Biomedical subjects

E Jirillo

Publications and source records attributed to E Jirillo.

At least 37 records · Page 2Linked to original sources

PubMed2002

The role of the liver in the response to LPS: experimental and clinical findings.

The liver plays an important physiological role in lipopolysaccharide (LPS) detoxification and, in particular, hepatocytes are involved in the clearance of endotoxin of intestinal derivation. In experimental shock models, tumor necrosis factor (TNF)-alpha induces hepatocyte apoptosis and lethal effects are due to secreted TNF-alpha and not to cell-associated TNF-alpha. An exaggerated production of TNF-alpha has been reported in murine viral infections, in which mice become sensitized to low amounts of LPS and both interferon (IFN)-gamma and IFN-alpha/beta are involved in the macrophage-induced release of TNF-alpha. The prominent role of LPS and TNF-alpha in liver injury is also supported by studies of ethanol-induced hepatic damage. In humans, evidence of LPS-induced hepatic injury has been reported in cirrhosis, autoimmune hepatitis, and primary biliary cirrhosis and a decreased phagocytic activity of the reticulo-endothelial system has been found in these diseases. The origin of endotoxemia in hepatitis C virus (HCV) infected patients seems to be multifactorial and LPS may be of exogenous or endogenous derivation. In endotoxemic HCV-positive patients responsive to a combined treatment with IFN-alpha/ribavirin (RIB), endotoxemia was no longer detected at the end of the therapeutic regimen. By contrast, 48% of the non-responders to this treatment were still endotoxemic and their monocytes displayed higher intracellular TNF-alpha and interleukin (IL)-1beta levels than responders. Moreover, in responders, an equilibrium between IFN-gamma and IL-10 serum levels was attained. In the non-responders, serum levels of IL-10 did not increase following treatment. This may imply that an imbalance between T helper (Th)1 and Th2 derived cytokines could be envisaged in the non-responders.

Animals↗

PubMed2002

Biological and clinical significance of endotoxemia in the course of hepatitis C virus infection.

Endotoxins or lipopolysaccharides (LPS), major components of the cell wall of Gram-negative bacteria, once released from the bacterial outer membrane bind to specific receptors and, in particular, to a membrane-bound receptor, the CD14 (mCD14) and the toll-like receptor 4 present on monocytes/ macrophages. In turn, LPS-activated monocytes/ macrophages release in the host tissue an array of so-called proinflammatory cytokines and, among them, Tumor Necrosis Factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-12 are the major mediators. Before therapy (To) and at the end of 6-month interferon (IFN)-alpha/Ribavirin (RIB) treatment (T6), circulating endotoxin levels were measured in responder and non responder HCV+ patients. At T0, 57% of the non responders were endotoxin-positive and had, on average, 54 pg/ml of plasma LPS while in 50% of the responder patients endotoxin were found with an average of 29 pg/ml. At T6, in responders LPS were no longer detectable, while in 42% of the non responders LPS were found (average levels 45 pg/ml). In terms of serum cytokine concentration, at T6 IFN-gamma levels when compared to those detected at T0 were increased in both endotoxin-positive and endotoxin-negative patients. However, at T6 IL-10 concentration was significantly increased only in the group of endotoxin-negative subjects (responder patients), in comparison to T0 values. The origin of endotoxemia in HCV+ patients seems to be multifactorial, likely depending on impaired phagocytic functions and reduced T-cell mediated antibacterial activity. In these patients, however, one cannot exclude the passage of LPS from the gut flora to the blood stream, owing a condition of altered intestinal permeability. At the same time, a less efficient detoxification of enteric bacterial antigens at the hepatic level should be taken into consideration. Finally, novel therapeutic attempts aimed to neutralize LPS in the host are discussed.

Autoantibodies↗

PubMed2002

Modifications of the immune responsiveness in patients with hepatitis C virus infection following treatment with IFN-alpha/ribavirin.

The balance between T helper (h)1 and Th2 responsiveness seems to represent a key event in the evolution of hepatitis C virus (HCV) infection. In particular, Th1 cytokines [interleukin (IL-2) and interferon (IFN-gamma)] have been demonstrated to mediate the antiviral immune response. Serum levels of Th1 cytokines (IL-2 and IFN-gamma) as well as of Th2 products (IL-4 and IL-10) were determined in a group of HCV-positive patients before and after treatment with IFN-alpha and Ribavirin (RIB). Results indicate that responder patients exhibited increased levels of IFN-gamma and IL-10, while this enhancement was not observed in non-responder patients. In this respect, the major effect exerted by the combined therapy with IFN-alpha/RIB could be represented by the attainment of a re-equilibrium between inflammatory (Th1) and antiinflammatory (Th2) mechanisms. In this framework, according to current literature, novel therapeutical approaches to treat HCV infection are represented by administration of recombinant IL-2 and IL-10.

Drug Therapy, Combination↗

PubMed2002

Evaluation of the innate immune response in pups during canine parvovirus type 1 infection.

In two pups (A and B) naturally infected with canine parvovirus type 1 (CPV1) phagocytic responses were evaluated over a period of two weeks (day 0 = T0; day 3 = T1; day 7 = T2; day 14 = T3). CPV1 infection led to a marked reduction of monocyte (MO) phagocytosis in both pups. Also MO killing was impaired and in pup B this function was totally absent. Polymorphonuclear (PMN) phagocytosis values of both pups fluctuated within normal ranges, as well as PMN killing of pup A. In pup B, killing exerted by PMN was absent at T0, then increased but again dropped below normal ranges at T3. The described alterations of phagocytic functions may be regarded as possible viral mechanisms of immune evasion.

Animals↗

PubMed2002

Fish immunology. II. Morphologycal and cytochemical characterization and phagocytic activities of head kidney macrophages from rainbow trout (Salmo gairdneri Richardson).

In Salmo gairdneri Richardson trouts, a comparison was made between macrophages (MO) derived from head kidney and peripheral blood monocytes. Morphologically and cytochemically no differences were observed between these two types of mononucleated cells. On the other hand, in parallel studies the ability of trout erythrocytes to engulf Candida albicans (CA) was evaluated and compared to the MO phagocytosis. In erythrocytes, engulfment is preceded by binding to CA and cell membrane invagination, while this was not the case for MO. Finally, MO stimulated with lipopolysaccharides (LPS) did not modify their phagocytic capacities, thus suggesting a lack of LPS receptors or a tolerance to LPS.

Animals↗

PubMed2001

Combination therapy with ribavirin and alpha interferon for the treatment of chronic hepatitis C refractory to interferon.

BACKGROUND: Up to 80% of hepatitis C patients are refractory to treatment with interferon-alpha. These patients are not likely to benefit from higher dosages or longer duration of interferon alone. The addition of ribavirin has been shown to improve the response rate in patients resistant to a previous course of interferon-alpha alone. AIM: To evaluate whether a sustained hepatitis C virus (HCV) RNA response could be obtained with combination therapy of interferon-alpha and ribavirin in patients who did not respond to or relapsed after a standard interferon-alpha treatment. METHODS: A total of 73 patients, 59 non-responders and 14 relapsers after interferon-alpha alone, were treated with a combination of ribavirin (1000-1200 mg/day) and interferon-alpha (3 MU three times a week) for 24 weeks. Alanine aminotransferase levels and HCV RNA were checked for 24 weeks after completion of therapy. RESULTS: At the end of the combination therapy, 36 patients (49%) showed alanine aminotransferase normalization and in 20 patients (27%), HCV RNA was undetectable in serum. At the end of the 24 weeks follow-up period, only 12 patients (16%) had a sustained response with serum negativity of HCV RNA. This response was significantly higher in relapsers than in non-responders: five (36%) vs. seven (12%) patients (P=0.03), respectively. Adverse effects were restricted to flu-like symptoms and moderate haemolytic anaemia. CONCLUSIONS: Combination of interferon-alpha and ribavirin is quite limited, both in scope and efficacy, in HCV patients who had a non-response to monotherapy with interferon. Better results may be expected in relapsers, but larger studies are necessary.

Adult↗

PubMed2001

In vitro effects of naloxone on T-lymphocyte-dependent antibacterial activity in hepatitis C virus (HCV) infected patients and in inflammatory bowel disease (IBD) patients.

Naloxone acts as an opioid antagonist, displacing opioid drugs from cellular receptors. Among opioid substances, beta-endorphins are able to bind to several cell receptors, even including those expressed by immune cells. In this respect, evidence has been provided that in the course of viral infections, as well as in patients with ulcerative colitis high levels of beta-endorphins are detectable. Here, peripheral blood lymphocytes (PBL) from 21 HCV infected patients and 14 patients with IBD, respectively, were incubated with Naloxone and Naloxone + Ca2+ in order to evaluate a putative modulation of PBL-mediated antibacterial activity. In fact, previous studies have demonstrated a reduction of this T-cell activity in HCV and IBD patients. In general terms, the above treatment led to a recovery of the depressed antibacterial activity. In some cases, increase in T lymphocyte function was obtained with Naloxone alone, while in other cases the combination Naloxone + Ca2+ gave rise to a restorative effect. Of note, in some instances, lymphocytes were unresponsive to pharmacological modulation. The overall results suggest that beta-endorphins may down modulate T-cell antibacterial response in HCV and in IBD patients by saturating peripheral receptors on immune cells. Therefore, it is likely that Naloxone and/or Naloxone + Ca2+ may displace opioid drugs, thus antagonizing their effects.

Adolescent↗

PubMed2001

Circulating cytokines and gastrin levels in asymptomatic subjects infected by Helicobacter pylori (H. pylori).

The pathophysiology of hypergastrinemia in H. pylori infection has been largely investigated and different reports clearly show that the infected antrum has a marked inflammatory response with a suggestive local production of cytokines. Notwithstanding, a few data are available on the circulating levels of cytokines and gastrin in the asymptomatic people carrying H. pylori infection. Thus, aim of the study was to evaluate circulating proinflammatory cytokines [Interleukin (IL)-8, Interleukin (IL)-10, Interferon (IFN)-gamma, and Tumor Necrosis Factor (TNF)-alpha] and gastrin levels in H. pylori positive asymptomatic subjects vs. H. pylori negative ones. To this end, thirty healthy volunteers with no digestive symptoms or systemic disease were enrolled and H. pylori infection was identified by a 13C-urea breath test. Plasma levels of gastrin were determined using the RIA kit whereas IL-8, TNF-alpha, IL-10, and IFN-gamma levels in serum were measured with a solid-phase ELISA. Fifteen infected people showed significantly higher gastrin and TNF-alpha levels than uninfected subjects. On the contrary, IL-8 levels were significantly higher in the uninfected subjects than in H. pylori positive ones (P < 0.0422). IFN-gamma and IL-10 circulating levels were not affected by H. pylori presence, being not significantly different in the two groups.

Adult↗

PubMed2001

A syndrome characterized by psychiatric disorders, recurrent mucosal infections and natural immunity deficits: clinical approach.

The authors summarize their own previous work on the identification of a subset of patients characterized by psychiatric disorders, recurrency of mucosal infections and impaired natural immunity. The diagnostic approach to these patients based on the close collaboration between infectivologists, immunologists and psychiatrists is described with the aim to find out combined treatments for the amelioration of clinical manifestations.

Humans↗

PubMed2001

Helicobacter pylori infection, immune response and vaccination.

It is well known that abnormal immune responses may play a pathogenic role in the H. pylori-related gastropathy. Indeed, as far as humoral immune response is concerned, it is still debated whether specific anti-H. pylori antibodies have a protective or noxious effect in infected hosts. Besides proinflammatory cytokines released from macrophages, such as tumor-necrosis factor-a and interleukin-1beta, and IFN-gamma derived from T-helper 1 lymphocytes, also interleukin-10, a product of T-helper 2 lymphocytes with antiinflammatory properties, seems to be surprisingly involved in the pathogenesis of H. pylori-induced gastritis. In addition, lipopolysaccharide derived from the outher membrane of H. pylori acts as a chemoattractant for monocytes and induces release of free radicals, interleukin-1beta, interleukin-6, interleukin-8 and tumor necrosis factor-alpha. On the other hand, H. pylori lipopolysaccharide could be responsible for the increased polyamine concentrations in the gastric mucosa and polyamines, such as putrescine, spermidine and spermine, could be involved in the increased cell proliferation and consequent possible neoplastic transformation of the gastric mucosa. Incubation of peripheral blood mononuclear cells with H. pylori increases significantly the surface expression of CD95 receptor (Fas), thus suggesting that these bacteria are able to induce apoptosis. In animal models, different types of vaccination have been investigated, including stimulation of nasal and rectal lymphoid tissue, as well as adoptive transfer of T cell from donors immunized with H. pylori. However, results obtained are frequently disappointing. In humans, urease of H. pylori was safely used as oral vaccine in the absence or presence of adjuvants with encouraging results. Finally, DNA vaccines could offer in the future advantages for prophylactic H. pylori eradication, especially where population is infected by this microorganism since childhood.

Animals↗

PubMed2000

Phagocytosis, killing, lymphocyte-mediated antibacterial activity, serum autoantibodies, and plasma endotoxins in inflammatory bowel disease.

OBJECTIVE: Alteration of mucosal and systemic immune responses may play an important role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to evaluate natural immune responses (i.e., phagocytosis, killing, and antibacterial activity), serum autoantibodies (antineutrophil cytoplasmic antibodies [ANCA] and anti-lactoferrin [LF] antibodies), and plasma endotoxins in patients affected by ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Blood samples were obtained from 71 patients with UC, 32 patients with CD, and 32 control subjects. Disease activity was scored using Truelove's criteria in patients with UC and the Crohn's Disease Activity Index (CDAI) in patients with CD. Candida albicans served as a target for evaluation of phagocytosis and killing exerted by polymorphonuclear cells (PMN) and monocytes (MO), whereas Salmonella typhi was used for assessing lymphocyte-mediated antibacterial activity. ANCA were detected by indirect immunofluorescence, whereas anti-LF antibodies were assayed by means of enzyme-linked immunosorbent assay. Plasma endotoxins were measured by Limulus amoebocyte lysate assay. RESULTS: Phagocytosis and killing exerted by PMN and MO, as well as lymphocyte-mediated antibacterial activity, were significantly reduced (p < 0.0001) in patients affected by UC and CD in comparison with controls, irrespective of either disease activity or treatment. Plasma endotoxins were detected in 12/71 (17%) patients with UC, and in 10/32 (31%) patients with CD. ANCA were present in 42/71 (59%) patients with UC and in 3/32 (9%) patients with CD, whereas anti-LF antibodies were detected in 31 (44%) UC patients and in six (19%) CD patients. No significant differences in phagocytosis and killing exerted by PMN were found between ANCA-positive and ANCA-negative UC patients. CONCLUSIONS: Our data demonstrate an impairment of natural immunity exerted by peripheral blood phagocytes and lymphocytes in patients with UC and CD. ANCA and anti-LF antibodies were present mainly in UC patients but their presence did not affect PMN-mediated phagocytosis and killing. Finally, plasma endotoxins may contribute to the chronic inflammatory status, likely by inducing release of proinflammatory mediators.

Adolescent↗

PubMed2000

Hepatitis C virus infection: immune responsiveness and interferon-alpha treatment.

Hepatitis C virus (HCV) is responsible for most cases of posttransfusion hepatitis and sporadic or community-acquired non-A, non-B hepatitis. Different generations of enzyme-linked immunosorbent assay have been generated for detecting antibodies to HCV epitopes. HCV-RNA quantitative analysis has been developed by means of polymerase chain reaction technique. This approach is the only reliable method for HCV-RNA tissue localization, being helpful in early diagnosis. HCV infected liver is characterized by an inflammatory infiltrate including CD4+, CD8+, and B lymphocytes. Evidence has been provided that in HCV patients CD8+ cell response is associated with low level of viraemia and higher level of disease activity. CD4+ T cells exhibit specificity for the core antigen, also correlating with disease activity and viraemia. Costimulatory molecules, cytokines, oxygen radicals, the complex Fas/Fas-ligand and soluble class I HLA structures are discussed as putative cofactors involved in disease evolution. Various forms of interferon (IFN)-alpha have been evaluated for the treatment of patients with HCV infection. Initial enthusiasm has been attenuated by the evidence of a low sustained virological response rate and the constant side effects of IFN-alpha therapy in patients with chronic HCV disease. Among possible markers for predicting therapeutic outcome in HCV-positive individuals, anti-core antibodies correlate positively with response to IFN-alpha administration, as well as reduction of interleukin-2 serum levels has been detected in patients with a good therapeutic response. Association between HCV infection and autoimmune phenomena, also in relation to IFN-alpha therapy has been reported. Finally, results of the combined treatment with IFN-alpha/ribavirin are illustrated.

Arachidonic Acid↗

PubMed2000

In vivo effects of recombinant-interferon-beta1b treatment on polymorphonuclear cell and monocyte functions and on T-cell-mediated antibacterial activity in patients with relapsing-remitting multiple sclerosis.

Treatment with Interferon (IFN)-beta has been proposed as a therapeutic approach in multiple sclerosis (MS) patients, mostly in view of its immunomodulating actions. At the same time, evidence has been provided that MS patients exhibit polymorphonuclear cell (PMN) deficits, which can explain the increased susceptibility to infections in these subjects. Here, in 28 patients with relapsing-remitting (RR) MS under treatment with recombinant (r)-IFN-beta PMN polarization and PMN and monocyte (MO) phagocytosis and killing, as well as T-cell mediated antibacterial activity, were evaluated before treatment and over a period of nine months of treatment. Our results point out an enhanced rate of polarization (both "spontaneous" or N-formyl-methionyl-leucyl-phenylalanine-induced) in MS patients. After r-IFN-beta1b treatment the polarization rate was further increased. On the contrary, PMN and MO phagocytosis and killing were depressed in comparison to controls and values were further reduced by r-IFN-beta1b treatment. In patients T-cell mediated antibacterial activity was decreased at T0 and dramatically dropped in the course of r-IFN-beta1b therapy.

Adult↗

PubMed2000

Evaluation of the natural immunity in pups inoculated with a modified-live canine parvovirus type 2b (CPV-2b) strain.

Three pups 2-4 months old were vaccinated subcutaneously with the modified live canine parvovirus, CPV-2b/29-97 strain. During an observation period of two weeks pups remained clinically health, exhibiting a vigorous post-vaccinal active serological response (haemoagglutinating inhibiting antibody titers for CPV-2 ranging from 1:2560 to 1:5120 at 21 days post inoculation). Phagocytosis and killing of Candida albicans exerted by polymorphonuclear cells and monocytes did not undergo significant modifications 3-6 days post vaccination up to 30 days. Antibacterial activity mediated by peripheral blood lymphocytes (Salmonella typhi was used as a target) was slightly, but not significantly decreased 3 days post vaccination. Conclusively, in pups the CPV type 2b vaccine seems to be safe as far as natural immune responses are concerned, while its immunogenicity is preserved.

Animals↗

PubMed2000

Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance.

Ulcerative colitis (UC) and Crohn's disease (CD) [inflammatory bowel disease (IBD)] are both characterized by an exaggerated immune response at the gut associated lymphoreticular tissue level. Such an abnormal and dysregulated immune response may be directed against luminal and/or enteric bacterial antigens, as also supported by murine models of inflammatory bowel disease (IBD) caused by organisms such as Citrobacter rodentium and Helicobacter hepaticus. Bacterial endotoxins or lipopolysaccharides (LPS) have been detected in the plasma of IBD patients and an abnormal microflora and/or an increased permeability of the intestinal mucosa have been invoked as cofactors responsible for endotoxemia. At the same time, the evidence that phagocytosis and killing exerted by polymorphonuclear cells and monocytes and the T-cell dependent antibacterial activity are decreased in IBD patients may also explain the origin of LPS in these diseases. In IBD, pro-inflammatory cytokines and chemokines have been detected in elevated amounts in mucosal tissue and/or in peripheral blood, thus suggesting a monocyte/macrophage stimulation by enteric bacteria and/or their constituents (e.g. LPS). On these grounds, in experimental models and in human IBD, anti-cytokine monoclonal antibodies and interleukin receptor antagonists are under investigation for their capacity to neutralize the noxious effects of immune mediators. Finally, the administration of lactobacilli is beneficial in human IBD and, in murine colitis, this treatment leads to a normalization of intestinal flora, reducing the number of colonic mucosal adherent and translocated bacteria.

Animals↗

PubMed2000

MALP-2, a Mycoplasma lipopeptide with classical endotoxic properties: end of an era of LPS monopoly?

Although some activities of LPS are shared by other bacterial components, for half a century LPS has been regarded as unique in displaying many pathophysiological activities. Here we report on a synthetic lipopeptide, MALP-2 from Mycoplasma fermentans, which expresses potent endotoxin-like activity and whose lethal toxicity is comparable to that of LPS. With the exception of the Limulus lysate gelation test, in which MALP-2 was approximately 1000-fold less active than LPS, the synthetic lipopeptide induced all activities tested for, and in most cases to an extent comparable to that of LPS. Unlike LPS, the biological activities of MALP-2 were expressed both in LPS-responder and in LPS-non-responder mice (BALB/c/l, C57BL10/ScCr), indicating that MALP-2 signaling, unlike that of LPS, is not transduced via the Toll-like receptor (Tlr) 4 protein.MALP-2 expressed no toxicity in normal or sensitized Tlr2 knockout (Tlr2(-/-)) mice indicating that its toxic activity is induced via Tlr2 signaling. The phenomenology of the lethal shock induced by MALP-2 in normal or sensitized mice, i.e. the kinetics of its development and symptoms of illness exhibited by the treated animals, was very reminiscent of the lethal shock induced by LPS.

Animals↗

PubMed1999

Age-related effects of oxidative metabolism and cyclic AMP signaling on neutrophil apoptosis.

Spontaneous as well as Fas-induced polymorphonuclear cell apoptosis is unchanged in the elderly. However, a weak responsiveness to antiapoptotic signals elicited by proinflammatory molecules has been reported in neutrophils isolated from aged humans. To gain insight into this field, here we have evaluated the role of oxidative metabolism and cyclic AMP (cAMP) signaling on age-related neutrophil apoptotic cell death. Results show that although superoxide dismutase (SOD), added exogenously to cell cultures, is able to prolong neutrophil survival in both young and aged individuals, high amounts of the enzyme are further effective in cell cultures of young donors only. Notably, the addition of catalase gives rise to a more striking, yet comparable, inhibition of neutrophil-programmed cell death in both groups of subjects. Furthermore, even low amounts of catalase are enough to restore a normal apoptotic outcome in SOD-treated cell cultures of old donors. Unlike the oxidative metabolism, cAMP signaling activation does not reveal any difference in the apoptotic response of neutrophils isolated from young and aged donors. Thus, supplementation of cell cultures with prostaglandin E2, dibutyryl cAMP or, to a lesser degree, forskolin results in a dose-dependent inhibition of DNA cleavage product appearance in both groups of subjects. The data outline that an impairment of neutrophil antioxidant shield, leading to an augmented cell oxidative load, is likely to occur as a feature of age. This may increase the apoptotic rate of stimulated cells, which may in turn account for the increased susceptibility of elderly individuals to life-threatening infections.

Adult↗

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↗