Brescia, Italy
Brescia, Italy

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Reikie B.A.,University of British Columbia | Reikie B.A.,University of Calgary | Adams R.C.M.,Immunology Unit | Leligdowicz A.,University of British Columbia | And 9 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2014

Background: Early in life, HIV-exposed uninfected (HEU) infants are at an increased risk of morbidity and mortality from infectious disease compared with HIV-unexposed (UE) infants. To improve our understanding of the mechanisms underlying their increased risk, we contrasted innate immune development between HEU and UE infants in a developing world setting, where early life infectious disease risk is exceptionally high. Methods: A prospective longitudinal cohort of HEU and UE newborns was established, and the most detailed characterization to date of HEU infant immune development was performed. Single-cell cytokine production was analyzed by flow cytometry after stimulation of whole blood with pathogen-associated molecular patterns (PAMPs). Results: Monocyte, classical dendritic cell, and plasmacytoid dendritic cell composition was similar between HEU and UE infants throughout the first year of life. However, HEU mononuclear cells mounted an enhanced pro-inflammatory response to PAMP stimulation, both in quantity of cytokine produced per cell and in proportion of responder cells. Significant differences in cytokine production were detected on the single-cell level in a PAMP-specific pattern, but only at 2 and 6 weeks of age; all differences normalized by 12 months of age. Conclusions: This time course of innate immune deviation early in life corresponds to the clinical window of vulnerability to infections in HEU infants and may be at least partially responsible for their increased morbidity and mortality from infectious disease. Key Words: HIV-exposed uninfected, HIV uninfected, HIV in sub-Saharan Africa, immune development, innate immunity, early life immunity Copyright © 2014 by Lippincott Williams & Wilkins.


Del Campo J.A.,University of Seville | Ampuero J.,University of Seville | Rojas L.,University of Seville | Conde M.,Immunology Unit | And 7 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2013

Background Insulin resistance has been strongly associated with the attainment of sustained viral response (SVR) in hepatitis C patients. Aim To determine, in a cohort of Spanish patients with chronic hepatitis C treated with peginterferon plus ribavirin (P+R), whether insulin resistance predicts SVR independently of interleukin-28B rs12979860 polymorphism. Methods Insulin resistance was measured as [HOMA-IR = Insulin (IU/mL)glucose (mmol/L)/22.5]. Genotype, viral load and histological fibrosis using Scheuer score were also measured. Binary logistic regression analysis was used for statistical purposes. Results In a cohort of 240 patients [78% genotype 1, 24% showing advanced fibrosis, 71% high viral load (≥800 000 IU/mL), 31% IL28b genotype CC and 50% with HOMA >2] treated with P+R, 126 (53%) reached SVR. HOMA-IR index (HOMA <2: 63% vs. HOMA >2: 42%; P = 0.001 and IL28b (genotype CC: 68% vs. genotype CT/TT: 45%; P = 0.002) were significantly associated with SVR. In multivariable logistic regression analysis in the overall cohort, variables independently associated were: viral genotype OR: 0.29 (95% CI: 0.11-0.78), P = 0.01; fibrosis OR: 1.62 (95% CI: 1.22-2.16), P = 0.001; HOMA-IR OR: 1.22 (95% CI: 1.02-1.47), P = 0.03; and IL28B genotype OR: 2.43 (95% CI: 1.45-4.07), P = 0.001. The analyses also showed that degree of steatosis, HOMA-IR >2, mild fibrosis and IL28B CC genotype were significantly related to SVR in patients infected with HCV genotypes 1&4, but not in those with genotypes 2&3. No differences were seen in glucose, insulin level or HOMA-IR index segregated according to IL28B genotypes. Conclusion Our results suggest that insulin resistance, fibrosis stage and IL28B polymorphisms were independent variables associated with sustained viral response. © 2012 Blackwell Publishing Ltd.


PubMed | Bambino Gesu Childrens Hospital, Instituto Of Ricovero E Cura A Carattere Scientifico, Research Center and and Immunology Unit
Type: Journal Article | Journal: Journal of the American Society of Nephrology : JASN | Year: 2016

The pathogenesis of nephrotic syndrome is unclear. However, the efficacy of rituximab, a B cell-depleting antibody, in nephrotic syndrome suggests a pathogenic role of B cells. In this retrospective study, we determined by flow cytometry levels of B and T cell subpopulations before and after rituximab infusion in 28 pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome. At baseline, patients had lower median percentages of transitional and mature B cells than age-matched healthy controls (P<0.001). Rituximab induced full depletion of B cells (<1% of lymphocytes). At 1 year, most patients exhibited complete total and mature B cell recovery, whereas memory B cell subsets remained significantly depleted. Total T cell concentration did not change with rituximab, whereas the CD4(+)/CD8(+) T cell ratio tended to increase. Fourteen patients relapsed within 24 months, with a median follow-up of 11.2 months (interquartile range, 8-17.7 months). We observed no difference at baseline between nonrelapsing and relapsing patients in several clinical parameters and cell subset concentrations. Reconstitution of all memory B cell subpopulations, number of immunosuppressive drugs, and dose of tacrolimus during the last 4 months of follow-up were predictive of relapse in univariate Cox regression analysis. However, only delayed reconstitution of switched memory B cells, independent of immunosuppressive treatment, was protective against relapse in multivariate (P<0.01) and receiver operator characteristic (P<0.01 for percentage of lymphocytes; P=0.02 for absolute count) analyses. Evaluation of switched memory B cell recovery after rituximab may be useful for predicting relapse in patients with nephrotic syndrome.


PubMed | Astrazeneca, Dalhousie University, Hacettepe University, University of Basel and 16 more.
Type: Journal Article | Journal: Vaccine | Year: 2016

Vasculitides have been reported as adverse events following immunization (AEFI) following various vaccines. We describe reports of vasculitis to three international spontaneous reporting systems.All spontaneous reports of vasculitis following immunization between January 2003 and June 2014 were retrieved from Eudravigilance (EV), the Vaccine Adverse Event Reporting System (VAERS), and VigiBaseWe retrieved 1797 reports of vasculitis in EV, 1171 in VAERS, and 2606 in VigiBaseSimilar reporting patterns of vasculitides were observed in different databases. Implementation of standardized case definitions for specific vasculitides could improve overall data quality and comparability of reports.


PubMed | Research Affairs and Immunology Unit
Type: Journal Article | Journal: Hepatology research : the official journal of the Japan Society of Hepatology | Year: 2016

miRNA-122 (miR-122) is a new, interesting liver injury biomarker but little is known about its effects when there is an indirect acute liver injury.We investigated this by using indirect liver injury mice models with bilateral ureter obstruction (BUO), bilateral nephrectomy (BiNx) and cecal ligation and puncture (CLP). A direct liver injury model, liver ischemia/reperfusion injury (liver I/R), was performed in parallel. Liver injury (i.e. liver histology, alanine transaminase [ALT]), kidney damage (i.e. serum creatinine) and cytokines (i.e. tumor necrosis factor-, interleukin [IL]-6, IL-1, IL-10) were assessed.Six hours after BUO/BiNx/CLP, the ALT and serum cytokines were approximately 1.5-fold higher than the baseline whereas miR-122 did not change. After 6h of BiNx, there were prominent hepatocyte vacuolization but no elevations of miR-122. However, after 24h of BUO/BiNx/CLP, ALT, hepatocyte vacuolization and miR-122 increased. The cytokines at 6h might have induced the production of miR-122 at 24h. The results from the in vitro study with HepG2 cells and each of the cytokines resulted in increased miR-122. On the other hand, when the direct liver injury model was used, there was a fivefold and 22-fold increase in the ALT at 0.5 and 1h after surgery, respectively, and high serum miR-122 which corroborated the results from the liver histopathology.We demonstrated that prior serum cytokine accumulation increased serum miR-122 in indirect liver injury induced by BUO/BiNx and less severe sepsis mouse models. Cytokine accumulation may be responsible for miR-122 expression in these models. The clinical importance of liver injury demonstrated by the discordance between serum miR-122 and ALT was an interesting issue.


Lonardi S.,University of Brescia | Villanacci V.,University of Brescia | Lorenzi L.,University of Brescia | Lanzini A.,University of Brescia | And 4 more authors.
Virchows Archiv | Year: 2013

Small bowel intraepithelial lymphocytosis (IL) may depend from different causes, including celiac disease (CD). Demonstration of increased number of duodenal T cell receptor gamma-delta (TCRγδ) positive intraepithelial lymphocytes (IELs) has been used to support CD diagnosis on frozen material. This work evaluates a new commercially available anti-TCRγ antibody on formalin-fixed paraffin embedded (FFPE) small bowel biopsies. Anti-CD3 and anti-TCR CγM1 (clone γ3.20) from Thermo Scientific were applied by immunohistochemistry on 59 FFPE biopsies from 18 cases of CD with mild/severe atrophy, 19 cases of IL in CD patients on gluten-free diet (IL-GFD), 14 cases of IL (6/14 with positive CD-related serology), and 8 controls (CTR) with mild duodenitis and negative CD serology and genotyping. IELs/100 epithelial cells were counted in at least six high power fields. CD3+ and TCRγ+ IELs were significantly higher in CD, IL-GFD, and IL compared with CTR, but in contrast to CD3+ IELs, TCRγ+ IELs were significantly increased in CD and IL-GFD compared with IL. Furthermore, TCRγ+ IELs discriminated between IL with negative and positive CD-related serology (p = 0.02). TCRγ+ IELs can be identified on FFPE samples and their evaluation adds useful information for the work-up of small bowel biopsies in CD diagnosis. In fact, TCRγ staining coupled with CD3, may represent an additional tool to recognize cases of latent/potential CD when serology and clinical data are not conclusive or when the histological diagnosis remains equivocal. © 2013 Springer-Verlag Berlin Heidelberg.


Picchianti Diamanti A.,University of Rome La Sapienza | Rosado M.M.,Immunology Unit | Scarsella M.,Immunology Unit | Germano V.,University of Rome La Sapienza | And 6 more authors.
Clinical and Experimental Immunology | Year: 2014

The use of biological agents combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients has strongly improved disease outcome. In this study, the effects of abatacept on the size and function of circulating B and T cells in RA patients not responding to anti-tumour necrosis factor (TNF)-α have been analysed, with the aim of identifying immunological parameters helpful to choosing suitable tailored therapies. We analysed the frequency of peripheral B and T cell subsets, B cell function and T regulatory cell (Treg) inhibitory function in 20 moderate/severe RA patients, according to the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria, primary non-responders to one TNF-α blocking agent, who received abatacept+MTX. Patients were studied before and 6 months after therapy. We found that abatacept therapy significantly reduced disease activity score on 44 joints (DAS)/erythrocyte sedimentation rate (ESR) values without causing severe side effects. The size of the circulating B and T cell compartments in RA patients was not significantly different from healthy donors, but B cell proliferation and plasma cell differentiation was impaired before therapy and restored by abatacept. While Treg cell frequency was normal, its inhibitory function was absent before therapy and was partially recovered 6 months after abatacept. B and Treg cell function is impaired in RA patients not responding to the first anti-TNF-α agent. Abatacept therapy was able to rescue immune function and led to an effective and safe clinical outcome, suggesting that RA patients, in whom anti-TNF-α failed, are immunologically prone to benefit from an agent targeting a different pathway. © 2014 British Society for Immunology.


Musa B.O.P.,Immunology Unit | Onyemelukwe G.C.,Immunology Unit | Hambolu J.O.,Ahmadu Bello University | Mamman A.I.,Ahmadu Bello University | Isa A.H.,Ahmadu Bello University
Clinical and Vaccine Immunology | Year: 2010

The pathogenesis of sickle vaso-occlusive crisis (VOC) in sickle cell disease (SCD) patients involves the accumulation of rigid sickle cells and the stimulation of an ongoing inflammatory response, as well as the stress of infections. The immune response, via cytokine imbalances and deregulated T-cell subsets, also has been proposed to contribute to the development of VOC. In this study, a panel of high-sensitivity cytokine kits was used to investigate cytokines in the sera of SCD patients in VOC. The results were compared primarily with those for stable SCD patients and secondarily with those for normal healthy people who served as controls. The cytokines studied included interleukin-2 (IL-2), IL-4, and IL-10. Lymphocyte subsets of patients with VOC were also studied and were compared with those of both control groups (20 stable patients without crisis [SCD group] and 20 normal healthy controls [NHC]). The VOC group was notable for remarkably elevated levels of IL-4, among the three cytokines tested, compared with those for the SCD and NHC groups. Patients with VOC also differed from stable SCD patients and NHC by having notably lower IL-10 levels, as well as the lowest ratio of CD4+ to CD8+ T cells (0.7). The patterns of the proinflammatory cytokine IL-2 did not differ between VOC and stable SCD patients, but NHC had significantly lower IL-2 levels than both the VOC and SCD groups. Our results demonstrate coexisting levels, both high and low, of TH1-and TH2-type cytokines, as well as diminished levels of T-cell subsets in VOC. These results are discussed in an effort to better understand the importance of the immune system profile in the pathogenesis of sickle cell VOC. Since the possibility that a cytokine imbalance is implicated in the pathogenesis of sickle cell crisis has been raised, our results should prompt further investigation of the host immune response in terms of TH1 and TH2 balance in sickle cell crisis. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Kanat O.,Uludag University | Cubukcu E.,Uludag University | Avci N.,Uludag University | Budak F.,Immunology Unit | And 3 more authors.
Tumori | Year: 2013

Aims and background. The optimal treatment of cancer cachexia remains unknown. In this study, we compared the efficacy of three different treatment modalities in the management of cancer cachexia. Methods. Sixty-two assessable cachectic cancer patients were randomized to one of the following three arms: 1) megesterol acetate (MA) plus meloxicam (n = 23); 2) MA plus meloxicam plus oral eicosapentaenoic acid (EPA)-enriched nutritional supplement (n = 21); or 3) meloxicam plus oral EPA-enriched nutritional supplement (n = 18). Treatment duration was 3 months. Results. The treatment arms were well balanced at baseline. The primary efficacy (body weight and lean body mass) and secondary efficacy (body mass index, quality of life, and serum levels of IL-6 and TNF-α) parameters improved after treatment in all three arms. There were no statistically significant differences between treatment groups in the mean percentage changes in all efficacy parameters from baseline to end of study. Conclusions. MA plus meloxicam or EPA supplement plus meloxicam may be effective treatment options in the management of cancer cachexia. The combined use of these agents does not provide further advantages. © - Il Pensiero Scientifico Editore downloaded by ELSEVIER BV IP.


D'Alessio A.,Cell Biology and Biotherapy Unit | De Luca A.,Cell Biology and Biotherapy Unit | Maiello M.R.,Cell Biology and Biotherapy Unit | Lamura L.,Cell Biology and Biotherapy Unit | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2010

Treatment of breast cancer cells with a combination of the EGFR-tyrosine kinase inhibitor (EGFR-TKI) gefitinib and the anti-ErbB-2 monoclonal antibody trastuzumab results in a synergistic antitumor effect. In this study, we addressed the mechanisms involved in this phenomenon. The activation of signaling pathways and the expression of cell cycle regulatory proteins were studied in SK-Br-3 and BT-474 breast cancer cells, following treatment with EGFR and/or ErbB-2 inhibitors. Treatment with the gefitinib/trastuzumab combination produced, as compared with a single agent, a more prolonged blockade of AKT and MAPK activation, a more pronounced accumulation of cells in the G0/G1 phase of the cell cycle, a more significant increase in the levels of p27kip1 and of hypophosphorylated pRb2, and a decrease in the levels of Cyclin D1 and survivin. Similar findings were observed with the EGFR/ErbB-2 inhibitor lapatinib. Gefitinib, trastuzumab, and their combination increased the stability of p27kip1, with the combination showing the highest effects. Blockade of both receptors with gefitinib/trastuzumab or lapatinib induced a significant increase in the levels of p27kip1 mRNA and in the nuclear levels of the p27kip1 transcription factor FKHRL-1. Inhibition of PI3K signaling also produced a significant raise in p27kip1 mRNA. Finally, down-modulation of FKHRL-1 with siRNAs prevented the lapatinib-induced increase of p27kip1 mRNA. The synergism deriving from EGFR and ErbB-2 blockade is mediated by several different alterations in the activation of signaling proteins and in the expression of cell cycle regulatory proteins, including transcriptional and posttranscriptional regulation of p27 kip1 expression. © 2009 Springer Science+Business Media, LLC.

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