Simone Negrini

Publications (31)136.38 Total impact

• Article: A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer.

  Daniela Fenoglio, Paolo Traverso, Alessia Parodi, Laura Tomasello, Simone Negrini, Francesca Kalli, Florinda Battaglia, Francesca Ferrera, Stefania Sciallero, Giuseppe Murdaca, Maurizio Setti, Alberto Sobrero, Francesco Boccardo, Giuseppe Cittadini, Francesco Puppo, Domenico Criscuolo, Giorgio Carmignani, Francesco Indiveri, Gilberto Filaci
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  ABSTRACT: BACKGROUND: Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod. OBJECTIVE: The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints. EXPERIMENTAL DESIGN: GX301 was administered by intradermally injecting 500 μg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6 months from the first immunization. RESULTS: No grade 3-4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100 % of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses. CONCLUSION: GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy.
  Cancer Immunology and Immunotherapy 04/2013; · 3.70 Impact Factor
• Article: CD39 is highly involved in mediating the suppression activity of tumor-infiltrating CD8+ T regulatory lymphocytes.

  Alessia Parodi, Florinda Battaglia, Francesca Kalli, Francesca Ferrera, Giuseppina Conteduca, Samuele Tardito, Silvia Stringara, Federico Ivaldi, Simone Negrini, Giacomo Borgonovo, Alchiede Simonato, Paolo Traverso, Giorgio Carmignani, Daniela Fenoglio, Gilberto Filaci
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  ABSTRACT: CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (Treg). In this study, CD39 expression and function was analyzed in both CD8+ and CD4+CD25(hi) Treg from the peripheral blood of healthy donors as well as from tumor specimens. CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25(hi) Treg, and CD39 expression correlated with suppression activity mediated by CD8+ Treg. Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ Treg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function. Collectively, these findings, unveiling a new mechanism of action for CD8+ Treg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention.
  Cancer Immunology and Immunotherapy 01/2013; · 3.70 Impact Factor
• Article: Lactulose breath test to assess oro-cecal transit delay and estimate esophageal dysmotility in scleroderma patients.

  Lorenzo Gemignani, Vincenzo Savarino, Massimo Ghio, Andrea Parodi, Patrizia Zentilin, Nicola de Bortoli, Simone Negrini, Manuele Furnari, Pietro Dulbecco, Elisa Giambruno, Edoardo Savarino
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  ABSTRACT: OBJECTIVES: To assess the correlation between delayed oro-cecal transit time (OCTT) and esophageal motility abnormalities in a cohort of systemic sclerosis (SSc) patients. METHODS: We prospectively enrolled 50 consecutive SSc patients and 60 healthy volunteers (HVs) as controls. Both groups underwent glucose breath test (GBT) to exclude small intestine bacterial overgrowth, lactulose hydrogen, and octanoic acid breath tests (LHBT and OBT) to measure OCTT and gastric emptying (GE), respectively, and manometry to assess esophageal motility. RESULTS: Thirty-one (63%) SSc patients presented ineffective esophageal motility (IEM) compared with 3 HVs (5%; P<0.01), 37 (74%) had an abnormal OCTT compared with 4 HVs (7%; P <0.01), and 16 (32%) had an altered GE compared with 4 HVs (7%; P<0.01). The median OCTT and gastric t(½) were longer in SSc than in HVs (165min vs. 101min and 125min vs. 78min, respectively; P <0.01). A delayed GE was present in 12/37 (32%), whereas IEM in 27/37 (73%) SSc patients with prolonged OCTT. The prevalence of IEM increased in parallel with the prolongation of OCTT (31% when OCTT<150min, 73% when OCTT≥150min, and up to 85% when OCTT>180min, P<0.01). CONCLUSIONS: Abnormalities of both esophageal and small intestine motility are frequent in SSc patients and esophageal motility is altered in most cases with small bowel involvement. Delayed GE plays a limited role in prolonging OCTT. LHBT is a non-invasive, cheap, well-tolerated diagnostic tool that may be useful to estimate intestinal involvement and also to estimate a higher risk of esophageal hypomotility in SSc patients.
  Seminars in arthritis and rheumatism 01/2013; · 4.72 Impact Factor
• Article: Indoleamine 2,3 dioxygenase gene polymorphisms correlate with CD8+ Treg impairment in systemic sclerosis.

  Samuele Tardito, Simone Negrini, Giuseppina Conteduca, Francesca Ferrera, Alessia Parodi, Florinda Battaglia, Francesca Kalli, Daniela Fenoglio, Maurizio Cutolo, Gilberto Filaci
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  ABSTRACT: Systemic sclerosis (SSc) is characterized by tissue fibrosis, vasculopathy and autoimmunity. Indoleamine 2,3 dioxygenase (IDO) plays a pivotal role in immunological tolerance modulating regulatory T cell (Treg) generation and function. Single nucleotide polymorphisms (SNPs) of IDO gene could impact on Treg function and predispose to autoimmunity. Here, the existence of an association between specific IDO SNPs and SSc was analyzed. Five specific SNPs in IDO gene were searched in 31 SSc patients and 37 healthy controls by gene sequencing or restriction fragment length polymorphism. The function of both CD4+CD25+ and CD8+ Treg from SSc patients was analyzed by proliferation suppression assay. SNP rs7820268 was statistically more frequent in SSc patients than in controls. Notably, SSc patients bearing the T allelic variant of the rs7820268 SNP showed impaired CD8+ Treg function. Our unprecedented data show that a specific IDO gene SNP is associated with an autoimmune disease such as SSc.
  Human immunology 11/2012; · 2.55 Impact Factor
• Article: Th17 and regulatory T lymphocytes in primary biliary cirrhosis and systemic sclerosis as models of autoimmune fibrotic diseases.

  Daniela Fenoglio, Francesca Bernuzzi, Florinda Battaglia, Alessia Parodi, Francesca Kalli, Simone Negrini, Raffaele De Palma, Pietro Invernizzi, Gilberto Filaci
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  ABSTRACT: Fibrotic autoimmune diseases are characterized by an inflammatory process in which fibrogenic cytokines, such as TGFβ and IL6, have a major role. Interestingly, these cytokines are also involved in the generation and function of both an effector T lymphocyte subpopulation, the Th17 cells, and the regulatory T lymphocytes (Treg). These evidences raised the hypothesis that an unbalanced equilibrium induced by the overproduction of the fibrogenic cytokines may have pathogenic relevance in fibrotic autoimmune diseases. On this basis, this review analyzes the available data concerning Th17 and Treg generation and function in two representative fibrotic autoimmune diseases, primary biliary cirrhosis (PBC) and systemic sclerosis (SSc), as models for organ-specific and systemic diseases, respectively. With regard to the Th17 cells, their expansion was found to be a common feature associated with a relative contraction of Th1 immune responses. Concerning to the regulatory T cell compartment, quantitative and qualitative alterations were observed in both diseases. However, while PBC patients showed defects only in the CD8+ Treg subset, SSc patients demonstrated abnormalities regarding to both the CD4+CD25+ and the CD8+ Treg subpopulations. Hence, the CD8+ Treg subset seems to be the most involved in the pathogenic cascade leading to fibrotic disease onset and maintenance. Collectively, the reviewed data support the concept that altered homeostasis between effector and regulatory T cell circuits is present in fibrotic autoimmune diseases and that the major factors responsible for such disequilibrium are Th17 cells in the effector arm and CD8+ Treg in the regulatory arm.
  Autoimmunity reviews 05/2012; · 6.37 Impact Factor
• Article: Abscisic acid ameliorates the systemic sclerosis fibroblast phenotype in vitro.

  Santina Bruzzone, Florinda Battaglia, Elena Mannino, Alessia Parodi, Floriana Fruscione, Giovanna Basile, Annalisa Salis, Laura Sturla, Simone Negrini, Francesca Kalli, Silvia Stringara, Gilberto Filaci, Elena Zocchi, Daniela Fenoglio
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  ABSTRACT: The phytohormone abscisic acid (ABA) has been recently identified as an endogenous hormone in humans, regulating different cell functions, including inflammatory processes, insulin release and glucose uptake. Systemic sclerosis (SSc) is a chronic inflammatory disease resulting in fibrosis of skin and internal organs. In this study, we investigated the effect of exogenous ABA on fibroblasts obtained from healthy subjects and from SSc patients. Migration of control fibroblasts induced by ABA was comparable to that induced by transforming growth factor-β (TGF-β). Conversely, migration toward ABA, but not toward TGF-β, was impaired in SSc fibroblasts. In addition, ABA increased cell proliferation in fibroblasts from SSc patients, but not from healthy subjects. Most importantly, presence of ABA significantly decreased collagen deposition by SSc fibroblasts, at the same time increasing matrix metalloproteinase-1 activity and decreasing the expression level of tissue inhibitor of metalloproteinase (TIMP-1). Thus, exogenously added ABA appeared to revert some of the functions altered in SSc fibroblasts to a normal phenotype. Interestingly, ABA levels in plasma from SSc patients were found to be significantly lower than in healthy subjects. UV-B irradiation induced an almost 3-fold increase in ABA content in SSc cultures. Altogether, these results suggest that the fibrotic skin lesions in SSc patients could benefit from exposure to high(er) ABA levels.
  Biochemical and Biophysical Research Communications 04/2012; 422(1):70-4. · 2.48 Impact Factor
• Article: Cyclophosphamide inhibits the generation and function of CD8(+) regulatory T cells.

  Ilaria Traverso, Daniela Fenoglio, Simone Negrini, Alessia Parodi, Florinda Battaglia, Francesca Kalli, Giuseppina Conteduca, Samuele Tardito, Paolo Traverso, Francesco Indiveri, Gilberto Filaci
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  ABSTRACT: CD8(+) regulatory T cells (Treg) and CD4(+)CD25(+) Treg infiltrate human cancers, thus favoring tumor immune escape. Therefore, in the setting of antitumor therapeutic protocols, it is important to associate antitumor treatment with agents that are able to inhibit Treg function. Cyclophosphamide (CY) has been demonstrated to be effective in counteracting CD4(+)CD25(+) Treg activity. Hence, we tested its inhibitory efficacy on human CD8(+) Treg. Because CY is a prodrug, 4-hydroperoxycyclophosphamide (4-HC), a derivative of CY that in aqueous solution is converted to 4-hydroxycyclophosphamide, an active metabolite of CY, was used. 4-HC significantly inhibited CD8(+) Treg generation and function but only at the higher tested concentration (0.5 μg/mL), that is, in the therapeutic range of the drug. The lower 4-HC concentration tested (0.1 μg/mL) was almost ineffective. 4-HC inhibitory effects were related to apoptosis/necrosis induction. When CD8(+)CD28(+) non-Treg were analyzed for comparative purposes, significantly lower cytotoxic rates among these cells were observed than among CD8(+) Treg, which were differentiated because they did not express the CD28 molecule. These data demonstrate that CD8(+) Treg are inhibited through cytotoxic phenomena by CY, thus supporting the use of this drug at adequate concentrations and schedules of administration as a Treg inhibitor in combinatorial chemo- or immunotherapeutic anticancer protocols.
  Human immunology 03/2012; 73(3):207-13. · 2.55 Impact Factor
• Source

  Available from: Raffaele De Palma

  Article: Alteration of Th17 and Treg cell subpopulations co-exist in patients affected with systemic sclerosis.

  Daniela Fenoglio, Florinda Battaglia, Alessia Parodi, Silvia Stringara, Simone Negrini, Nicoletta Panico, Marta Rizzi, Francesca Kalli, Giuseppina Conteduca, Massimo Ghio, Raffaele De Palma, Francesco Indiveri, Gilberto Filaci
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  ABSTRACT: Aim of the study has been to understand the relationship between TH17 and Treg cell subsets in patients affected with systemic sclerosis (SSc). Phenotypes and functions of Th17 and Treg cell subsets were analyzed in a series of 36 SSc patients. Th17 cell concentration in the peripheral blood was found to be increased in SSc patients with respect to healthy controls independently from type or stage of disease. After PBMC stimulation with a polyclonal stimulus or Candida albicans antigens the frequency of Th17 T cell clones was significantly higher in SSc patients with respect to controls suggesting the skewing of immune response in SSc patients toward Th17 cell generation/expansion. Concerning the Treg compartment, both CD4+CD25+ and CD8+CD28- Treg subsets showed quantitative and qualitative alteration in the peripheral blood of SSc patients. Collectively, these data highlight the existence of an imbalanced ratio between Th17 and Treg cell subsets in SSc patients.
  Clinical Immunology 02/2011; 139(3):249-57. · 4.05 Impact Factor
• Article: Down regulation of human natural killer cell-mediated cytolysis induced by blood transfusion: role of transforming growth factor-β(1), soluble Fas ligand, and soluble Class I human leukocyte antigen.

  Massimo Ghio, Paola Contini, Simone Negrini, Clemente Mazzei, Maria R Zocchi, Alessandro Poggi
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  ABSTRACT: Human natural killer (NK) cells are thought to play a role in antiviral response and tumor immune surveillance. The molecular mechanisms of down regulation of NK-cell activity observed after red blood cell (RBC) transfusion is still undefined. Both effects of blood transfusion (ex vivo) and supernatants (SNs) derived from RBC units unstored (RBC-0) or stored for 5 or 30 days (RBC-5 or -30, respectively) in vitro were analyzed on NK cell-mediated cytolytic activity. We have found that NK cells isolated from transfused patients on Day 3 lysed the NK-sensitive target cells K562 to a lesser extent than before transfusion. This down regulation of NK-cell activation was evident also for NK-cell killing mediated through the engagement of NK cell-activating receptors as NKG2D, NKp30, NKp46, and CD16. Transfused patients reacquired NK cell-mediated cytolytic activity from Day 5 to Day 7 after transfusion. SN from RBC-30, but not from RBC-0 or RBC-5, strongly inhibited the generation of lymphokine-activated killer (LAK) cells and lysis of the NK-resistant target cell Jurkat in a dose-dependent manner. Transforming growth factor-β1 (TGF-β1) blocking antibodies partially restored the generation of LAK activity. In addition, the depletion of both soluble Class I human leukocyte antigens (sHLA-I) and soluble Fas ligand (sFasL) from SN of RBC-30 completely restored the generation of LAK activity. Altogether, these findings would support the idea that blood transfusion-mediated down regulation of NK-cell activity is mediated by sHLA-I, sFasL, and TGF-β1.
  Transfusion 01/2011; 51(7):1567-73. · 3.22 Impact Factor
• Article: Iodized oil pleural effusion in a patient previously treated with transarterial chemoembolization for hepatocellular carcinoma.

  Simone Negrini, Gabriele Zoppoli, Enzo Andorno, Antonino Picciotto, Francesco Indiveri
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  ABSTRACT: Transarterial chemoembolization (TACE) is a nonsurgical therapeutic option for the control of hepatocellular carcinoma (HCC) in patients with cirrhosis. Although less invasive than surgical approaches, this procedure can have severe side effects, with both local and extrahepatic complications, mostly related to treatment-induced ischemic damage. Here, we describe the case of a cirrhotic female patient affected by multinodular HCC, who presented with sudden onset dyspnea and chest pain. After a thorough follow-up, her condition was found to be due to iodinized oil pleural effusion following diaphragm rupture by a fistula. This had developed from a sterile abscess formed on the site of a previously performed TACE. We discuss the differential diagnosis and the management of this case, which, to our knowledge, has never been described as a late side effect of TACE.
  Chest 07/2010; 138(1):193-5. · 5.25 Impact Factor
• Article: Brachial artery endothelial-dependent flow-mediated dilation identifies early-stage endothelial dysfunction in systemic sclerosis and correlates with nailfold microvascular impairment.

  Daniela Rollando, Gian Paolo Bezante, Alberto Sulli, Manrico Balbi, Nicoletta Panico, Carmen Pizzorni, Simone Negrini, Claudio Brunelli, Antonio Barsotti, Maurizio Cutolo, Francesco Indiveri, Massimo Ghio
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  ABSTRACT: To assess possible correlations between endothelial-dependent flow-mediated dilation (FMD) of the brachial artery and nailfold videocapillaroscopy (NVC) in patients with systemic sclerosis (SSc). Evidence has shown that vascular impairment in SSc may be a sign of endothelial dysfunction involving both microvascular and macrovascular systems, although the pathological mechanisms of the dysfunction are poorly understood. Forty-three consecutive patients (mean age 51 +/- 11 yrs) with SSc were studied. Thirty patients had limited cutaneous SSc, 13 had diffuse cutaneous SSc. Twenty-seven healthy subjects (mean age 48 +/- 8 yrs) were recruited as controls. Ultrasound assessment of FMD was performed on all subjects in order to evaluate macrovascular function. Patients were divided into 3 patterns of microvascular damage on the basis of NVC (early, active, and late), and the microangiopathy evolution score was calculated, as reported elsewhere. FMD was significantly reduced in patients with SSc compared to healthy subjects [median 8.0% (3.0%-9.0%) vs 15.0% (12.0%-16.0%), respectively; p < 0.0001]. Patients with an early pattern of microangiopathy showed reduced FMD values compared to controls (p = 0.0001). FMD was significantly reduced in patients with SSc who had the late NVC pattern of microangiopathy compared to active and early patterns (p = 0.003 and p = 0.001, respectively). FMD was inversely correlated with the microvascular damage rate in patients with SSc (p < 0.0001). We demonstrated the simultaneous presence of macrovascular and microvascular impairment in patients with SSc, which was already present in the early phase of the vascular disease.
  The Journal of Rheumatology 06/2010; 37(6):1168-73. · 3.69 Impact Factor
• Article: Lipocalin-2 controls the expression of SDF-1 and the number of responsive cells in bone.

  Delfina Costa, Roberta Biticchi, Simone Negrini, Roberta Tasso, Ranieri Cancedda, Fiorella Descalzi, Giuseppina Pennesi, Sara Tavella
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  ABSTRACT: Lipocalin-2 (LCN2) is a member of the lipocalin family, small secreted proteins functioning as modulators of many different physiological processes including cell differentiation, proliferation and apoptosis. LCN2 expression is also up-regulated in several pathological conditions, including inflammation and cancer. LCN2 synthesis has been described in epithelia, bone and cells of the immune system. Despite its wide expression the role of LCN2 remains to be fully elucidated. To better understand the role of this lipocalin in the bone/bone marrow system we generated transgenic mice over-expressing LCN2 specifically in bone under the control of a type I collagen promoter. In the bone marrow of these transgenic mice we observed an increased expression of SDF-1 that correlated with an increased number of CD34+/CXCR4+ (SDF-1 receptor) cells. To some extent, this appeared due to an enhanced cell proliferation rate. The higher level of the factor synthesis and the increased number of cells expressing its receptor was maintained during animal aging. Our results show that LCN2 could play a role in determining the number of CD34+/CXCR4+ precursor cells in the bone marrow thus contributing to the control of the bone marrow microenvironment.
  Cytokine 03/2010; 51(1):47-52. · 3.02 Impact Factor
• Article: Soluble HLA‐I‐mediated secretion of TGF‐β1 by human NK cells and consequent down‐regulation of anti‐tumor cytolytic activity

  Massimo Ghio, Paola Contini, Simone Negrini, Silvia Boero, Alessandra Musso, Alessandro Poggi
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  ABSTRACT: Soluble HLA class I (sHLA-I) molecules can regulate survival of NK cells and their anti-tumor killing activity. Herein, we have analysed whether interaction of sHLA-I with CD8 and/or different isoforms of killer Ig-like receptors (KIR) induced secretion of transforming growth factor (TGF)-β1. CD8+KIR− NK cell clones secreted TGF-β1 upon the interaction of sHLA-I with CD8 molecule. sHLA-Cw4 or sHLA-Cw3 alleles engaging inhibitory isoforms of KIR, namely KIR2DL1 or KIR2DL2, strongly downregulated TGF-β1 production elicited through CD8. On the other hand, sHLA-Cw4 or sHLA-Cw3 alleles induced secretion of TGF-β1 by ligation of stimulatory KIR2DS1 or KIR2DS2 isoforms. TGF-β1 strongly reduced NK cell-mediated tumor cell lysis and production of pro-inflammatory cytokines such as TNF-α and IFN-γ. Also, TGF-β1 inhibited NK cell cytolysis induced by the engagement of stimulatory receptors including NKG2D, DNAM1, 2B4, CD69, NKp30, NKp44 and NKp46. The IL-2-dependent surface upregulation of some of these receptors was prevented by TGF-β1. Furthermore, TGF-β1 hampered IL-2-induced NK cell proliferation but not IL-2-mediated rescue from apoptosis of NK cells. Depletion of TGF-β1 restored all the NK cell-mediated functional activities analysed. Taken together these findings suggest that sHLA-I antigens may downregulate the NK cell-mediated innate response by inducing TGF-β1 release.
  European Journal of Immunology 11/2009; 39(12):3459 - 3468. · 5.10 Impact Factor
• Article: sHLA-I contaminating molecules as novel mechanism of ex vivo/in vitro transcriptional and posttranscriptional modulation of transforming growth factor-beta in CD8+ T lymphocytes and neutrophils after intravenous immunoglobulin treatment.

  Massimo Ghio, Paola Contini, Simone Negrini, Michele Proietti, Roberta Gonella, Gianluca Ubezio, Luciano Ottonello, Francesco Indiveri
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  ABSTRACT: Numerous mechanisms have been proposed to explain the beneficial action of intravenous immune globulin (IVIG) in autoimmune and systemic inflammatory disorders. Among others' data, an in vitro increase of intracellular TGF-beta expression when culturing CD4+ T lymphocytes in the presence of IVIG has been reported. As IVIG infusion involves administration of soluble contaminants likewise all hemoderivative preparations, we hypothesized that, besides several other immunomodulatory proposed mechanisms, the clinical effects of IVIG therapy might be, at least partly, due to contaminating soluble HLA Class I (sHLA-I) molecules capable to exert pleiotropic immunomodulatory effects among which TGF-beta(1) modulation. Ex vivo and in vitro transcriptional and posttranscriptional modulation of TGF-beta(1) in CD8+ T lymphocytes and neutrophils after IVIG infusion was analyzed. Ex vivo analysis of cells drawn from 10 enrolled IVIG recipients pointed out a significant increase of TGF-beta(1) mRNA and intracellular TGF-beta(1) molecules in both leukotypes. In vitro comparable results were obtained incubating CD8+ T lymphocytes and neutrophils from healthy donors with IVIG. The immunodepletion of sHLA-I and/or soluble Fas ligand (sFasL) abolished TGF-beta(1) modulation in both leukotypes. Coculture with human immunoglobulin (Ig)M monoclonal antibody or chimeric IgG (MabThera, Roche), whose manufacturing excludes "contamination," did not exert any mRNA modulation. Finally, IgM or MabThera plus purified sHLA-I molecules enhanced TGF-beta(1) mRNA in both white blood cells to levels comparable to those obtained with IVIG incubation. On the whole, these data lead us to speculate that the ability of IVIG administration to modulate TGF-beta(1) might be related to the immunomodulatory activities of sHLA-I and sFasL molecules on activated CD8+ T lymphocytes and neutrophils.
  Transfusion 11/2009; 50(3):547-55. · 3.22 Impact Factor
• Article: Soluble HLA-I-mediated secretion of TGF-beta1 by human NK cells and consequent down-regulation of anti-tumor cytolytic activity.

  Massimo Ghio, Paola Contini, Simone Negrini, Silvia Boero, Alessandra Musso, Alessandro Poggi
  [show abstract] [hide abstract]
  ABSTRACT: Soluble HLA class I (sHLA-I) molecules can regulate survival of NK cells and their anti-tumor killing activity. Herein, we have analysed whether interaction of sHLA-I with CD8 and/or different isoforms of killer Ig-like receptors (KIR) induced secretion of transforming growth factor (TGF)-beta1. CD8+KIR- NK cell clones secreted TGF-beta1 upon the interaction of sHLA-I with CD8 molecule. sHLA-Cw4 or sHLA-Cw3 alleles engaging inhibitory isoforms of KIR, namely KIR2DL1 or KIR2DL2, strongly downregulated TGF-beta1 production elicited through CD8. On the other hand, sHLA-Cw4 or sHLA-Cw3 alleles induced secretion of TGF-beta1 by ligation of stimulatory KIR2DS1 or KIR2DS2 isoforms. TGF-beta1 strongly reduced NK cell-mediated tumor cell lysis and production of pro-inflammatory cytokines such as TNF-alpha and IFN-gamma. Also, TGF-beta1 inhibited NK cell cytolysis induced by the engagement of stimulatory receptors including NKG2D, DNAM1, 2B4, CD69, NKp30, NKp44 and NKp46. The IL-2-dependent surface upregulation of some of these receptors was prevented by TGF-beta1. Furthermore, TGF-beta1 hampered IL-2-induced NK cell proliferation but not IL-2-mediated rescue from apoptosis of NK cells. Depletion of TGF-beta1 restored all the NK cell-mediated functional activities analysed. Taken together these findings suggest that sHLA-I antigens may downregulate the NK cell-mediated innate response by inducing TGF-beta1 release.
  European Journal of Immunology 10/2009; 39(12):3459-68. · 5.10 Impact Factor
• Article: TGF-beta and IL-17 serum levels and specific immunotherapy.

  Giorgio Ciprandi, Mara De Amici, Simone Negrini, Gianluigi Marseglia, Maria Angela Tosca
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  ABSTRACT: Two new T cell subsets may be involved in allergic rhinitis (AR) pathogenesis: Th17 and T regulatory cells, mainly producing IL-17 and TGF-beta respectively. Successful Sublingual Immunotherapy (SLIT) induces relevant immunological changes, thus the aim of this study was to evaluate serum IL-17 and TGF-beta levels in AR patients treated with SLIT for 2 years. Patients' blood samples were collected before initiating SLIT (baseline), three months after the end of the first pre-seasonal SLIT course, and at the end of the second pre-seasonal course. IL-17 was detectable only in the most severe allergic patients. SLIT significantly induced an increase in serum TGF-beta levels. There was moreover a significant relationship between TGF-beta and symptom severity and drug use at the end of the study. Therefore, this study provides clinically relevant evidence that two pre-seasonal SLIT courses may significantly affect serum TGF-beta levels.
  International immunopharmacology 08/2009; 9(10):1247-9. · 2.21 Impact Factor
• Article: Two year sublingual immunotherapy affects serum leptin.

  Giorgio Ciprandi, Mara De Amici, Mariangela Tosca, Simone Negrini, Giuseppe Murdaca, Gian Luigi Marseglia
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  ABSTRACT: It has been demonstrated that serum leptin is elevated in females with allergic rhinitis. Recently, it has been reported that one course of sublingual immunotherapy (SLIT) does not affect serum leptin levels. The aim of this study was to evaluate the serum leptin levels in a cohort of patients with pollen-induced allergic rhinitis, before and after two pre-seasonal SLIT courses. Forty-one patients (22 males and 19 females, median age 39 years) with AR, due to pollen allergy, and 34 healthy subjects (16 males and 18 females, median age 43 years) were included in the study. Blood sampling for assessing serum leptin was performed in all subjects before and after the second SLIT course. All patients were responders to SLIT. Serum leptin was significantly increased only in males (p=0.0056) after the second SLIT course. This preliminary study shows that at least two pre-seasonal SLIT courses were required to induce significant modifications in serum leptin levels, but it occurred only in males. Some hypotheses might be outlined, including a leptin protective effect, however further studies must clarify this issue.
  International immunopharmacology 07/2009; 9(10):1244-6. · 2.21 Impact Factor
• Article: Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring.

  Edoardo Savarino, Marco Bazzica, Patrizia Zentilin, Daniel Pohl, Andrea Parodi, Giuseppe Cittadini, Simone Negrini, Francesco Indiveri, Radu Tutuian, Vincenzo Savarino, Massimo Ghio
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  ABSTRACT: Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) is associated with increased morbidity and mortality. Gastroesophageal reflux (GER) is considered a contributing factor in the pathogenesis of ILD. To characterize GER (acid and nonacid) in patients with SSc with and without ILD. Patients with SSc underwent pulmonary high-resolution computer tomography (HRCT) scan and 24-hour impedance-pH monitoring off-proton pump inhibitor therapy. The presence of pulmonary fibrosis was assessed using validated HRCT-scores. Reflux monitoring parameters included number of acid and nonacid reflux episodes, proximal migration of the refluxate, and distal esophageal acid exposure. Unless otherwise specified, data are presented as median (25th-75th percentile). Forty consecutive patients with SSc (35 female; mean age, 53 yr; range, 24-71; 15 patients with diffuse and 25 with limited SSc) were investigated; 18 (45%) patients with SSc had pulmonary fibrosis (HRCT score >or= 7). Patients with SSc with ILD had higher (P < 0.01) esophageal acid exposure (10.3 [7.5-15] vs. 5.2 [1.5-11]), higher (P < 0.01) number of acid (41 [31-58] vs. 19 [10-23]) and nonacid (25 [20-35] vs. 17 [11-19]) reflux episodes, and higher (P < 0.01) number of reflux episodes reaching the proximal esophagus (42.5 [31-54] vs. 15 [8-22]) compared with patients with SSc with normal HRCT scores. Pulmonary fibrosis scores (HRCT score) correlated well with the number of reflux episodes in the distal (r(2) = 0.637) and proximal (r(2) = 0.644) esophagus. Patients with SSc with ILD have more severe reflux (i.e., more reflux episodes and more reflux reaching the proximal esophagus). Whether or not the development of ILD in patients with SSc can be prevented by reflux-reducing treatments needs to be investigated.
  American Journal of Respiratory and Critical Care Medicine 01/2009; 179(5):408-13. · 11.08 Impact Factor
• Article: Paralytic ileus and liver failure--an unusual presentation of advanced erythropoietic protoporphyria.

  Simone Negrini, Gabriele Zoppoli, Maurizio Setti, Maria Domenica Cappellini, Francesco Indiveri
  Digestive Diseases and Sciences 12/2008; 54(2):411-5. · 2.12 Impact Factor
• Article: Serum leptin levels in patients with pollen-induced allergic rhinitis.

  Giorgio Ciprandi, Gilberto Filaci, Simone Negrini, Mara De Amici, Daniela Fenoglio, Gianluigi Marseglia
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  ABSTRACT: Several studies have outlined a possible relationship between an increased body mass index (BMI) and respiratory allergic diseases, such as asthma and rhinitis. The aim of the study was to evaluate the serum leptin levels in a cohort of patients with pollen-induced allergic rhinitis, enrolled outside the pollen season, and in a group of healthy controls. The study included 75 subjects: 41 patients with moderate-severe persistent allergic rhinitis due to a pollen allergy and 34 normal subjects. All subjects were prospectively and consecutively evaluated. A skin prick test and blood sampling for assessing serum leptin levels, eosinophils, specific IgE, and nasal challenge were performed in all subjects. After analyzing genders separately, female allergic patients showed significantly higher levels than normal females (p = 0.031), whereas the comparison between allergic and normal males was not significant (p = 0.9651). Leptin serum levels were significantly related with age in normal (p = 0.0059) and allergic (p = 0.0042) females. In addition, BMI and leptin levels were significantly correlated (p = 0.01) in all allergic patients; there were other significant relationships between leptin levels and symptom severity in females (p = 0063, r = 0.68), peripheral eosinophils in males (p = 0.023, r = 0.49), and allergen threshold dose at nasal challenge in both genders (males: p = 0.0001, r = -0.85; females: p = 0.0001, r = -0.95). This preliminary study provides the first evidence of significantly higher leptin serum levels in female patients with pollen-induced allergic rhinitis outside the pollen season.
  International Archives of Allergy and Immunology 11/2008; 148(3):211-8. · 2.40 Impact Factor