Mario Mondelli - Academia.edu (original) (raw)
Papers by Mario Mondelli
PloS one
We describe the production and characterization of human monoclonal antibodies (mAb) specific for... more We describe the production and characterization of human monoclonal antibodies (mAb) specific for the major hepatitis B virus (HBV) S protein. The mAbs, two IgG1κ and one IgG1λ, were secreted by B-cell clones obtained from peripheral blood mononuclear cells (PBMC) of one person convalescent from acute hepatitis B and one vaccinated individual. The former recognized a denaturation-insensitive epitope within the p24 protein whereas the latter recognized a denaturation-sensitive, conformational epitope located within the HBsAg common "a" determinant. This mAb, denominated ADRI-2F3, displayed a very high protective titer of over 43,000 IU/mg mAb and showed an extremely potent neutralizing activity in the in vitro model of HBV infection using primary hepatocytes from Tupaia belangeri as target. Recombinant variable heavy and light domain sequences derived from mAb ADRI-2F3 were cloned into eukaryotic expression vectors and showed identical fine specificity and 1 log10 higher ti...
Le infezioni in medicina : rivista periodica di eziologia, epidemiologia, diagnostica, clinica e terapia delle patologie infettive, 2008
To date, four different nucleoside/nucleotide analogues are available in the treatment of chronic... more To date, four different nucleoside/nucleotide analogues are available in the treatment of chronic hepatitis B (CHB): lamivudine, adefovir dipivoxil and entecavir; telbivudine, a deoxythymidine analogue that specifically inhibits polymerase-DNA of HBV, approved by the European Medicines Agency (EMEA), has recently become obtainable in Italy. Lamivudine, the first antiviral drug to be used in the treatment of chronic hepatitis B, shows an excellent bioavailability, a virtual absence of significant adverse drug reactions, and a high efficacy in reducing the viral load. Such good pharmacological features are not paralleled by a high genetic barrier. Adefovir dipivoxil, a nucleotide analogue, is considered an effective alternative option to lamivudine, due to the better genetic barrier (almost 30 percent of resistant mutants after 5 years of treatment). However, at the therapeutic approved doses (10 mg/die), adefovir demonstrates sub-optimal efficacy in suppressing viral replication. By ...
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 2014
The statements produced by the consensus conference on infection in end-stage liver disease promo... more The statements produced by the consensus conference on infection in end-stage liver disease promoted by the Italian Association for the Study of the Liver, are here reported. The topics of epidemiology, risk factors, diagnosis, prophylaxis, and treatment of infections in patient with compensated and decompensated liver cirrhosis were reviewed by a scientific board of experts who proposed 26 statements that were graded according to level of evidence and strength of recommendation, and approved by an independent jury. Each topic was explored focusing on the more relevant clinical questions. By systematic literature search of available evidence, comparison and discussion of expert opinions, pertinent statements answering specific questions were presented and approved. Short comments were added to explain the basis for grading evidence particularly on case of controversial areas.
Journal of Hepatology, 2014
More than one and half of current cases of hepatocellular carcinoma in the US, Europe, and Japan ... more More than one and half of current cases of hepatocellular carcinoma in the US, Europe, and Japan are attributable to hepatitis C virus (HCV) infection. HCV is also the primary cause of death in patients with HCV-related cirrhosis, with annual incidences of 0.5%-5% in Europe and 4%-10% in Asia. Screening is based on serum alpha-fetoprotein determination and liver ultrasound scan, but the sensitivity of the former is far less than optimal, and screening intervals are still poorly defined for the latter. Risk factors related to the host or environment, or both, appear to be more relevant than viral factors, such as HCV genotype, in determining disease progression to cirrhosis and cancer, and include age, male gender, severity of liver disease at presentation, coinfection with hepatitis B virus or human immunodeficiency virus, and alcohol abuse. Early liver transplantation in selected cases can be curative, but most patients are not eligible for liver grafting and are treated with locoregional ablative therapies, after which recurrence is common. Recently, orally available inhibitors of the vascular endothelial growth factor receptor have shown a significant, albeit modest, increment of survival in patients with advanced hepatocellular carcinoma, thus paving the way for modern molecular approaches to treatment of this highly malignant tumor.
Natural killer (NK) cells are involved in innate immune responses to viral infections either via ... more Natural killer (NK) cells are involved in innate immune responses to viral infections either via direct cytotoxicity which destroys virus-infected cells or production of immunoregulatory cytokines which modulate adaptive immunity and directly inhibit virus replication. These functions are mediated by different NK subpopulations, with cytotoxicity being generally performed by CD56 dim NK cells, whereas CD56 bright NK cells are mainly involved in cytokine secretion. NK functional defects are usually combined so that impaired degranulation is often associated with deficient cytokine production. Innate immunity is thought to be relevant in the control of hepatitis virus infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV), and recent findings reproducibly indicate that NK cells in chronic viral hepatitis are characterized by a functional dichotomy, featuring a conserved or enhanced cytotoxicity and a reduced production of interferon (IFN)-γ and tumor necrosis factor-α. In chronic HCV infection this appears to be caused by altered IFN-α signaling resulting from increased signal transducer and activator of transcription 1 (STAT1) phosphorylation, which polarizes NK cells toward cytotoxicity, and a concomitantly reduced IFN-α induced STAT4 phosphorylation yielding reduced IFN-γ mRNA levels. These previously unappreciated findings are compatible on the one hand with the inability to clear HCV and HBV from the liver and on the other they may contribute to understand why these patients are often resistant to IFN-α-based therapies.
To compare results of liver stiffness measurements by transient elastography (TE) obtained in our... more To compare results of liver stiffness measurements by transient elastography (TE) obtained in our patients population with that used in a recently published meta-analysis.
... In some of them, hepati-tis flares have been shown to be preceded by recovery of CD4-mediated... more ... In some of them, hepati-tis flares have been shown to be preceded by recovery of CD4-mediated T cell reactivity to HBV nucleocap-sid antigens [54, 55] and to be followed by a significant rise in IL-12 and Th1 cytokine production that can pre-cede or occur simultaneously with ...
Background & Aims: Chronic microbial infections are frequently associated with B-cell activation ... more Background & Aims: Chronic microbial infections are frequently associated with B-cell activation and polyclonal proliferation, potentially leading to autoimmunity and lymphoproliferative disorders. We assessed B-cell phenotype and function in chronic hepatitis B (HBV) and chronic hepatitis C (HCV) virus infection. Methods: We studied 70 patients with chronic HCV infection, 34 with chronic HBV infection and 54 healthy controls. B-cell phenotype was assessed by flow cytometry using monoclonal antibodies specific for CD27, the CD69, CD71, and CD86 activation markers and the chemokine receptor CXCR3. Differentiation into immunoglobulin-producing cells (IPC) was analysed by ELISpot upon stimulation and with CD40 ligand ± IL-10 as surrogate bystander T-cell help or CpG oligodeoxynucleotide ± IL-2, as innate immunity signal. Proliferation was examined by flow cytometry using carboxyfluorescein diacetate succinimidyl ester (CFSE) after stimulation with CpG. Results: A significantly higher proportion of B cells from both HCV-and HBV-infected patients expressed activation markers compared with controls and a positive correlation was found between CXCR3 + B cells and HCV RNA values. Memory B cells from patients with chronic HCV and HBV infections showed enhanced differentiation into IPC compared with controls, although this was restricted to IgG and at a lower level in HCVcompared with HBV-infected patients. Moreover, patients' activated B cells displayed significantly lower proliferative ability compared to healthy donors despite low expression of the FcRL4 exhaustion marker. Conclusions: B-cell activation, but not exhaustion, is common in chronic viral hepatitis. However, enhanced B-cell differentiation and deficient proliferative capacity were not associated with commitment to terminal differentiation. Ó
Eradication of hepatitis C virus (HCV) by antiviral therapy is the treatment of choice for mixed ... more Eradication of hepatitis C virus (HCV) by antiviral therapy is the treatment of choice for mixed cryoglobulinemia secondary to this infection, but many patients fail to achieve sustained viral responses and need second-line treatments. Several studies have demonstrated that the infusion of the anti-CD20 monoclonal antibody rituximab is highly effective for refractory mixed cryoglobulinemia, with a clinical response in approximately 80% of patients, although the relapse rate is high. Virtually all published studies employed a rituximab dosage of 375 mg/m 2 given four times, a schedule used for treating non-Hodgkin's lymphomas. Based on a prior pilot study, we designed a phase II single-arm two-stage study (EUDRACT n. 2008-000086-38) to evaluate the efficacy of a lower dosage of rituximab, 250 mg/m 2 given twice, for refractory mixed cryoglobulinemia. We present here the preliminary results in the first 27 patients enrolled. The overall response rate in 24 evaluable patients was 79%, and the mean time to relapse was 6.5 months, similar to the 6.7 months reported in studies with high-dose rituximab. Side effects were comparable to those seen in patients treated with high-dose. Increase of HCV viral load, reported in some high-dose studies, was not observed in our patients. Low-dose rituximab may provide a more cost/effective and possibly safer alternative for treating refractory HCV-associated mixed cryoglobulinemia.
Studies aimed at correlating the intrahepatic hepatitis C virus (HCV)-RNA level and anatomo-clini... more Studies aimed at correlating the intrahepatic hepatitis C virus (HCV)-RNA level and anatomo-clinical features have been difficult because of sensitivity and specificity shortcomings of available techniques. We titered the genomic-and minus-strand HCV RNAs by a strand-specific, semiquantitative, genotype-independent reverse-transcriptase polymerase chain reaction (RT-PCR) in the liver tissue of 61 patients with chronic hepatitis C. Findings were correlated with the levels of HCV RNA in the serum, the HCV genotype, the expression of intrahepatic HCV antigens, the histological activity (using separate scores for the lobular and the portal/periportal necroinflammatory activity and for the fibrosis), and the response to interferon alfa (IFN-␣) treatment. Genomic-and minus-strand HCV RNA were detected in 59 and 57 liver specimens, respectively. The HCV-RNA level in the serum correlated with the genomic-strand, but not with the minus-strand, HCV-RNA titer in the liver. No correlations were found between either strand of the intrahepatic HCV RNA and the level of expression of HCV antigens in the liver, or with the grading/staging of the underlying liver disease. The response to IFN-␣ treatment could be predicted by the serum HCV-RNA level and genotype, but not by the intrahepatic level of genomicor minus-strand HCV RNA. These results suggest that, although the detection of the minus-strand HCV RNA reliably identifies the presence of replicating HCV in its target organ, the quantitative measurement of viremia remains the clinically meaningful ''golden standard'' for assessing the level of HCV replication. (HEPATOLOGY 1999; 29:536-542.)
Previous studies demonstrated that peripheral blood lymphocytes are cytotoxic to autologous hepat... more Previous studies demonstrated that peripheral blood lymphocytes are cytotoxic to autologous hepatocytes in patients with chronic hepatitis B virus infection. We examined whether cytotoxicity is specifically directed against hepatocytes expressing HBsAg or HBcAg. Viral antigens were detected by immunofluorescence in isolated hepatocytes before and after exposure to T and non-T lymphocytes from 28 patients with chronic HBV infection in an autologous cytotoxicity assay.
PloS one
We describe the production and characterization of human monoclonal antibodies (mAb) specific for... more We describe the production and characterization of human monoclonal antibodies (mAb) specific for the major hepatitis B virus (HBV) S protein. The mAbs, two IgG1κ and one IgG1λ, were secreted by B-cell clones obtained from peripheral blood mononuclear cells (PBMC) of one person convalescent from acute hepatitis B and one vaccinated individual. The former recognized a denaturation-insensitive epitope within the p24 protein whereas the latter recognized a denaturation-sensitive, conformational epitope located within the HBsAg common "a" determinant. This mAb, denominated ADRI-2F3, displayed a very high protective titer of over 43,000 IU/mg mAb and showed an extremely potent neutralizing activity in the in vitro model of HBV infection using primary hepatocytes from Tupaia belangeri as target. Recombinant variable heavy and light domain sequences derived from mAb ADRI-2F3 were cloned into eukaryotic expression vectors and showed identical fine specificity and 1 log10 higher ti...
Le infezioni in medicina : rivista periodica di eziologia, epidemiologia, diagnostica, clinica e terapia delle patologie infettive, 2008
To date, four different nucleoside/nucleotide analogues are available in the treatment of chronic... more To date, four different nucleoside/nucleotide analogues are available in the treatment of chronic hepatitis B (CHB): lamivudine, adefovir dipivoxil and entecavir; telbivudine, a deoxythymidine analogue that specifically inhibits polymerase-DNA of HBV, approved by the European Medicines Agency (EMEA), has recently become obtainable in Italy. Lamivudine, the first antiviral drug to be used in the treatment of chronic hepatitis B, shows an excellent bioavailability, a virtual absence of significant adverse drug reactions, and a high efficacy in reducing the viral load. Such good pharmacological features are not paralleled by a high genetic barrier. Adefovir dipivoxil, a nucleotide analogue, is considered an effective alternative option to lamivudine, due to the better genetic barrier (almost 30 percent of resistant mutants after 5 years of treatment). However, at the therapeutic approved doses (10 mg/die), adefovir demonstrates sub-optimal efficacy in suppressing viral replication. By ...
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 2014
The statements produced by the consensus conference on infection in end-stage liver disease promo... more The statements produced by the consensus conference on infection in end-stage liver disease promoted by the Italian Association for the Study of the Liver, are here reported. The topics of epidemiology, risk factors, diagnosis, prophylaxis, and treatment of infections in patient with compensated and decompensated liver cirrhosis were reviewed by a scientific board of experts who proposed 26 statements that were graded according to level of evidence and strength of recommendation, and approved by an independent jury. Each topic was explored focusing on the more relevant clinical questions. By systematic literature search of available evidence, comparison and discussion of expert opinions, pertinent statements answering specific questions were presented and approved. Short comments were added to explain the basis for grading evidence particularly on case of controversial areas.
Journal of Hepatology, 2014
More than one and half of current cases of hepatocellular carcinoma in the US, Europe, and Japan ... more More than one and half of current cases of hepatocellular carcinoma in the US, Europe, and Japan are attributable to hepatitis C virus (HCV) infection. HCV is also the primary cause of death in patients with HCV-related cirrhosis, with annual incidences of 0.5%-5% in Europe and 4%-10% in Asia. Screening is based on serum alpha-fetoprotein determination and liver ultrasound scan, but the sensitivity of the former is far less than optimal, and screening intervals are still poorly defined for the latter. Risk factors related to the host or environment, or both, appear to be more relevant than viral factors, such as HCV genotype, in determining disease progression to cirrhosis and cancer, and include age, male gender, severity of liver disease at presentation, coinfection with hepatitis B virus or human immunodeficiency virus, and alcohol abuse. Early liver transplantation in selected cases can be curative, but most patients are not eligible for liver grafting and are treated with locoregional ablative therapies, after which recurrence is common. Recently, orally available inhibitors of the vascular endothelial growth factor receptor have shown a significant, albeit modest, increment of survival in patients with advanced hepatocellular carcinoma, thus paving the way for modern molecular approaches to treatment of this highly malignant tumor.
Natural killer (NK) cells are involved in innate immune responses to viral infections either via ... more Natural killer (NK) cells are involved in innate immune responses to viral infections either via direct cytotoxicity which destroys virus-infected cells or production of immunoregulatory cytokines which modulate adaptive immunity and directly inhibit virus replication. These functions are mediated by different NK subpopulations, with cytotoxicity being generally performed by CD56 dim NK cells, whereas CD56 bright NK cells are mainly involved in cytokine secretion. NK functional defects are usually combined so that impaired degranulation is often associated with deficient cytokine production. Innate immunity is thought to be relevant in the control of hepatitis virus infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV), and recent findings reproducibly indicate that NK cells in chronic viral hepatitis are characterized by a functional dichotomy, featuring a conserved or enhanced cytotoxicity and a reduced production of interferon (IFN)-γ and tumor necrosis factor-α. In chronic HCV infection this appears to be caused by altered IFN-α signaling resulting from increased signal transducer and activator of transcription 1 (STAT1) phosphorylation, which polarizes NK cells toward cytotoxicity, and a concomitantly reduced IFN-α induced STAT4 phosphorylation yielding reduced IFN-γ mRNA levels. These previously unappreciated findings are compatible on the one hand with the inability to clear HCV and HBV from the liver and on the other they may contribute to understand why these patients are often resistant to IFN-α-based therapies.
To compare results of liver stiffness measurements by transient elastography (TE) obtained in our... more To compare results of liver stiffness measurements by transient elastography (TE) obtained in our patients population with that used in a recently published meta-analysis.
... In some of them, hepati-tis flares have been shown to be preceded by recovery of CD4-mediated... more ... In some of them, hepati-tis flares have been shown to be preceded by recovery of CD4-mediated T cell reactivity to HBV nucleocap-sid antigens [54, 55] and to be followed by a significant rise in IL-12 and Th1 cytokine production that can pre-cede or occur simultaneously with ...
Background & Aims: Chronic microbial infections are frequently associated with B-cell activation ... more Background & Aims: Chronic microbial infections are frequently associated with B-cell activation and polyclonal proliferation, potentially leading to autoimmunity and lymphoproliferative disorders. We assessed B-cell phenotype and function in chronic hepatitis B (HBV) and chronic hepatitis C (HCV) virus infection. Methods: We studied 70 patients with chronic HCV infection, 34 with chronic HBV infection and 54 healthy controls. B-cell phenotype was assessed by flow cytometry using monoclonal antibodies specific for CD27, the CD69, CD71, and CD86 activation markers and the chemokine receptor CXCR3. Differentiation into immunoglobulin-producing cells (IPC) was analysed by ELISpot upon stimulation and with CD40 ligand ± IL-10 as surrogate bystander T-cell help or CpG oligodeoxynucleotide ± IL-2, as innate immunity signal. Proliferation was examined by flow cytometry using carboxyfluorescein diacetate succinimidyl ester (CFSE) after stimulation with CpG. Results: A significantly higher proportion of B cells from both HCV-and HBV-infected patients expressed activation markers compared with controls and a positive correlation was found between CXCR3 + B cells and HCV RNA values. Memory B cells from patients with chronic HCV and HBV infections showed enhanced differentiation into IPC compared with controls, although this was restricted to IgG and at a lower level in HCVcompared with HBV-infected patients. Moreover, patients' activated B cells displayed significantly lower proliferative ability compared to healthy donors despite low expression of the FcRL4 exhaustion marker. Conclusions: B-cell activation, but not exhaustion, is common in chronic viral hepatitis. However, enhanced B-cell differentiation and deficient proliferative capacity were not associated with commitment to terminal differentiation. Ó
Eradication of hepatitis C virus (HCV) by antiviral therapy is the treatment of choice for mixed ... more Eradication of hepatitis C virus (HCV) by antiviral therapy is the treatment of choice for mixed cryoglobulinemia secondary to this infection, but many patients fail to achieve sustained viral responses and need second-line treatments. Several studies have demonstrated that the infusion of the anti-CD20 monoclonal antibody rituximab is highly effective for refractory mixed cryoglobulinemia, with a clinical response in approximately 80% of patients, although the relapse rate is high. Virtually all published studies employed a rituximab dosage of 375 mg/m 2 given four times, a schedule used for treating non-Hodgkin's lymphomas. Based on a prior pilot study, we designed a phase II single-arm two-stage study (EUDRACT n. 2008-000086-38) to evaluate the efficacy of a lower dosage of rituximab, 250 mg/m 2 given twice, for refractory mixed cryoglobulinemia. We present here the preliminary results in the first 27 patients enrolled. The overall response rate in 24 evaluable patients was 79%, and the mean time to relapse was 6.5 months, similar to the 6.7 months reported in studies with high-dose rituximab. Side effects were comparable to those seen in patients treated with high-dose. Increase of HCV viral load, reported in some high-dose studies, was not observed in our patients. Low-dose rituximab may provide a more cost/effective and possibly safer alternative for treating refractory HCV-associated mixed cryoglobulinemia.
Studies aimed at correlating the intrahepatic hepatitis C virus (HCV)-RNA level and anatomo-clini... more Studies aimed at correlating the intrahepatic hepatitis C virus (HCV)-RNA level and anatomo-clinical features have been difficult because of sensitivity and specificity shortcomings of available techniques. We titered the genomic-and minus-strand HCV RNAs by a strand-specific, semiquantitative, genotype-independent reverse-transcriptase polymerase chain reaction (RT-PCR) in the liver tissue of 61 patients with chronic hepatitis C. Findings were correlated with the levels of HCV RNA in the serum, the HCV genotype, the expression of intrahepatic HCV antigens, the histological activity (using separate scores for the lobular and the portal/periportal necroinflammatory activity and for the fibrosis), and the response to interferon alfa (IFN-␣) treatment. Genomic-and minus-strand HCV RNA were detected in 59 and 57 liver specimens, respectively. The HCV-RNA level in the serum correlated with the genomic-strand, but not with the minus-strand, HCV-RNA titer in the liver. No correlations were found between either strand of the intrahepatic HCV RNA and the level of expression of HCV antigens in the liver, or with the grading/staging of the underlying liver disease. The response to IFN-␣ treatment could be predicted by the serum HCV-RNA level and genotype, but not by the intrahepatic level of genomicor minus-strand HCV RNA. These results suggest that, although the detection of the minus-strand HCV RNA reliably identifies the presence of replicating HCV in its target organ, the quantitative measurement of viremia remains the clinically meaningful ''golden standard'' for assessing the level of HCV replication. (HEPATOLOGY 1999; 29:536-542.)
Previous studies demonstrated that peripheral blood lymphocytes are cytotoxic to autologous hepat... more Previous studies demonstrated that peripheral blood lymphocytes are cytotoxic to autologous hepatocytes in patients with chronic hepatitis B virus infection. We examined whether cytotoxicity is specifically directed against hepatocytes expressing HBsAg or HBcAg. Viral antigens were detected by immunofluorescence in isolated hepatocytes before and after exposure to T and non-T lymphocytes from 28 patients with chronic HBV infection in an autologous cytotoxicity assay.