cells in chronic active hepatitis C.

OBJECTIVE: Beside the hypothesis of a direct viral cytopathy, several lines of evidence argue in favour of hepatic damage triggered by immune-mediated mechanisms in hepatitis C virus (HCV) infection. The intrahepatic localization of HCV antigen-specific cytotoxic T-lymphocytes (CTLs) to disease sites has been described; however, very few data are available about the degree and the role of hepatic-infiltrating natural killer (NK) cells in chronically HCV-infected subjects. DESIGN: In a series of percutaneous needle liver biopsies obtained from 35 consecutive untreated patients with chronic active hepatitis C, we performed an in-situ immunophenotyping study to evaluate the degree of cytotoxic NK cell infiltration as compared to CTLs, the hepatocyte expression of human major histocompatibility complex antigens class I and class II (HLA-I and HLA-II), and cell adhesion molecules (CAM) in the context of liver inflammatory infiltrates. The data were correlated with the histological activity index (HAI) of disease. RESULTS: In-situ immunophenotyping analysis of CAM provided evidence for the intrahepatic expression of leucocyte adhesion molecules (CD11a and CD2) and their corresponding ligands on hepatocytes (CD54 and CD58) in all cases. A significant parallel expression of CD11a and CD54 as well as CD2 and CD58 structures, restricted to hepatic lobules within the disease sites, was also observed, even if their induction exhibited different degrees of correlation with biological and/or histological activities. A membranous pattern of HLA-I and HLA-II antigen expression on hepatocyte clusters was found in all tissue samples, although HLA-I expression was significantly higher than HLA-II. Moreover, lymphocyte subset analysis displayed a CD8+ T-cell lobular infiltration within inflammatory and/or spotty necrosis areas in all cases, while CD4+ T-cells were confined to the portal and periportal levels. A few scattered CD56+ and CD16+ NK cells, mainly distributed at periportal areas within inflammatory and/or necrotic foci, were detected in 7/35 (20%) and in 5/35 (14.2%) cases, respectively. On the other hand, CD8+ T-cell lobular expression exhibited a linear correlation with HAI (r: 0.698, P < 0.01). Finally, cytotoxic cell infiltration degree did not correlate with HCV serotypes. CONCLUSION: Our findings suggest a limited role for NK cells in the immune mechanism of liver injury in chronic active hepatitis C, while providing further support for the involvement of CD8+ T-cells at disease sites.

Adult↗

PubMed1997

Pathogenetic role of phagocytic abnormalities in human virus immunodeficiency infection: possible therapeutical approaches. A review.

Polymorphonuclear cells (PMN) and monocytes/macrophages (M/M) represent the first defence line against invading microorganisms. Both phagocytic cell functions are precociously compromised in human immunodeficiency virus (HIV)-infected subjects, thus leading to infectious and neurological complications in the late stages of disease. Among intracellular pathogens, emerging bacteria such as Bartonella henselae and Rhodococcus equi can cause peculiar clinical pictures, i.e. the bacillary parenchimal angiomatosis and a classical pyogranulomatous broncopneumonia, respectively. On the other hand, overproduction of proinflammatory cytokines (CKs) and, in particular, tumor necrosis factor-alpha under HIV or lipopolysaccharide stimulation may cause neural damage in terms of demyelination and subsequent development of acquired immunodeficiency syndrome (AIDS) dementia complex. Some therapeutical attempts have been made with colony stimulating factors in order to increase the number and potentiate the function of PMN and M/M. On the other hand, the use of drugs able to reduce exaggerated release of CKs by M/M is suggested in AIDS patients in order to prevent a further aggravation of the clinical condition.

HIV Infections↗

PubMed1997

Successful treatment of herpes simplex virus (HSV) recurrent genital infection with recombinant human (rh) granulocyte-macrophage colony stimulating factor (GM-CSF): a case report.

In the present work, we describe the treatment with rhGM-CSF of a woman affected by HSV recurrent genital infection and not responsive to specific antiviral therapy. The therapeutic regimen consisted of a subcutaneous administration of 300 mg/day of rhGM-CSF for six days. Before treatment with rhGM-CSF, polymorphonuclear cell and monocyte functional capacities and the antibacterial activity exerted by T cells were profoundly depressed. After treatment, a normalization of immune functions and a progressive disappearance of clinical manifestations were observed.

Adult↗

PubMed1997

In vitro effects of recombinant human granulocyte-macrophage colony-stimulating factor (RhGM-CSF) on polymorphonuclear cell (PMN) and monocyte (MO) functional capacities in ovarian cancer patients versus human volunteers.

Human polymorphonuclear cells (PMN) and monocytes (MO) from four ovarian cancer patients and seventeen normal donors were in vitro pretreated with different concentrations (25, 50 and 100 IU, respectively) of rhGM-CSF. Phagocytosis and killing of PMN and MO as well as PMN polarization were evaluated in cancer patients before treatment (T0) and at the end of each chemotherapeutic cycle (T1, T2, T3 and T4, respectively) in comparison with normal donors. RhGM-CSF did not affect phagocytosis and killing of PMN and MO. On the other hand, this cytokine was per se endowed with the capacity to enhance PMN polarization in both cancer patients (at T2 interval) and normal donors.

Aged↗

PubMed1997

Role of lipopolysaccharide and related cytokines in Helicobacter pylori infection.

Helicobacter pylori is a gram-negative bacterium which accounts for the development of chronic gastritis and peptic ulcer in man. In this review, emphasis has been laid on the role of lipopolysaccharide (LPS) of the H. pylori cellular wall in the pathogenesis of gastroduodenal disease. H. pylori LPS exhibits a reduced endotoxic potency in terms of pyrogenicity, lethality, toxicity, mitogenicity, cytokine (CK) release and chromogenic limulus amebocyte lysate assay. This low biological activity of the LPS could be ascribed to the underacylation and underphosphorylation pattern of the lipid A backbone. However, also LPS core structures seem to contribute to the biological activity of the molecule. Despite this low immunological potential, an array of proinflammatory CKs are produced both in vitro and in vivo following stimulation of mucosal cells with H. pylori organisms. It is likely that LPS plays a major role in triggering interleukin (IL)-8, IL-1 and tumor necrosis factor-alpha production from both epithelial cells and macrophages. Finally, the lower immune response elicited by H. pylori LPS in comparison with other enterobacterial LPS may represent an escape mechanism from the host immunosurveillance exerted by this bacterium, thus allowing its survival and persistence in the gastric niche.

Animals↗

PubMed1997

CD45RA and CD45RO isoform expression on intrahepatic T-lymphocytes in chronic hepatitis C.

A liver tissue recruitment of antigen-specific cytotoxic cells has been reported in chronic hepatitis C virus (HCV) infection, but whether they really play a role in viral clearance is still a matter of investigation. To further evaluate T-cell involvement in HCV-induced hepatic disease, the authors analysed, in a cohort of chronic hepatitis C patients, the intrahepatic T-cell expression of CD45 isoforms by using specific monoclonal antibodies. Within hepatic specimens, CD45RA+ (naive) cell frequency at the portal tract level was significantly higher than that exhibited at lobular level. At the same time, a large number of CD45RO+ (memory) cells was found at periportal sites in comparison with the lobular counterpart. The evaluation of CD45RA and CD45RO isoform topographical distribution in relation to CD4+ and CD8+ lymphocytes, as determined on serial sections, showed that CD45RA antigen expression was predominantly coexpressed with CD4+ lymphocytes at the portal tract level, and the CD45RO phenotype with CD8 structure at the lobular and periportal sites. The levels of CD45 isoforms did not show any correlation with biological and/or histological disease activities. The results suggest that a liver recruitment of both naive and memory cells occurs during chronic HCV infection, even if their functional role needs to be further clarified.

Adolescent↗